Chem. Rev.

2004, 104, 849902

849

The Chemistry and Biochemistry of Vanadium and the Biological Activities

Exerted by Vanadium Compounds
Debbie C. Crans,* Jason J. Smee, Ernestas Gaidamauskas, and Luqin Yang
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523-1872
Received June 6, 2003

Contents
1. Introduction
2. Aqueous V(V) Chemistry and the
PhosphateVanadate Analogy
2.1. Aqueous V(V) Chemistry
2.2. Mimicking Cellular Metabolites:
VanadatePhosphate Analogy
(Four-Coordinate Vanadium)
2.3. Structural Model Studies of Vanadate Esters
2.4. Vanadate Esters: Functional Analogues of
Phosphate Esters
2.5. Vanadate Anhydrides: Structural Analogy
with Condensed Phosphates
2.6. Potential Future Applications of
Vanadium-Containing Ground State
Analogues in Enzymology
3. Haloperoxidases: V(V) Containing Enzymes and
Modeling Studies
3.1. Bromoperoxidase
3.2. Chloroperoxidase
3.3. From Haloperoxidases to Phosphatases
3.4. Structural Modeling Studies of the
Vanadium-Dependent Haloperoxidases
3.5. Spectroscopic Modeling Studies of the
Vanadium-Dependent Haloperoxidases
3.6. Functional Modeling of the
Vanadium-Dependent Haloperoxidases
3.7. Oxidation of Sulfides by Haloperoxidases
(VHPOs)
4. Inhibition of Phosphorylases by V-Compounds:
Phosphatases, Ribonuclease, Other
Phosphorylases, and ATPases
4.1. Phosphatases
4.1.1. Vanadate: An Imperfect Transition State
Analogue of Phosphatases
4.1.2. V(IV) Chemistry and Inhibition of
Phosphatases by V(IV)
4.1.3. Inhibition of Alkaline and Acid
Phosphatases by Vanadium Compounds
4.1.4. Inhibition of Protein Phosphatases by
Vanadium Compounds
4.1.5. Inhibition of Purple Acid Phosphatases by
Vanadium Compounds
4.1.6. Phosphatase and Other Phosphorylase
Inhibition by Oxometalates
4.1.7. Structural Models of the Transition State
of Phosphate Ester Hydrolysis

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* To whom co rrespondence should be addressed. Phone: 970-4917635. Fax: 970-491-1801. E-mail: [email protected].

4.2. Ribonuclease
4.2.1. Structural Characterization of Model
Compounds for Inhibitors of Ribonuclease
4.2.2. Characterization of the
Nucleoside-Vanadate Complexes that
Form in Solution and Inhibit Ribonuclease
4.2.3. VanadiumNucleoside Complexes:
Functional Inhibitors of Ribonuclease
4.3. Other Phosphorylases
4.4. ATPases
4.4.1. Structural Precedence for the
VanadatePhosphate Anhydride Unit:
Five- or Six-Coordinate Vanadium
4.4.2. Vanadate as a Photocleavage Agent for
ATPases
5. Amavadine and Siderophores
5.1. Amavadine
5.1.1. Amavadine: Structure
5.1.2. Amavadine: Activities and Roles
5.2. Siderophores
5.2.1. Effects of Vanadium on
Siderophore-Mediated Iron Transport
5.2.2. Characterization of
VanadiumSiderophore Complexes and
Model Complexes
5.2.3. Vanadium Citrate Complexes: Structure
and Speciation
5.2.4. V(V) and V(IV) Hydroxamate Complexes
6. Tunicates and the Polychaete Fan Worm
6.1. Tunicates
6.1.1. Location of Vanadium in Tunicate Blood
Cells
6.1.2. Aqueous V(III) Chemistry
6.1.3. Oxidation State of Vanadium in Tunicates
6.1.4. Uptake of Vanadate into Tunicates
6.1.5. Vanadium Binding Proteins: Vanabins
6.1.6. Model Complexes and Their Chemistry
6.1.7. Catechol-Based Model Chemistry
6.1.8. Vanadium Sulfate Complexes
6.2. Fan Worm Pseudopotamilla occelata
7. Vanadium Nitrogenase
7.1. Nitrogenases
7.2. Biochemistry of Nitrogenase
7.3. Clusters in Nitrogenase and Model Systems:
Structure and Reactivity
7.4. Structural Model Complexes of the VFe
Cofactor Binding Site
7.5. Homocitrate
7.6. Activation of Nitrogen

10.1021/cr020607t CCC: $48.50 2004 American Chemical Society

Published on Web 01/29/2004

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850 Chemical Reviews, 2004, Vol. 104, No. 2

7.7. Formation of Hydrazine and Other Reduced

Compounds
8. Additional Focus Areas in Biomimetic Vanadium
Chemistry
8.1. Peroxidase Activity of Vanadium Compounds
8.2. Catalase Activity of Vanadium Compounds
8.3. Vanadium Porphyrins
8.4. Insulin-Like Effect of Vanadium Compounds
8.5. Affinity for Transport Proteins: Transferrin
and Serum Albumin
8.6. Newly Discovered Class of
Vanadium-Containing Enzyme
9. Summary
10. Acknowledgments
11. List of Abbreviations
12. References

Crans et al.

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1. Introduction
Vanadium is a trace element, which may be beneficial and possibly essential in humans1 but certainly
essential for some living organisms.2-11 Metal ions
and thus vanadium ions can play a role in biology as
counterions for protein, DNA, RNA, and in various
biological organelles. The structural role is often
manifested by the maintenance of various biological
structures, whereas a functional role is to bring key
reactivity to a reaction center for a protein. Vanadium ions have many structural roles reflected by its
structural and electronic analogy to phosphorus.9,12-20
In addition, the vanadium ion is an enzyme cofactor,7,9,21-30 and is found in certain tunicates4-11,16
and possibly mammals.1 Reviews on how vanadium
can act and function in the biosphere include investigations into the fundamental coordination and
redox chemistry of the element,16-18,29,31-35 as well as
structural and functional aspects of biological systems and/or metabolites.12,36 Modeling biological activities of various types have long been of interest to
chemists, with this discipline focusing on the structural modeling until about a decade ago when the
focus shifted to functional modeling. Clearly modeling
that includes both aspects will be most informative,
and the ultimate goals for model chemists. Although
the latter in general may be of greater interest at
the present time, the structural aspects of the various
oxidation states are defining its effects in many
biological systems. In this review, we have combined
the two fundamentally different aspects of modeling
because the coverage of only one of these areas in
our opinion would not provide the reader the proper
sense of the effects and activities exerted by vanadium compounds (V-compounds).
This review describes the voyage from the discovery of the first vanadium-containing enzymes in
1984, haloperoxidases,7,9,21-26,37,38 to the current X-ray
crystallographic studies; it is a fascinating story that
provides inspiration to chemist in many fields. These
studies map out the enzyme active site24,39-43 and
demonstrate the structural and functional link between apohaloperoxidases and certain phosphatases.24,39-43 These discoveries now give the bioinorganic chemists clear directives. The detailed mecha-

Debbie C. Crans did her undergraduate work at the University of

Copenhagen, Denmark, where she was born. She came to the United
States for the first time in 1975 to Washington State University as a Danish
exchange student. She returned to the United States in 1980 as a Ph.D.
student at Harvard University, and did her postdoctoral studies at the
University of California, UCLA. She is a Professor in Organic and Inorganic
Chemistry at Colorado State University where she began teaching in 1987.
Her research interests include bioinorganic chemistry, with a particular
interest in vanadium chemistry, biochemistry, and applications in enzymology. She is married to Christopher R. Roberts and is the mother of three
daughters, Patricia Crans Roberts (8), Gerri Marie Roberts (8), and Mia
Crans Roberts (3). In 1997, she co-organized the first symposium in
Vanadium Chemistry and Biochemistry and is presently the Program
Chair for the Inorganic Chemistry Division of the American Chemical
Society.

Jason J. Smee received his B.Sc. at Kansas State University in 1994.

He then pursued a Ph.D. under the direction of Marcetta Y. Darensbourg
at Texas A&M University in College Station, Texas. After graduating in
2000, he moved on to Colorado State University where he is a postdoctoral
associate with Debbie C. Crans. His research focuses on the synthesis
and characterization of novel vanadium complexes as potential therapeutic
drugs in the treatment of diabetes. In his spare time he enjoys reading,
playing softball, and long bike rides.

nistic studies revealing how the enzyme-catalyzed

reaction takes place,7,22,23,37,38 to the design of simple
vanadium complexes (V-complexes) exhibiting similar activities as the enzyme show how much the
chemists can do.7,9,29,38,44-48 Inhibition of phosphatases
by V-compounds is firmly established,9,12-15,19,20 and
often the versatility of the vanadium to bind as a
four-coordinate ground state analogue and a fivecoordinate transition state analogue is not generally
recognized; thus, V-compounds can act as substrates
although bioinorganic chemists are more familiar
with the five-coordinate transition state analogy as
exemplified in the potent inhibition of phosphatases,
ribonuclease,49,50 and other phosphorylases. Although

Chemistry and Biochemistry of Vanadium

Ernestas Gaidamauskas, born in 1971 in Vilnius, Lithuania, received his

Ph.D. in physical chemistry at the Vilnius University in 1999. From 2000
to 2003, he undertook postdoctoral studies at the Colorado State University
under the supervision of Professor Debbie C. Crans. In 2003, Ernestas
was appointed to his current position of lecturer and research associate
at Vilnius University. His research interests include the metal speciation
with various bioligands and redox chemistry of metal complexes.

the second V-containing enzyme, the V-nitrogenase,7,27,28,51 is not as well understood as the vanadiumcontaining haloperoxidases, it is currently a target
for both mechanistic7,27-29 and modeling52,53 studies
with novel structural information constantly modifying the current understanding this system. Combined, these studies bode well for new classes of
V-containing proteins, the vanabins,2,5,10,11 which
have been proposed to be transport proteins for
vanadium, and promise exciting developments in the
future.
The elucidation of the structure of the vanadiumcontaining natural product, amavadine,54 remains an
interesting structural investigation,29,55-58 although
questions now being addressed in this area have
shifted to the investigations of this complexs catalytic
properties. Perhaps these developments will provide
additional clues to the function of this unique compound. The investigations into tunicate metabolism
and biology,2,3,11,59,60 the recognition of the important
role of sulfate in the intact blood cells, and the firm
documentation that V(III) does exist in some species
as well as the discovery of a V-containing transport
protein present key developments to understanding
why and how these organisms contain vanadium.
Finally, the boom of investigations into the insulinlike action of V-complexes documents the ability of a
variety of V-complexes to lower elevated glucose
levels in diabetic animals treated with V-compounds.30,61-64 Although only V(IV)-compounds are
generally considered in this regard, reports of vanadium in oxidation states V and III are likely to firmly
establish the general insulin-like activity of V-compounds.30,63-68 While insulin-like activity of V-compounds is linked to the inhibitory effects of Vcompounds of phosphatases, undoubtedly other activities will emerge now that the vanadium-dependent
haloperoxidase and phosphatase association has been
made. Indeed, we summarize briefly other enzyme
activities that have been reported with V-compounds
in the final section of the review. The many discoveries reviewed here document the versatile nature of

Chemical Reviews, 2004, Vol. 104, No. 2 851

V-compounds and the multitude of reactions they can

catalyze or affect through structural analogy.
The topics in this review have been organized
according to oxidation state of the metal in a particular system, since the oxidation state of the
vanadium ion is important to the species that direct
the chemistry that can occur16-18,29,31-35 in the reactions. After initially describing the V(V) chemistry,
the areas in the biosphere associated with V(V)
haloperoxidases and potent inhibition of phosphorylases will be reviewed. This is followed by the V(IV)containing amavadine and vanabins. The tunicates
and the polychaete worm contain both vanadium (IV)
and (III) depending on the species. The oxidation
state of vanadium in the metal clusters of the
nitrogenase is less obvious but generally believed to
vary from (II) to (IV). Vanadium in lower oxidation
states is not found in the biosphere.69 In the final
section, various other systems are briefly described,
and this section is also organized beginning from the
highest oxidation state and then sequentially describing systems based on increasing vanadium ion
reduction. Since we have reviewed these two different
aspects of modeling, this review includes sections
targeting more chemically inclined readers as well
as sections targeting more biochemically inclined
readers, including areas that have not been reviewed
previously and others that have frequently been
reviewed.

2. Aqueous V(V) Chemistry and the

PhosphateVanadate Analogy
2.1. Aqueous V(V) Chemistry
Vanadium in oxidation state V forms vanadate and
vanadate derivatives in aqueous solution. Vanadate
has long been recognized as a structural (1-3) and
electronic analogue of phosphate with similar protonation reactions (eqs 1-3).9,12-20 This analogy is most
evident in the tetrahedral trianionic forms (VO43- (1)
and PO43-). However, the similarities of the pKa
values for vanadate (3.5, 7.8, and 12.5)15 with those
of phosphate (2.1, 7.2, and 12.7)15 document that the
analogy also extends to the electronic properties of
these species. One difference is that near neutral pH
the vanadate monomer exists primarily as a monoanion (H2VO4-), while phosphate exists primarily as
a dianion (HPO42-). In contrast to the high stability
of H3PO4, the existence of H3VO4 although occasionally inferred has not been documented,70,71 presumably reflecting the conversion to VO2+, which is the
major species of aqueous vanadate solutions at pH
1. Thermodynamic evidence has now been provided
to suggest that the high stability of VO2+ is due to
the increased coordination number of the hydrated
form as compared to H3VO4.72

H3VO4 + H2O h H2VO4- + H3O+ pKa 3.5 (1)

H2VO4- + H2O h HVO42- + H3O+ pKa 7.8 (2)
HVO42- + OH- h VO43- + H2O pKa 12.7

(3)

Around neutral pH, H2VO4- and HVO42- oligomerize to form dimeric (4), tetrameric (5), and pentameric

852 Chemical Reviews, 2004, Vol. 104, No. 2

Crans et al.

2.2. Mimicking Cellular Metabolites:

VanadatePhosphate Analogy (Four-Coordinate
Vanadium)

Figure 1. An E vs pH diagram showing the oxidation state

of vanadium species as a function of pH and reduction
potential. Reproduced with permission from ref 31. Copyright 1976 Wiley & Sons, Inc.

(6) structures.70,71 These species are analogues to

pyrophosphate, oligomeric, and polymeric phosphate
species and contain anhydride bonds. These vanadate
species readily undergo exchange in aqueous solution,73,74 and since pyrophosphate and the corresponding oligomeric phosphate derivatives are stable
and kinetically inert, there is no doubt that the V-P
analogy breaks down with regard to the energetics
of anhydride bonds and their interconversions. Another important difference lies in the fact that, under
physiological conditions, vanadates can undergo redox chemistry31 while phosphates do not.
Structural information on the oligomeric species in
aqueous solution is difficult to obtain. Oligomeric
systems have been prepared, primarily from organic
solvents75,76 and in enzyme complexes,77 and such
structural information may not reflect the species
formed in aqueous solution. The biological effects of
aqueous solutions containing mixtures of oxovanadates reflect that some structural analogy to the
corresponding phosphate derivatives does exist. In
Figure 1, an E vs pH diagram indicates that at high
pH V(V) is the most stable form of vanadium in
aqueous solution, whereas at low pH the V(IV)
species is more favored.31 From pH 2 to 6, the major
V(V) species is the decamer, [V10O28]6- (7) and its
various protonated forms; this highly yellow-orange
colored species is thermodynamically unstable at
neutral and alkaline pH values but, serves as the
thermodynamic sink between pH 3 and 6. This
oxoanion contains three different types of vanadium
atoms, the most unusual being the nonoxo VO6-type
observed for the two central vanadium atoms (see
below).

Given the central role of phosphate and phosphates

in biology, a wide range of effects of two classes of
V-compounds, vanadate esters and vanadate anhydrides, can be envisioned. Phosphate esters are
common and important cellular metabolites with the
phosphate group increasing the solubility and the
anionic charge serving to increase the enzyme recognition between cellular substrate and enzyme. In
ATP, phosphate serves to store about 7 kcal/mol of
energy by forming a anhydride bond compared to the
phosphate ester bond storing about 3 kcal/mol.
Phosphate plays a key structural and functional role
in both the structure and function of RNA and DNA.
The V-P analogy has been used successfully with
enzymes that catalyze reactions of phosphate esters
(8) and phosphate anhydrides (9).14,78-81 Given the
importance of the phosphate esters and anhydrides
in the literature, the potential formation of vanadium
analogues of phosphate esters as shown in eq 4 and
phosphate anhydrides as shown in eq 5 have resulted
in studies probing both the structural and functional
aspects of the corresponding classes of V-compounds.
The effects of vanadate and various derivatives as
phosphate analogues will be reviewed in greater
detail below describing both the ground state analogy
and the transition state analogy with phosphorus
compounds. In particular, the analogy of fivecoordinate V-compounds with the transition state of
phosphate ester hydrolysis has been documented for
years. These types of compounds are commonly
referred to as transition state analogues of the
phosphate ester hydrolysis reactions, and explain
why so many V-compounds are known to be potent
inhibitors of ribonucleases, phosphatases, ATPases,
and other phosphorylases.

ROH + H2VO4- h ROVO3H- + H2O

(4)

ROPO3H- + H2VO4- h
ROP(O)2OV(O)2OH2- + H2O (5)

2.3. Structural Model Studies of Vanadate Esters

A wide range of model systems have been investigated to examine if trialkoxo oxovanadium(V) complexes (10) indeed are structurally similar to triphosphate esters. A large number of vanadium trisalkoxides have been reported,82-85 with the simplest
systems first reported in 1913.82 In general, the
studies focusing on structural characterization have
shown that for a wide range of alkoxide ligands, the
V(V) center becomes five-coordinate (11) by dimerization even in the absence of other coordinating
ligands.85-89 Dimerization is observed in solutions
with 10 mM or more of the oxovanadium trisalkoxides and association is observed between molecules.85,86,89 As the concentration decreases, the
fraction of presumed four-coordinate vanadium trisalkoxides increases. Interestingly, the V-P analogy
was generally accepted despite an early X-ray structure report of a highly disordered oxovanadium(V)

Chemistry and Biochemistry of Vanadium

trimethoxide with a six-coordinate V(V) atom,90 which

highlights differences between these systems. The
fact that this simple system fails to show the V-P
analogy may be related to the simple alkoxide that
allows intersheet interactions between the V and O
atoms to generate a wide network with six-coordinate
vanadium. Thus, although the most common coordination geometry of trisalkoxide oxovanadium complexes may be five-coordinate, important exceptions
occur when the alkoxides used contain steric bulk.
Complexes with various levels of steric bulk have
been prepared, and those oxovanadium(V) complexes
with t-butoxide,84 tert-butylsiloxide,91 norbornenoxide,89 adamantanoxide,89 2,6-diisopropylphenoxide,92 or with bidentate, sterically restricted dialkoxides93,94 contain four-coordinate vanadium. This
geometry is observed both in solution89 and in the
solid state.91-95 Of these examples, one contains
true four-coordinate vanadium and has recently
been structurally characterized as tris(2,6-diisopropylphenoxide)oxovanadium(V) (12).92 This structure
firmly establishes that the four-coordinate V-P analogy exists (8). This structure is joined by earlier
reports with several examples of four-coordinate
V(V)-complexes in which the alkoxide/phenoxide/
siloxide support the four-coordinate vanadium atom;
complexes with a biphenolic diol (13),94 tri-tertbutylsiloxide (14)91 and with ethylene diol (15) were
reported.93
A theoretical evaluation of the effects of ligands on
vanadium coordination geometry in these simple
systems suggested that electronic effects did not
induce the coordination differences, but that subtle
ligand effects such as the gem-dimethyl effect were
invoked.96 Of the numerous complexes structurally
characterized, the system with the cyclopentanol
ligand resulted in the vanadium atom showing differential V-O bond lengths (up to about 0.3 ) (16)
depending on whether the alkoxide group was directly bound to the vanadium or merely associated
with its dinuclear partner.88 This structure clearly
reflects the favorable alkoxide association even with
cyclopentanol, a sterically bulky ligand.
Through this work, structural precedence for the
formation of vanadate esters of both aliphatic and
aromatic alcohols has been demonstrated. The pro-

Chemical Reviews, 2004, Vol. 104, No. 2 853

tonation of the vanadium ester has similarly been

demonstrated in a model system.97-99 The fivecoordinate geometries of V(V) that serve to mimic
transition states of phosphorylase reactions will be
described below after the functional aspects of vanadate esters as ground-state analogues have been
reviewed.

2.4. Vanadate Esters: Functional Analogues of

Phosphate Esters
Vanadate esters (alkoxides) form readily in aqueous solution (eq 4) and are found to be enzyme
substrates for a range of enzymes including dehydrogenases, isomerases, and aldolases.14,78-81 The
formation constant of the vanadate esters in aqueous
solution is on the order of 0.1-0.2 M-1 for aliphatic
esters100,101 and is about 3-5 times larger for the
formation of aromatic esters.100,101 When attempting
to isolate these vanadate esters, reactions are typically done in organic solutions. The vanadate-ester
bonds are much more labile in aqueous solution than
phosphate esters.74 In aqueous solution, these vanadate esters readily fall apart (on a millisecond time
scale), and should the alcohol concentration be sufficiently high and the equilibrium be favorable,
alcohol exchange will take place.74 The rate of this
reaction and the equilibrium can be fine-tuned;
sterically hindered alcohols form alkoxides for which
the reactions are much slower.89 Phosphate esters
play an important role in biology, and the potential
for forming analogous bonds rapidly at ambient
temperature, when phosphate esters only form slowly
(solutions take years to equilibrate), is important
even though the formation constants of these vanadate esters are small.
One example of vanadate ester formation is the
reaction between D-glucose and vanadate. D-Glucose
contains one primary and several secondary hydroxyl
groups that can form vanadate esters. Indeed, many
species form in such solutions as evidenced by 1H and
13C NMR spectroscopy (data not shown). However,
as was shown first by Gresser and Tracey, the small
amount of glucose-6-vanadate (17) that forms is
recognized by glucose-6-phosphate dehydrogenase.78,79 In Scheme 1, the proposed conversions are
Scheme 1. Reaction of D-Glucose with Vanadate to
Form D-Glucose-6-vanadate, a Substrate for
Glucose-6-phosphate Dehydrogenasea

a Refs 78 and 79. The oxidation of D-glucose catalyzed by

glucose-6-phosphate dehydrogenase is shown next, followed by the
hydrolysis of the vanadate ester.

854 Chemical Reviews, 2004, Vol. 104, No. 2

shown explaining the rapid oxidation of D-glucose to

D-gluconate that does not take place in the absence
of vanadate at a rapid rate. Practical applications of
vanadate esters in enzyme catalyzed synthesis are,
in general, better served with arsenate esters78,79
because the arsenate esters can be formed in higher
concentrations than the vanadate esters. Although
arsenate esters form more slowly than vanadate
esters, incubations with high concentrations of arsenate for several hours will generate correspondingly higher concentrations of arsenate esters. The
corresponding solutions containing higher concentrations of vanadate form vanadate oligomers, and
barely increase the formation of vanadate monomer,
which in turn barely increases the vanadate monomer concentration, resulting in no significant increases in the concentrations of vanadate esters.
However, examples of vanadium-cofactor analogues
of AMP and NADP have been reported such as AMV
(18),102 ADPV (19), and NADV (20).80,81 The vanadate
ester in NADV is a more effective cofactor in supporting enzyme reactions than the corresponding
arsenate ester, which had little, if any, activity.80,81
The potency of the vanadium analogue has been
attributed to the formation of the cyclic derivative
for which the enzyme has greater affinity over the
natural cofactor NADP.

2.5. Vanadate Anhydrides: Structural Analogy

with Condensed Phosphates
The analogue to the pyrophosphate bond exists for
vanadium in oligomeric vanadate species such as the
dimer (4), tetramer (5), and pentamer (6).70,71 A
number of solid-state investigations of the properties

Crans et al.

of a variety of these V-O materials have been carried

out, and go beyond the scope of this work. Suffice to
say that the tetramer and pentamer are cyclic in
solution and fail to show a structural analogy with
the biologically interesting linear phosphates. It has
been suggested that the tetramer and the pentamer
are observed either because the stability of these
cyclic derivatives exceeds that of the linear (21) and
cyclic (22) trimers, or because they may not readily
form due to electronic repulsion.73 The linear trivanadate (21) has been observed in solution by 51V NMR
spectroscopy from pH about 8.8 to 9.2 at high ionic
strength accounting for less than 5% of the total
vanadium in solution.103 The structure for this compound is presumably linear since two different 51V
NMR signals are observed for this species. A cyclic
trimer has also recently been prepared and structurally characterized76 as have the known tetra- and
pentanuclear analogues.75,104 However, importantly
a linear vanadate trimer was recently reported
complexed to phosphatase PhoE from Bacillus stearothermophilus.77 Prior to this report, the structural
analogy of these homovanadates were limited to the
analogy between pyrophosphate and the vanadate
dimer in purely inorganic systems.105 No information
is currently available on systems that support fourcoordinate vanadium in a basic O3POVO3 unit.
However, structural information is available when
this unit is part of larger complexes, clusters, or
polymeric structures and the vanadium is five- or sixcoordinate (vide infra).
Regardless of the missing structural analogue, the
potentially most important examples of the vanadate-phosphate systems in biology are the various
heterovanadates containing both phosphate and vanadate (23). The most important analogues are of
ADP, ATP, and other nucleotides. Although a range
of ADP and ATP analogues have been prepared in
aqueous solution and spectroscopically observed, the
most useful analogues are AMPV (24) and ADPV
(19).106,107 Applications of both these analogues as
probes have been met with some success14 particularly when the analogue is binding in allosteric sites.
The limited ability of these analogues to induce the
biological responses of the corresponding phosphates
presumably can be traced, in part, to the fact that
none of these analogues contain the 7 kcal/mol
pyrophosphate bond. The corresponding heterovanadate-phosphate bond of 2-3 kcal/mol does not
provide the necessary energy. The fact that the
vanadate-phosphate analogue does not appear to
bind magnesium as do linear phosphates further
complicates and diminishes the fit that such an
analogue will have when binding to an enzyme.
Presumably, the latter explains why fewer effects of
vanadate on kinase reactions17,108 have been reported
compared to the well-established inhibition by vanadate of phosphatases.13
Although most work in this area has involved
vanadium in oxidation state V, both ATP and other
nucleotides are expected to form complexes with the
vanadyl cation (i.e., vanadium in oxidation state IV).
Early studies indeed showed that complexation takes
place.109 More recent studies employing speciation

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 855

Scheme 2. Vanadium Bromoperoxidase
(VBPO)-Catalyzed Bromide Oxidation by
Hydrogen Peroxidea

a Redrawn from ref 129. Copyright 2001 American Chemical

Society.

have extended these studies, and it was concluded

that the nucleotide base is involved in complexation
of the vanadium.110,111 The structural information for
this type of interaction shows vanadium to have a
coordination number greater than four, as described
in greater detail below. No information is yet available on the possibility that such complexes can
replace ATP or other nucleotide complexes in biology.

2.6. Potential Future Applications of

Vanadium-Containing Ground State Analogues in
Enzymology
The vanadium nucleotide analogues, AMV (18),
AMPV (24), and ADPV (19), will be reasonable
analogues when binding to allosteric sites on proteins
and as inhibitors in the active sites of enzymes. The
most likely proteins to bind these analogues will have
a binding constant of a micromolar or less, and the
best binding site will be an allosteric site where Mg2+binding is not critical for nucleotide binding. Enzymes with less affinity for the parent nucleotides
are not likely to be affected by vanadium analogues.
D-Glucose-6-phosphate dehydrogenase has also shown
high affinity for the vanadate substrate as well as
the vanadium-substituted cofactor NADV (20). NADV
remains the most explored vanadium-containing
substrate analogue and its about 20-fold better kcat/
Km provides precedence for applications of vanadiumcontaining ground-state analogues of organic phosphates. Successful applications of the V-P analogy
such as those reported in X-ray crystallographic
investigations show very tight binding of the parent
anion and the vanadate analogue.112-127

3. Haloperoxidases: V(V)-Containing Enzymes

and Modeling Studies
Haloperoxidases are enzymes that catalyze the
two-electron oxidation of a halide by hydrogen peroxide and consist of chloroperoxidases, bromoperoxidases, and iodoperoxidases. There are three different
classes of haloperoxidases known. Two classes contain a prosthetic group, one of which is a heme group
in the heme-containing haloperoxidases and the other
is a vanadate ion in the case of the vanadiumcontaining haloperoxidases.25 In addition, a third
class of haloperoxidases, the so-called metal-free
haloperoxidases, was recently described.21,128 The
historical classification and the nomenclature convention are based on the most electronegative halide
that the enzyme can oxidize (i.e., the chloroperoxidases (VCPO) can oxidize both Cl- and Br- and

bromoperoxidases (VBPO) can oxidize Br-). The

reaction is illustrated in Scheme 2.
The discovery of VBPO (and later VCPO), the first
enzymes found to use vanadium as a cofactor, has
resulted in one of the most active areas in vanadium
chemistry and biochemistry. In 1984, bioinorganic
chemists were first able to cite an example of an
enzyme that required vanadium.25,130 Should such an
enzyme be important and required for existence it
would explain how this element could be beneficial
at low concentrations. Furthermore, the practical
applications of VBPO and VCPO in the halogenation
of organic substrates under mild conditions have
generated a great deal of interest in industry; the
enzyme catalyzes the conversion of X- to X+ (where
X+ is presumably in the form of HOX, X2, etc.)
followed by nonenzymatic halogenation of the organic
substrate (eqs 6 and 7). In the past decade, multiple
reviews have been written on various aspects of
this area including enzyme structure,24,30,39-43
function,9,21-26,30 mechanism,7,22,23,37 and structural
and functional model chemistry.7,9,29,30,44-48 We refer
the readers to these reviews written by contributors
in this area for details beyond the scope of this
review. Since the discovery of the VHPO enzymes
inspired the report of several hundred V(V) and (IV)
coordination compounds, many of which have been
structurally characterized, but even more that have
not been characterized in such detail. We will briefly
summarize key recent advances, as well as some of
the fundamental experiments important to the studies in this area.
VCPO

Cl- + H2O2 + RH 98 RCl + 2H2O

VBPO

Br- + H2O2 + RH 98 RBr + 2H2O

(6)
(7)

3.1. Bromoperoxidase
Although peroxidase activity has been known in
marine extracts for many years,26 it was not until
1984 when Vilter discovered that vanadium content
was required in a bromoperoxidase from Ascophyllum
nodosum.25,130 The enzyme mechanism was examined
using structural, kinetic, and spectroscopic methods,
and issues such as the oxidation state of the metal
and its coordination geometry have been investigated
in detail. The oxidation potentials of the halides are
pH-dependent, and, in general, more acidic pH values
are required to oxidize the more electronegative
halides; this suggests that there is some flexibility
in these enzyme systems. Substrate specificity and
product distribution remain key areas of interest, and

856 Chemical Reviews, 2004, Vol. 104, No. 2

Scheme 3. Proposed Mechanism for the
VCPO-catalyzed Oxidation of Chloride by
Hydrogen Peroxidea

a Refs 7, 139-142, and 146. Reproduced with permission from

ref 146. Copyright 2003 Elsevier.

many studies documenting the usefulness of these

enzymes in synthesis have been reported.129,131-133
The crystal structures of a series of vanadatedependent haloperoxidases have been solved. There
is a significant overlap of the active site between the
VBPOs and VCPO despite the fact that these enzymes are distinct from each other. The structures
have been solved with several small molecules in the
active site, including phosphate or vanadate. The
structure of the VCPO from Curvularia inaequalis134,135 was reported first, followed by the structures
of the VBPOs from As. nodosum.136 The VBPO
residues being phosphorylated are His551 in Corallina
officinalis39 and His486 in As. nodosum.136 The structure of VBPO from Co. officianalis137 followed with
the structure of the recombinant bromoperoxidase (rVBPO) from Corallina pilulifera.138 This enzyme was
of particular interest because it contained a second
histidine near the active site (His478) instead of the
phenylalanine (Phe397) in the VCPO from C. inaequalis. Since the structure for VCPO was reported first,
much of the structural work with the VBPO was
directly compared with that reported for the VCPO,138
and also with the acid phosphatase (vide infra).39
On the basis of spectroscopic evidence, it is now
believed that the oxidation state of the vanadium
remains at V and does not change during catalysis.
A general consensus now exists for the mechanism
for both the VBPO and VCPO catalyzed reactions and
is described in Scheme 3.7,139-142 Since the vanadium
remains its highest oxidation state, the oxidation of
the bromide ion cannot involve reduction of the metal
ion in the first step. Mechanistic investigations have
involved product analysis, kinetics, and have included studies of both the enzyme and the model
systems. The reaction proceeds initially by H2O2
addition, which is followed by protonation of the
bound peroxide and addition of the halide, respectively. Spectroscopic evidence for the VO2-O2 species
was obtained using 17O NMR spectroscopy.143 Enzyme intermediates include a protein-peroxovanadium complex and a protonated protein-peroxovanadium complex. There is no evidence for an intermediate in which the bromide (halide) binds to the
vanadium atom.144,145 The rate-determining step in

Crans et al.

the catalytic cycle is the nucleophilic attack of the

halide on the protonated protein-peroxide complex
generating a Br+ (X+) species, which immediately
reacts with organic substrates and brominates (halogenates) them. This step will generate singlet
oxygen in the absence of RH, and has been investigated in detail with Cl-, Br-, and I-.
The VBPO and VHPOs in general have little
substrate specificity, and this has been used to
generate a wide range of products132 including the
bromination and cyclization of terpenes.131 Specific
oxidative conversions of organic substrates in aqueous media are desirable and regio- and/or stereospecific product formation has been achieved to varying
degrees. The regiospecific VBPO catalyzed oxidation
of 1,3-di-tert-butylindole by the marine algae As.
nodosum and Co. officinalis enzymes to produce
exclusively nonbrominated 1,3-di-tert-butyl-2-indolinone was recently reported.129 In contrast to most
haloperoxidases and perhydrolases, newly detected
NADH/FAD-dependent halogenases are substratespecific and regioselective.21 These systems do not
contain vanadium;21 however, further information on
these enzymes is likely to provide yet more information on another aspect of the vanadium-containing
haloperoxidase enzymes.

3.2. Chloroperoxidase
Haloperoxidases have been isolated from red, brown,
and green algae,7,26 seaweed,7,26 a lichen,7,147 and a
VCPO from terrestrial fungi.47 In the first X-ray
structure of VCPO from the fungus C. inaequalis, the
vanadium is bound as monoprotonated vanadate(V)
in a trigonal-bipyramidal coordination geometry.134
The metal is coordinated to three oxygens in the
equatorial plane, to an OH group at one apical
position, and to the N nitrogen of a histidine at the
other apical position. The key residues in the active
site are Lys353, Arg360, His404, Arg490, and His496
(Figure 2, bottom). The protein fold is mainly R-helical with two four-helix bundles as the main structural
motifs. An amino acid sequence comparison with
VBPO from the seaweed As. nodosum shows high
similarities in the metal binding site. All residues
interacting with vanadate(V) are conserved except for
Lys353, which is an asparagine in VBPO.134,148 The
crystal structure has been determined for the apoenzyme,135,149 and with vanadate,134 tungstate,150 and
peroxovanadate135,149 in the active site. Although
overall the two structures of the vanadium- and
tungsten-bound proteins are virtually identical, one
major difference exists in the active site. In the
vanadium-protein structure, the vanadium-histidine bond is strong, whereas in the tungstateprotein bound structure such bonding is either lacking or very weak. This observation demonstrates the
fine-tuning that exists in this system for metalcofactor binding.150 Investigations into the V-binding
in native and mutant chloroperoxidase show that the
latter holds the vanadium ion less tightly; however,
the mutant maintains bromoperoxidase activity.151
The X-ray structures of the chloroperoxidase from C.
inaequalis and active site mutants document the
intricate H-bonding network that is in place to

Chemistry and Biochemistry of Vanadium

Figure 2. Comparison of the active sites of VCPO and rat

prostatic acid phosphatase. Top: Structure of the active
site of the rat prostatic acid phosphatase with complexed
vanadate.120 Bottom: Structure of the active site of vanadium haloperoxidase from the fungus C. inaequalis.135
Reprinted with permission from ref 153. Copyright 1999
Wiley-VCH.

stabilize five-coordinate vanadium in the active

site.152

3.3. From Haloperoxidases to Phosphatases

The amino acid sequence of the active site of
VHPOs are conserved within three families of acid
phosphatases, including several lipid phosphatases,
the mammalian glucose-6-phosphatase, and bacterial
nonspecific acid phosphatases.154-156 These studies
were followed by structural confirmation of the
similarities between the VCPO and VBPOs39 and
phosphatases.39,43,154,155,157-159 The amino acids that
are involved in phosphate binding in the acid phosphatase enzymes and those that are coordinated to
vanadium in the VHPOs appear to be conserved.39
The structurally characterized VCPO of the fungus
C. inaequalis shows vanadate covalently linked to the
protein through an axially bound histidine residue,
His496, embedded in the protein through an extensive
hydrogen-bonding network (Figure 2, bottom).135 In
the case of the rat prostatic acid phosphatase, the

Chemical Reviews, 2004, Vol. 104, No. 2 857

motif is very similar, although His12 is the residue

that is bound to vanadate (Figure 2, top).120
Since phosphatase activity can be catalyzed by
apohaloperoxidases,160,161 the possibility that peroxidase activity could be observed for vanadate-inhibited
phosphatases has been investigated for several systems.39,43,154,156,162,163 The first observation of chloroperoxidase activity was reported with phytase, added
vanadate and H2O2.162 Since then reports have been
made demonstrating that other phosphatases can be
converted to peroxidases in the presence of vanadate
and H2O2.39,43,154,156,162,163 Thus, at this time the analogy between these classes of enzymes includes both
structural and catalytic aspects. A major issue at the
present time (and in the future) is whether the dual
activity of these enzymes observed in vitro extends
to the function and role of these enzymes in vivo.
It remains to be investigated whether observations
with one class of enzymes will lead to reliable
predictions with regard to the other class of enzymes,
although limited success in this regard can be
anticipated. For example, the observation that VCPO
has a higher affinity for peroxovanadate than vanadate was used to suggest that glucose-6-phosphatase
has a higher affinity for this species considering the
evolutionary relationship between the haloperoxidase
and glucose-6-phosphatase.160 This prediction is in
contrast to an earlier report in which the Ki value
for the dipicolinato monoperoxovanadium(V) complex
is about 10-fold less than that of vanadate and the
parent dipicolinate acid for alkaline phosphatase.19
Furthermore, sequence alignment predicted the role
of the various amino acid residues based on their role
in VCPO and suggested that the His404 in VCPO
would have the same role as His119 in glucose-6phosphatase. However, the recent studies aiming at
identifying the His residue that is covalently bound
to the phosphate moiety showed that the His176 and
not the His119 was the residue phosphorylated during
catalysis.164 Another important and different role of
residues identified by sequence homology is found for
Lys76 that in glucose-6-phosphatase was predicted to
stabilize substrate by hydrogen bonds as Lys353 in
VCPO, but instead this residue appears to be found
in a membrane bound section of the protein. Although the recognized sequence analogy between
VHPO and some phosphatases may not extend to all
structural and functional details of the respective
protein, such differences are not unexpected considering the differences in reaction mechanism even
among the VBPO and VCPO enzymes. The possibility
that the haloperoxidase activity is an artifact has also
been raised because haloperoxidase activity has also
been reported as an artifact of lipases and esterases
that normally catalyze hydrolysis of lipids and esters.128 The dual catalytic activities of the VHPO and
phosphatase enzymes are observed, but their importance and possible functions remain to be uncovered.

3.4. Structural Modeling Studies of the

Vanadium-Dependent Haloperoxidases
Three general categories of complexes have been
described as structural model complexes for haloperoxidase enzymes, if structural model complexes

858 Chemical Reviews, 2004, Vol. 104, No. 2

are broadly defined as done in the introductions in

the multitude of papers reporting new vanadium
coordination complexes for the last two decades. The
structural information regarding the haloperoxidases
active sites have now shown that most of these
complexes are poor structural model systems. The
first class defined as containing V(IV) and (V) bound
to ligands with O and N donors is the largest and
thus contains most coordination complexes. The
largest group within this class of compounds are the
Schiff base complexes;165-169 some examples are
shown in structures (25-27).7 More than 200 crystal
structures of V-containing Schiff bases can be found
in a search of the crystallographic database and
document the widespread interest in these types of
compounds. Other fundamental ligand systems such
as hydroxyethyliminodiacetate and related simple
ligands remain of key interest because of the functional properties of their V-complexes (vide infra).
Systems belonging to this class of complexes are
shown in structures (28-32) and are described below
with regard to their spectroscopic properties and/or
their ability to carry out the VHPO reaction as a
functional mimic.7,9,29,44-48,168,170,171

The second class of model complexes includes all

peroxovanadium complexes. These complexes are of
interest not only because they are intermediates in
the catalytic cycle of the VHPO reaction, but because
of their use as catalysts in organic synthesis.172,173
In addition, administration of these complexes to cell
cultures are found to increase the protein phosphorylation of the insulin receptor (IR) presumably by
inhibiting a protein phosphatase (vide infra).174-177
Aqueous V(V) in the presence of H2O2 at acidic pH
was found to functionally mimic VBPO178,179 and a
protein-peroxovanadium(V) complex has now been
structurally characterized demonstrating the details
in the active site when the vanadium ion is coordinated to a peroxo group.41 A wide range of peroxovanadium complexes have been reported, and several
reviews are dedicated to the discussion of the structure and chemistry of these systems.173,180,181 In Table
1 we summarize the known peroxovanadium complexes with O and N donor atoms and their structures (33-46).143,182-229 A summary of all known
peroxovanadium(V) systems including those with
ligand donors others than O and N have been
reported elsewhere.230 In addition to the spectroscopic
characterization of these species, a combined method

Crans et al.

using electrospray ionization-mass spectrometry (ESIMS), 51V NMR spectroscopy, and ab initio calculations has been found to be an excellent tool for
obtaining direct information about the structure and
chemistry of peroxovanadates in solution.44,231,232

The number of peroxo groups and the auxiliary

ligand that are coordinated to the vanadium atoms
dictate the structures (and reactivity) of the peroxovanadium complexes. The peroxo group is bound sideon to the V(V) atom with V-O bond lengths on the
order of 1.85 and O-O bond lengths of about 1.4
. Only one example of a side-on bound alkylperoxide
V-complex has been reported.233 Complexes are known
with one, two, three, and four peroxo groups, although only the two former classes of complexes are
found under the conditions required of functional
mimics. Coordination numbers around the vanadium
are generally 6 or 7, and the elaborate dimeric
structures often fall apart upon dissolution of the
compounds. However, detailed speciation has been
characterized for a few simple systems, and this area
has been recently reviewed.234
The third category of structural model complexes
involves complexes in which the H-bonding patterns
in the VHPO are the focus of the investigations.235
At this time, relatively few systems exist in this
category of models because the protein structural
information to investigate such systems has not been
known for that long, and in part because such models
require a different approach to designing model
systems that contain H-bonded networks.143,235-237
The first structural characterization of a model
complex in which intramolecular H-bonding between
a pendant amine functionality and a V(V)-bound
peroxide has been reported (Figure 3).235 This system
structurally models the VCPO-V(O2)2 recently reported.41 A tungstate layered, double hydroxide catalyst was prepared, inspired by the reaction of the
VBPO.238 The tungstate-exchanged layered double
hydroxide halogenates an organic compound, or
oxidizes a second H2O2 molecule to generate one
molecule of excited-state singlet oxygen. The rate of
Br- oxidation is faster than using homogeneous
oxometalates or heterogeneous titanium catalysts.
Changing the elemental composition of the octahedral layer of the layered double hydroxide can
enhance the rate even further.238 Mimicking the
important role of water molecules in the active site
has been investigated using model complexes.144

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 859

Table 1. Summary of the Structural Features of the Crystallographically Characterized Peroxo Model
Complexesa,b,c
ligand set
on Va

peroxo
ligands

nonperoxo,
nonoxo ligand(s)b

CN

N (NO5)
NO2 (NO5)
NO (NO6)

2
1
2

6
7d
7

NO3 (NO6)
NO3 (NO6)
NO3 (NO6)
N2O (N2O4)
N2 (N2O5)
N2 (N2O5)
N2O2 (N2O5)
N2O2 (N2O5)

1
1
1
1
2
2
1
1

7
7
7
6
7
7
7

N2O2 (N2O5)
N2O2 (N2O5)

1
1

7
7

N2O2 (N2O5)

N2O (N3O4)
N3O (N3O4)

1
1

7
7

N3O (N3O4)
N3O (N3O4)
N3O (N3O4)
N3O (N3O4)
N4 (N4O3)
O (O6)
O2 (O6)

1
1
1
1
1
4
2

7
7
7
7
7
6,6
6,6

O2,3 (O6,7)

7,7 or 6,6f

O (O7)
O (O7)
O2 (O7)
O2 (O7)
O4 (O7)
O5 (O7)

3
4
2
2
1
2

7
7,7
7
7
7
7,7

ammonia/imidazole
iminodiacetic acid
picolinic acid/3-hydroxy-picolinic acid/
2,4-pyridine dicarboxylic acid/
3-acetatoxy-picolinic acid
picolinic acid, H2O 2
dipicolinic acid, H2O
N-(2-hydroxyethyl)-iminodiacetic acid
glycylglycine
bipyridine (4 structures)
5-nitro-phenanthroline
phenanthroline, H2O 2
picolinic acid 2/
pyrazine-2-carboxylic acid 2
D,L-N-carboxymethyl-histidine
ethylenediamine-tetracetic acid
(two structures)
N-(carbamoylmethyl)-iminodiacetatic acid
(2 structures)/N-(carbamoylethyl)iminodiacetatic acid
1-(2-pyridylazo-)-2-naphthol, pyridine
picolinic acid, bipyridine/picolinic acid,
phenanthroline
Tris(3,5-diisopropyl-pyrazol-1-yl)borate,H2O
nitrilotriacetic acid (5 structures)
N,N-bis(2-pyridylmethyl)-glycine
N,N-bis(2-pyridylmethyl)--alanine
bipyridine 2/phenanthroline 2
H2O (three structures)
glycolic acid 2/D-lactic acid, L-lactic acid
(two structures)/L-lactic acid 2/
mandelic acid 2
citric acid (two structures)/
malic acid (four structures)
hydroxide
oxide (two structures)/hydroxide
oxalic acid (three structures)
carbonate
oxalic acid 2
L-tartaric acid 2, H2O (L)

ligand
denticity

structural
illustrationc

ref(s)

1
3
2

33
34
35

182, 183
184
185, 186

2,1,1
3,1
4
3
2
2
2,1,1
2,2

36
37
38
39
35
35
36
40

187
188
189
190
191-194
195
196
196, 197

4
4

38
38

198
199

38

200-202

3,1
2,2

37
40

203
196,204

3,1
4
4
4
2,2
1
2,2

37
38
38
38
40
41
42

205
206-209
189
143
210
211-213
214-217

3,3

43

218-221

1
1
2
2
2,2
2,2,1

44
45
35
35
40
46

222
223-225
191, 222, 226
227
228
229

a The complexes are sorted by the overall donor ligand set, which is given in parentheses after the donor ligand set of the
nonperoxo and nonoxo ligands. b The ligand sets of each structure are separated by a slash. If two (or three) of the same ligands
are present in a given structure, then the number of such ligands is denoted by 2 or 3; the number of structures of the same
complex appears in parentheses. c The key to the structural illustrations is shown in Figure 3. d The complex forms an extended
array with an adjacent VdO group serving as the seventh ligand. f The terminal carboxylate oxygens trans to the doubly bonded
oxo ligands weakly interact with the vanadium (V-Ocarboxylate distance 2.5 ).

Figure 3. Ball and stick representation of [VO(O2)(BrNH2pyg2)]-. All protons have been omitted for clarity.
Reproduced from the spatial coordinates given in ref 235.
Copyright 2002 American Chemical Society.

3.5. Spectroscopic Modeling Studies of the

Vanadium-Dependent Haloperoxidases
51V

NMR spectroscopy has become a routine tool

for studying V(V)-complexes, and its usefulness and
high information content has contributed to the

exponential growth in the number of new V(V)

coordination complexes. Detailed spectral information on a range of V-complexes has been reported for
several decades by the Rehder,239,240 the
Tracey,14,100,241-243 the Crans62,67,73,80,81,87,89,95,244,245
groups, and more recently by other groups using this
technique to characterize, in detail, the systems that
exist in aqueous solution. Several groups have used
51V NMR spectroscopy to (i) predict chemical shifts
for known compounds and use 51V NMR as an
additional characterization technique and (ii) predict
approximate coordination environments for complexes in which characterization is limited.7,100,244,245
Although caution is needed in such studies, for
structurally related systems this method is extremely
useful. Such considerations are possible because the
51V chemical shifts can qualitatively be predicted by
considering the electronegativity and hardness of the
donor atom as well as the specific geometric arrangement of the V-atom. As Pecoraro and co-workers have

860 Chemical Reviews, 2004, Vol. 104, No. 2

demonstrated, such trends do not hold when noninnocent ligands with low energy, ligand-to-metal
charge-transfer bands are used in the complexes.246
For example, catecholate and hydroxamate V(V)complexes give rise to chemical shifts that are
unusually far downfield. However, for complexes with
O and N donors such as water, hydroxide, alcohols,
monodentate carboxylates, and amines, shifts in the
range of -400 to -600 ppm are observed. Shifts
upfield of -600 ppm tend to result from negatively
charged multidentate ligands that form three- or
four-membered chelate rings such as peroxides.7,239,240
Early 51V NMR studies on the VBPO from As.
nodosum show an unusually broad signal at about
-1200 ppm and remains an observation that needs
further investigation.247 It is known that association
of the quadrupolar vanadium nucleus with a large
protein can broaden the signal width if the tumbling
of the complex becomes sufficiently slow. Considering
the current information of model studies and the
crystal structure of the various V-complexes, a protein complex is likely to contain at least three O
donors and one N (histidine) donor. Although noninnocent ligand complexes may give rise to a complex
with a -1200 ppm chemical shift, the ligands found
so far in the crystal structures of protein-V-complexes are not consistent with the reported spectrum.
Pecoraro and co-workers have spearheaded studies
using ESEEM on model complexes to explore the
coordination environment in the protein system.7
Recent ESEEM spectra of model complexes suggested
that the ESEEM of the reduced enzyme7 was consistent with the presence of one imidazole ligand in
the axial position as well as a second imidazole in
the equatorial plane of the vanadyl ion observed in
the original ESEEM spectra.248 The possibility that
V(V) binds to both histidine residues in the active
site would be consistent with the inactivity of this
form of the enzyme because the second histidine that
functions as an acid-base catalyst is firmly bound
to the protein.249 ESEEM is also useful for investigation of histidine-V-complexes modeling the histidine-V-complex in proteins.7,169 Many of the wellcharacterized model systems are Schiff bases; the
corresponding V(V) catechol complex with the ligand
HSALIMH is shown (25).250 Recently, Butler and coworkers reported the reactivity of recombinant and
mutant vanadium bromoperoxidase from Co. officinalis. Mutation of the conserved histidine residue to
an alanine (H480A) resulted in the loss of the ability
to efficiently oxidize bromide, although the ability to
oxidize iodide is retained.249

3.6. Functional Modeling of the

Vanadium-Dependent Haloperoxidases
Effective modeling of the VHPO activity was obtained for cis-dioxovanadium (VO2+) in acidic aqueous
solution by Butler and co-workers.178,179 Aqueous V(V)
peroxide chemistry is complex, and it was found that
the dinuclear species (V2O2(O2)3) was the active
species and has been described in detail previously.7,37,251 These studies importantly demonstrated
that not only do systems exist that mimic the enzyme
reaction, but if the simple ion can catalyze this

Crans et al.

reaction, complexing ligands should be able to enhance and/or retard this reaction. Since then, a range
of systems have been reported competent to carry out
this reaction.7,9,29,44-48,170,252 These complexes include
the first monomeric complexes 26 and 27 reported
by Butler and co-workers,252 which showed that the
bromination of the organic substrates proceeded
exclusively via an electrophilic mechanism and involved no radical intermediates. Other complexes
found to be competent in oxidizing bromide include
complexes from additional Schiff base ligands, nitrilotriphosphoric acid and citrate.189 Interestingly,
pyridine-2,6-dicarboxylic acid is found to protect H2O2
against reduction by bromide. Other ligands such as
picolinic acid do not form sufficiently stable adducts
to exist in the presence of H2O2.189
Pecoraro and co-workers designed a model system
with ligands which completed the coordination sphere
of an oxoperoxovanadium unit (28-31).189,253,254 The
most efficient complex of this class, [VO(O2)Hheida](28), showed some properties to be different than
those in the Butler systems; acid was required for
both catalytic and stoichiometric catalytic activity.189,253 However, in the presence of excess acid and
peroxide, up to 10 turnovers were accomplished
within 3 min, and thus increased the rate of reaction
by at least an order of magnitude greater than that
observed for previous systems. Furthermore, this
model system was the first vanadium model compound to demonstrate both the halogenation and
catalase reaction catalyzed by VBPO.254 Detailed
mechanistic studies were carried out with these
complexes, and supported a mechanism with a protonation preequilibrium preceding the halide oxidation step.189 Studies with H218O2 showed persuasively
that the oxidation of bromide produced O2, which was
completely labeled with 18O and thus indicated that
peroxide is oxidized without oxygen-oxygen bond
cleavage.189
Pecoraro and co-workers proposed a variation on
the enzyme mechansim in which an L group replaces
the EnzO3 for the catalysis of the oxidation by model
compounds.7 In this mechanism, the halide is oxidized by peroxovanadium complexes via nucleophilic
attack by the halide on a protonated oxoperoxovanadium species. The trihalide is the only product
observed under conditions of excess halide and is not
directly specified in such a mechanism recognizing
that the initial formation of hypohalous acid (HOX)
is formally equivalent to OH- + X+. This variant
mechanism is also consistent with the data reported
with Butler and co-workers when considering that
the proton-independent oxidation reaction in reality
results in the liberation of one equivalent of acid
when peroxide binds.7 A two-phase system was
designed,255 and ab initio calculations were carried
out to provide evidence for the hypobromite-like
V-complex.256

3.7. Oxidation of Sulfides by Haloperoxidases

(VHPOs)
Application of VBPO, VCPO, and their functional
mimics have been explored as potential catalysts in
the oxidation of sulfides.162,257-259 Such activity had

Chemistry and Biochemistry of Vanadium

been known for some time with heme-containing

haloperoxidases26 and peroxovanadium compounds.260
The report that VBPO from the Co. officinalis alga
catalyze the oxidation of bicyclic sulfides to the
corresponding (S)-sulfoxides in up to 91% enantiomeric excess accomplished a goal pursued by several
groups.261 VBPO from As. nodosum, in contrast, was
found to generate the (R)-enantiomer of methyl
phenyl sulfoxide.262 Although the r-VCPO from the
C. inaequalis fungus is competent to oxidize a typical
heme peroxidase substrate in contrast to the other
VHPOs,263 the fact that only racemic mixtures of
sulfoxides are produced reduces the synthetic potential of this enzyme.262 Distinct mechanistic differences
are proposed between the VCPO and the VBPO to
account for the varying product ratios.264
The stereoselectivity of the products formed from
catalysis by VBPOs is influenced by several factors
including pH and the presence of cosolvents.264,265
Excess hydrogen peroxide was found to reduce both
the yield and stereoselectivity of the product formed
by the reaction catalyzed by the VBPO from Co.
officinalis.261 The addition of bromide ion caused a
rapid loss of stereoselectivity presumably due to the
chemical oxidation of bromide and subsequent formation of a bromosulfonium intermediate.264,265 In
the reaction catalyzed by the As. nodosum VBPO, the
presence of electron donating substituents in the
para-position of the phenyl ring of methyl phenyl
sulfide increased the stereoselectivity of the reaction,
while electron-withdrawing substituents decreased
the stereoselectivity.266 Alterations in substrates
changed the reaction yields of the enzyme-catalyzed
reaction and for the cyano- and nitro-substituted
substrates the oxidation reaction was almost completely shut down.
The VBPO from As. nodosum catalyzed oxidation
reaction using 18O-labeled hydrogen peroxide produced the (R)-sulfoxide and is attributed to direct
oxygen transfer from the peroxovanadium.264 In
contrast, the r-VCPO from C. inaequalis catalyzed
formation of a racemic mixture containing small
amounts of 18O-labeled sulfoxide. These results suggest differences in the reaction mechanisms for the
VBPO- and VCPO-catalyzed reactions. In the heme
peroxidase from Caldariomyces fumago the sulfoxidation has also been proposed to take place by direct
oxygen transfer267-269 to substrate that is bound near
the active site. Similarly the VBPO from As. nodosum
binds organic substrates,270 and it is possible that
sulfide substrates also undergo direct oxygen transfer.264 The nature of the protonation state of the
peroxovanadium intermediate is still under scrutiny.
A mechanism in which the bound peroxide is directly
being attacked by the sulfide has been proposed264
as well as a mechanism in which the peroxide is
protonated before sulfide attack.30,257 Mechanistic
details between the VCPO and the VBPO enzymes
must vary somewhat to account for the resulting
different product ratios.264 Although the mechanism
for the VCPO-catalyzed reaction has been examined
in less detail than the VBPO-catalyzed reaction, it
has been proposed that the sulfide undergoes a oneelectron oxidation to yield a radical cation (RRS+)264,

Chemical Reviews, 2004, Vol. 104, No. 2 861

which could then go on to abstract oxygen.267-269 Such

a mechanism would be consistent with formation of
racemic sulfoxides.

4. Inhibition of Phosphorylases by
V-Compounds: Phosphatases, Ribonuclease,
Other Phosphorylases, and ATPases
4.1. Phosphatases
Phosphatases catalyze the hydrolysis of phosphate
ester bonds (eq 8), and the mechanism involves
formation of five-coordinate, high-energy intermediates. These enzymes are generally potently inhibited
by vanadate, which is recognized to be a transition
state analogue for the phosphatase-catalyzed reaction. The inhibition by oxometalate inhibitors of
phosphatases has involved kinetic studies19,121,174,271-280
as well as structural studies.112-127

R-PO3H- + H2O f ROH + H2PO4-

(8)

Phosphatases can be divided into four classes of

enzymes based on the nucleophile in the active site,
and three of these classes are illustrated in Figure
4. These enzymes therefore will show some variation
in their interaction with the V-compounds.13,273,281
The first class of phosphatases, the alkaline phosphatase, has a nucleophilic serine residue in the
active site so that a hydroxyl group forms the
covalent species with the phosphate esters to be
hydrolyzed. A second class of phosphatases is comprised of the acid phosphatases and some protein
phosphatases; these contain a nitrogen ligand mostly
in the form of a histidine residue in the active site,
and thus an imidazole group forms the covalent
species with the phosphate esters in the active site.
Other protein phosphatases have a cysteine residue
in the active site so that the thiol group forms the
covalent species with the phosphate ester. The final
class of phosphatases contains a dinuclear metal ion
core in the active site; a metal-bound hydroxyl group
is the nucleophile facilitating hydrolysis of the phosphate ester (eq 8). Structural characterization of
oxometalate-protein complexes shows the oxometalate in either a four-coordinate117-120 or five-coordinate geometry112-116,121 for a range of different phosphatases.

Figure 4. Phosphointermediate forms for an alkaline

phosphatase (Ser residue in TS complex), acid phosphatase
(His residue in TS complex), and a protein phosphatase
(Cys residue in TS complex).

4.1.1.Vanadate: An Imperfect Transition State Analogue

of Phosphatases
Phosphatases are, in general, inhibited by oxometalate anions such as vanadate, arsenate, molybdate, and tungstate, which are also often described
as phosphate analogues.12,13,121,273,274,278,279 Studies of
less common analogues such as sulfate, rhenate, and

862 Chemical Reviews, 2004, Vol. 104, No. 2

periodate have also been reported.273,274,280 Although

the inhibition of oxometalates should be viewed as
product inhibition, the fact that oxovanadates (and
a few other oxometalates) also mimic the fivecoordinate transition state of phosphate ester hydrolysis (11) indicates that the mode of inhibition for
these anions is more consistent with the potent
transition state analogue inhibition observed for
many phosphatases.
The concept of vanadate as a transition state
analogue for phosphate ester hydrolysis was first
described three decades ago and has now become
dogma.12,13,273,282 The potent inhibition of acid phosphatase by oxometalate anions was attributed to
these anions either acting as transition state analogues or by formation of strong chelates.273 Recent
studies, designed to probe how good a transition state
analogue vanadate may be, have been probing the
origin of the observed inhibition.283 A perfect transition state analogue has an affinity for the enzyme
that exceeds the affinity of the substrate by a factor
equivalent to the increased catalytic rate in the
enzymatic reaction relative to the corresponding
nonenzymatic reaction. Recent studies investigating
the affinity of vanadate or vanadate derivatives
suggest that although the affinity is enhanced by
multiple orders of magnitude, vanadate, for example,
comes up short by a few orders of magnitude with
regard to its affinity for Yersinia PTPase.283 This
result reflects the fact that vanadate is probably not
a perfect transition state analogue, although these
studies do demonstrate that it comes very close and
by many criteria can be characterized as an excellent
transition state analogue.

4.1.2. V(IV) Chemistry and Inhibition of Phosphatases by

V(IV)
The fact that the VOSO4 has also been reported to
be a potent inhibitor for some phosphatases remains
an unexplained fact.275,284 How can a cation and an
anion both be potent inhibitors of, for example,
Escherichia coli alkaline phosphatase? To understand
this seeming discrepancy, we will describe the aqueous V(IV) chemistry in detail.
The most well-known V(IV) species is the vanadyl
cation (VO2+-cation, [VO(H2O)5]2+, (47)).12,31-33 The

VO2+-cation ([VO(H2O)5]2+) (47) is stable at acidic pH

and is the major species at pH 3. This species has a
distinct eight-line ambient temperature EPR spectrum, which reflects the 7/2 spin285 of the vanadium
nucleus and is shown in Figure 5. As the pH
increases to 4, a proton begins to be lost (reported
VO2+ pKa values range from 5.0 to 6.433,285,286) and
the hydrolyzed species [VO(H2O)4(OH)]+ forms in
solution as shown in Schemes 4 and 5. Scheme 4
shows the relatively simple speciation existing at
nano- to submicromolar V(IV) concentrations, and

Crans et al.

Figure 5. The isotropic, ambient temperature, 8-line EPR

spectrum of [VO(H2O)5]2+. Reprinted with permission from
ref 285. Copyright 1975 American Chemical Society.
Scheme 4. Aqueous [VO(OH2)5]2+ Hydrolysis
Products at Nano to Submicromolar V(IV)
Concentrationsa

a The insoluble hydroxide {VO(OH) } is in equilibrium with

2 n
the positively and negatively charged monomeric species.

Scheme 5. Aqueous [VO(OH2)5]2+ Hydrolysis

Products at Micro to Millimolar V(IV)
Concentrations

Scheme 5 shows the speciation at millimolar V(IV)

concentrations.
As [VO(H2O)4(OH)]+ forms, an EPR silent285 dimer
([{VO(OH)}2]2+) begins to form in solutions containing millimolar V(IV) in this pH region.12,33,230,286,287
Increasing the pH of the solution to above 5 results
in an abrupt drop in the EPR signal intensity due to
the formation of insoluble {VO(OH)2}n.285 Upon a
further increase in pH, {VO(OH)2}n dissolves to form
a dimer [(VO)2(OH)5]-288 and subsequently, a monomer [VO(OH)3]-.289 Only the latter species has been
well characterized by means of EPR and UV-Vis
spectroscopy,289 whereas formation of the dimer
[(VO)2(OH)5]- was deduced from potentiometric analysis.288 The prominent existence of [(VO)2(OH)5]- at
pH 6-8, although recognized by speciation chemists,
has not been generally appreciated by most scientists
interested in vanadium chemistry and biochemistry.
The description shown here in Figure 6 and
Scheme 4 deviates only from those previously reported12,31,33,230,288 in that a lower concentration range
is selected. This seemingly minor modification of the
speciation diagram clearly illustrates the existence
of negatively charged monomeric V(IV) species at
neutral pH and thus provides a very different structural image of the V(IV) species that exist in aqueous
solution.
In the neutral pH range (pH 6-8), the concentration of free [VO(H2O)5]2+ is determined by the {VO-

Chemistry and Biochemistry of Vanadium

Figure 6. Predominance area diagram for aqueous V(IV)

species which is represented as the logarithm of the total
molar concentration of vanadium(IV) vs pH. Solid lines
represent the condition where the concentrations of two
soluble species are equal. The following hydroxo-complexes
were assumed [VO(OH)]+ (log1-1 ) -5.94),286 [(VO)2(OH)2]2+ (log2-2 ) -5.94),286 [VO(OH)3]- (log1-3 ) -18.0),33
[(VO)2(OH)5]- (log2-5 ) -22.5).288 Here pq are concentration formation constants pq ) [(VO)pHq]2p+q/[VO2+]p[H+]q
for each species formed according to the general equation
pVO2+ + qH+ ) [(VO)pHq]2p+q. {VO(OH)2}n (s) solubility
product value of Ksp ) 6.6 10-23 M3 (taken from ref 288)
was used to evaluate the concentration of free [VO(OH2)5]2+.

(OH)2}n solubility product unless the total concentration of V(IV) drops below 10-6 M. The predicted
solubility of V(IV) based solely on the positively
charged species ([VO(H2O)5]2+, [VO(H2O)4(OH)]+, and
[{VO(OH)}2]2+) is significantly less than the observed
soluble V(IV). The missing components of V(IV) are
a negatively charged monomeric and dimeric anionic
species ([VO(OH)3]- and [(VO)2(OH)5]-). Concentrations of positively charged species under these conditions are extremely low (for example, with a saturated V(IV) solution at pH 7.4 the expected nanomolar
concentrations of V(IV) species are calculated to be
[VO(H2O)5]2+ ) 1, [VO(H2O)4(OH)]+ ) 30, [{VO(OH)}2]2+ ) 0.8, [(VO)2(OH)5]- ) 350 000, and
[VO(OH)3]- ) 20 000), suggesting that indeed negatively charged species play a key role in biological
systems under anaerobic noncomplexing conditions.
The formula [VO(OH)3]- implies a four-coordinate
species, and the spectroscopic signature of this species was investigated using UV-visible and EPR
spectroscopy to confirm the geometry.289 The results
were not found to be consistent with four- or fivecoordinate species but, rather, with a six-coordinate
species. Neither potentiometry nor other spectroscopic methods employed to date can provide information on the exact number of water molecules
associated with the metal ion in solution. Presumably, two water molecules are associated with the
metal ion making the stoichiometry of this negatively
charged ion [VO(OH)3(H2O)2]-. Note that such a
stoichiometry would readily convert this anion to the
well-known vanadyl cation (47) by three protonation
steps with no changes in the coordination sphere.
The existence of higher oligomeric species (i.e.,
[(VO)2(OH)6]2-, [(VO)4(OH)10]2-, and polymeric {(VO)(OH)3}nn-) was suggested in neutral and basic

Chemical Reviews, 2004, Vol. 104, No. 2 863

solution12,290-292 at submicromolar concentrations.

V(IV) concentrations of these species are usually
neglected.293,294 At physiological pH in a noncomplexing media, no EPR spectrum can be observed.12,285
The observation of a EPR spectrum at neutral pH
indicates that either a complexing ligand is present
in solution or that the pH is no longer neutral. The
presence of buffers and their complexes formed with
V(IV) have been used successfully to investigate the
complexation of V(IV) to proteins at neutral
pH.12,33,36,230,295
Recent studies have investigated the interaction of
V(IV) with low molecular weight ligands existing in
biological systems providing some information on the
concentrations of such complexes and the concentration of free V(IV) to be expected. The ligands investigated include phosphate,296,297 oxalate,298 lactate,299
glutathione,300,301 NAD,302 NADP,302 and sugars.303,304
These analyses were carried out in the presence of a
V(IV) complexing ligand and thus attempted to mimic
a situation in which a V(IV)-complex was administered to a system. The results support the speciation
described above in which [(VO)2(OH)5]- is the predominant species at pH 7-7.5 when the total V(IV)
concentration of all species is in the range 1-10 M.
Although the major V(IV) species existing in solution is negatively charged, the complexes formed are
between the positively charged V(IV) and negatively
charged ligands. This fact reflects that these systems
are under thermodynamic control, and the most
stable complexes formed will be between negatively
charged ligands and VO2+ in many biological fluids.
To our knowledge, the only stable coordination
complexes in which V(IV) is bound to a positively
charged ligand occur when V(IV) is bound to a large
positively charged protein or peptide. Of all the
ligands in the blood plasma (at the level of 10-4 M)
investigated, citrate305,306 was the only ligand able to
displace strongly bound hydroxo-groups and sequester V(IV).
The complexity of the aqueous V(IV) chemistry and
the likelihood of oxidation of V(IV) to V(V) at neutral
pH have led most investigators to assume that any
affinity of phosphatases for V(IV) reflected the oxidation of V(IV) to V(V). However, when V(IV) is a more
potent inhibitor than V(V), this line of reasoning is
not sound. As described above, the major monomeric
species present in solution at neutral pH is not a
positively charged form of V(IV) but [VO(OH)3]-. The
fact that anionic V(IV) species exist near neutral pH
would explain the seemingly inconsistent result that
V(IV) also inhibits phosphatases284 despite the fact
that the coordination geometry of the ion may be
somewhat different than that of phosphorus in
phosphate anions. The specific nature of the interaction of VO2+ with E. coli has not been elucidated;284
however, potent inhibition is also observed with a
wide range of mammalian phosphatases demonstrating that this effect is not limited to the E. coli alkaline
phosphatase.275 Inhibition of alkaline phosphatase by
aqueous V(IV) may indeed be more similar to the
inhibition by vanadate and in line with the inhibition
of a transition state analogue.

864 Chemical Reviews, 2004, Vol. 104, No. 2

Crans et al.

4.1.3. Inhibition of Alkaline and Acid Phosphatases by

Vanadium Compounds
Because the acid and alkaline phosphatases are
compatible with V(V)-compounds, they are particularly well suited to test the effects of V-complexes
structures on the phosphatase inhibition. The vanadium model compounds for the phosphatase hydrolysis reaction are five-coordinate complexes that have
distorted trigonal-bipyramidal or square-pyramidal
geometries (vide supra).12,29,230 Although the distortion from the perfect trigonal bipyramidal geometry
may lessen the structural analogy with the phosphate
ester hydrolysis transition state,307 all V-compounds
tested are found to be inhibitors for alkaline and acid
phosphatases.19,174,277,308-313 However, the inhibitory
potency of five- (48), six- (49), and seven-coordinate
(50) vanadium dipicolinate complexes was tested in
detail, and the inhibition was correlated with intact
V-compound.19 The five-coordinate vanadate-dipicolinate complex was the most potent inhibitor, in
line with the prediction that a compound with
geometry most similar to that of a transition state
analogue would be the most potent inhibitor. It is
possible that the five-coordinate complex will coordinate to the phosphatase when forming the protein
complex and perhaps, in the process, lose a ligand,
considering the mechanism of these proteins. Alternatively, the active site may be sufficiently flexible
to accommodate a small change. Interestingly, the
six- (49) and seven-coordinate (50) complexes are also
strong inhibitors.19
Studies with both acid and alkaline phosphatases
show the increased affinity of vanadate in the presence of phenol.274 This observation is interpreted as
the formation of the phenyl vanadate ester, which is
a much more potent inhibitor for these enzymes than
the vanadate anion.274 These considerations and
those introduced below show that a perfect transition
state geometry does not seem necessary for potent
inhibition of phosphatases and some differences are
to be anticipated depending on the specific phosphatase under consideration.

4.1.4. Inhibition of Protein Phosphatases by Vanadium

Compounds
Studies carried out with a variety of complexes
show that most V-compounds are potent inhibitors
of PTPases.174,277 Lower inhibition is generally observed for the serine/threonine protein phosphatases,
which accept serine and threonine phosphate esters
as substrates, as compared to the inhibition of
tyrosine protein phosphatases.13 Exceptions have
been reported, and there are examples of protein
phosphatases other than PTPases that are potently
inhibited by vanadate and V-compounds.278 The effects of a range of different classes of V-compounds
have been investigated including V(V)174,277,313-317 and

Figure 7. The active site residues in the glutathione-Stransferase fusion protein of domain 1 of pp1B obtained
by NMR studies and modeling studies with a N,N-dimethylhydroxylamine derivative placed in the active site. Redrawn from ref 316. Copyright 1998 The Society of Biological Inorganic Chemistry.

V(IV)318 coordination compounds, peroxovanadium

compounds,174,277,295,314,318,319 hydroxylamidovanadium
compounds,313,315-317 and simple salts.314,318 Some of
these complexes19 are more potent phosphatase inhibitors than the simple V(V) salt whereas others are
less potent.316 A few V-complexes have no inhibitory
activity but may be inhibitors if actually examined
under assay conditions where they remain intact.277
In addition, a variety of studies have been carried
out in which the inhibitory effects of these compounds
have been measured by indirect means.13,177,277,318,320-322
The active site cysteine nucleophile of many protein
phosphatases introduces the possibility that redox
chemistry can occur between the phosphatase thiol
group and a V(V)-compound. Two lines of evidence
have been provided that explore this issue. A study
was carried out in which the nature of the interaction
of vanadate with two protein phosphatases, CD45
and ppB1, was studied using mass spectrometry.319
Both vanadate and peroxovanadate inhibited these
phosphatases, but the mass spectrum of the inhibited
protein showed that only peroxovanadate irreversibly
modified both protein phosphatases.319 Since vanadate fails to oxidize these phosphatases, V(IV)complexes are also not likely to interact reversibly
with these proteins. This interpretation was confirmed in studies with pp1B.318 Kinetic evidence is
available for the isoelectronic analogue of the peroxovanadium compounds, the hydroxylamido oxovanadium complexes.316 Both leucocyte antigen related protein tyrosine phosphatase (LAR) and pp1B
were found to be reversibly inhibited by the N,Ndimethylhydroxylamido V(V)-complex,316,317 showing
a significant difference between how these compounds act and how the corresponding peroxovanadium(V) compounds act. Modeling studies suggest
that the R group on the hydroxylamine complex is
pointing out of the active site pocket, and explains
why structural variation is possible in the R group
(Figure 7).316 Other possible adducts that can form
with, for example, thiolate groups313,315 will also be

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 865

Figure 8. Correlation between kcat and kcat/Km of vanadate

with a series of mutants. Reproduced from ref 283. Copyright 2002 American Chemical Society.

inhibitory. The effects of V-compounds on signaling

cascades reflect a synergy between the initiation of
signals by PTKs and the loss of control by PTPs and
may be attributed to redox-linked activation of key
PTKs.314,323 In addition to the well-known effect of
V-compounds as transition state analogues, some
V-complexes can also participate in the redox regulation of protein phosphatases.324
Projecting from the known redox chemistry of
V-compounds, in general, few V-compounds will be
able to oxidize the protein phosphatases under physiological conditions. Indeed, reports demonstrate that
significant differences are observed when the simple
complexes, oxodiperoxo(1,10-phenanthroline)vanadium(V) (pV(phen)) and bis(maltolato)-oxovanadium(IV) [(VO(malto)2] or BMOV), were metabolized
after addition to Jurkat cells.318 The effects of the
latter complex are currently of great interest since
[VO(malto)2] and the closely related ethyl derivative
are currently undergoing evaluation for consideration
as therapeutic antidiabetic agents.325
The possibility that vanadate was a perfect transition state analogue for Yersinia PTPase was investigated using various mutants of the active site
(T410A, D356N, W354A, R409K, and D356A).283 To
be a perfect transition state for this PTPase, the
affinity for the analogue has to exceed that of the
substrate by 1010- to 1011-fold, and the apparent
dissociation constant for the Yersinia is almost 4
orders of magnitude less than this. In addition, the
steady-state parameters for wild type and mutants
failed to follow the linear trend predicted for a true
transition state analogue (Figure 8). Furthermore,
the bond orders of vanadate complexes investigated
by Raman spectroscopy did not follow the predicted
trend. The possibility that phenoxyl vanadate may
be a better transition state analogue for the phosphoenzyme and that local structural changes in the
active site exist cannot be ruled out and could explain
some of the apparent failure to adhere to the predictions.
Studies have been carried out between a small
active site pp1B peptide (VHCSAG-NH2) and V(IV)
to model the interactions between pp1B and VO2+
(Figure 9). Complexes were observed with the active
site cysteine (51) and the active site histidine (52)

Figure 9. The EPR studies of the complexes formed

between the pp1B model peptide (VHCSAG-NH2) and
V(IV). Reprinted with permission from ref 326. Copyright
1995 American Chemical Society.

residues, respectively.326 The histidine complex is

favored at a pH slightly below neutral and the
cysteine complex is favored at a pH slightly above
neutral. At neutral pH both complexes form (Figure
9). Since this peptide is conserved across the PTP
family of proteins, this study documents that both
complexes are competent to form326 and is consistent
with the wide range observed for other peptides when
complexing to V(IV).33,300,301

Inhibition of protein phosphatases are likely to be

important to the insulin-like action of V-compounds.177,318,327-330 In addition, other biological processes that these compounds affect which are likely
to involve effects on protein phosphatases include osteoporosis,312,331-334 apoptosis,335-341 and cancer.336,338,342 The specifics with regard to which phosphatase and the level of inhibition required remain
to be elucidated.

4.1.5. Inhibition of Purple Acid Phosphatases by

Vanadium Compounds
The purple acid phosphatases belong to a family
of phosphatases containing a dinuclear metal center,
and a metal-bound hydroxide has been invoked as
the active site nucleophile in the catalytic mech-

866 Chemical Reviews, 2004, Vol. 104, No. 2

anism.343-345 Alkaline phosphatase and some acid

phosphatases also contain two metal ions, the former
containing two zinc(II) ions and the latter containing
two Fe, one Fe, and one Zn(II), or one Fe and one
Mn(II).345,346 The purple acid phosphatases, which
contain a redox active metal ion, can exhibit yet a
different mode of inhibition by vanadate. Uteroferrin
is potently inhibited by vanadate, although two types
of interactions were observed, one of which describes
vanadate as being a slow binding inhibitor.347 Recently, the initial rates of reaction with a series of
oxometalate anions with uteroferrin using stop flow
techniques were investigated.348 Little difference was
found among reactions with molybdate, tungstate,
and vanadate despite the known differences in lability among these anions. The authors modified the
existing mechanism of phosphate ester hydrolysis by
suggesting that a step other than the one involving
attack on the substituting anion as being ratelimiting.348 Related oxoanions such as arsenate, molybdate, and tungstate have been investigated in
detail using X-ray diffraction, spectroscopic, and
enzymatic methods, and have been found to bind in
the active site and in some cases bridge the dinuclear
metal ions.343,345 Model studies have been carried out
on this system although few included investigations
with vanadium.349 Recently, the ability of the purple
acid phosphatase to act as a haloperoxidase has been
demonstrated.350
Purple acid phosphatase, calceneurin, alkaline
phosphatase, and bacteriophage protein phosphatase all contain two metal ions important for
catalysis. Interestingly, vanadate is a poor inhibitor
of calceneurin,351 but a potent inhibitor of alkaline
phosphatase,274,308 purple acid phosphatase,347,348 and
bacteriophage protein phosphatase.278 These studies
demonstrate that the bimetallic phosphatases exhibit
a range of responses when exposed to oxometalates.

Crans et al.

V(V)-complexes have successfully generated several

types of complexes (13, 14, 57, 58). The Schiff-base
ligands as well as related ligands have been found
to be excellent in stabilizing the vanadium
atom.98,99,355-362 In these complexes, the geometries
are distorted trigonal-bipyramidal (55, 57)355,363 and
square-pyramidal (58).364 The Schiff-base ligands
were also used to structurally characterize and
investigate different classes of vanadate ester bonds
and the corresponding protonated vanadate ester
bonds.98,99,355-359,361,362,365 The structure, redox properties and reactivity of these complexes are often
investigated, and the supporting ligand is found to
fine-tune the properties of the OdV-O, OdV-OR,
and OdV-O(H)R units.
The number of crystallographically characterized
pure trisalkoxide parent systems (12, 16, 56)89,92,95
is much lower than the number of systems characterized using stabilizing ligands (13-15, 53-55, 57, 58)
of which many novel compounds are not specifically
shown here.98,99,355-362,365-367 This testifies as to how
critical the supporting ligand is to the properties of
these systems and how such a ligand provides
structural precedence for biologically relevant chemistry.

4.1.6. Phosphatase and Other Phosphorylase Inhibition

by Oxometalates
Vanadium-containing oxometalates have shown
affinity for selected phosphatases such as the Leishmania phosphatase.352 A variety of phosphorylases
are inhibited by oxometalates; examples include the
rabbit skeletal muscle phosphorylase that has been
found to be inhibited by decavanadate, decamolybdate, and decatungstate353 and ribonuclease by decavanadate.354

4.1.7. Structural Models of the Transition State of

Phosphate Ester Hydrolysis
Monomeric complexes containing five-coordinate
vanadium have been targets of bioinorganic chemists
for several years. This is primarily because of the
potent inhibitory effects of vanadate on the ribonuclease and phosphatase reactions. Although the first
complexes 53, 54 were dimeric, a variety of monomeric (15, 16, 55) and dimeric (56) complexes have
been prepared, and new examples continue to be
reported (12, 57, 58). Although pure trisalkoxides
generally dimerize and thus prefer to be fivecoordinate (16, 53, 56), the use of various types of
supporting ligands to prepare and study mononuclear

4.2. Ribonuclease
Ribonucleases are enzymes that catalyze the cleavage of RNA as shown in a simplified manner in
Scheme 6.368 If the cleavage reaction occurs in the
middle of an RNA chain, the ribonuclease is classified
as an endonuclease, and if the cleavage occurs at the
end of the RNA chain it is classified as an exonuclease. Depending on the type of ribonuclease (A or
T1 for example), the RNA cleavage will be specific for

Chemistry and Biochemistry of Vanadium

Scheme 6. The Ribonuclease A Catalyzed
Hydrolysis of an RNA Chain Simplified to Two
Steps

a pyrimidine or purine base. In the first step of the

reaction, a free 5-hydroxyl group is formed on one
RNA chain, and a 2,3-cyclic phosphate is formed on
the other. In the second step of the reaction, the cyclic
phosphate is opened by the reaction with a water
molecule generating a 3-phosphate end on the second
RNA chain. Vanadate, vanadyl cation, and their
respective complexes potently inhibit hydrolysis of
the phosphodiester in RNA and DNA. Vanadiumnucleoside complexes are well-known inhibitors of
ribonuclease catalysis having been first reported by
Lienhard and co-workers in 1973.369 The inhibitory
V(IV)-nucleoside complex of ribonuclease was first
prepared in situ.370 For a few years, vanadate was
the reagent used to prevent ribonuclease cleaving
RNA in cellular isolations of RNA until more potent
agents were discovered.369,371,372

4.2.1. Structural Characterization of Model Compounds for

Inhibitors of Ribonuclease
Early structural studies of the protein-V-complex
suggested a five-coordinate vanadium atom mimicking the transition state of RNA hydrolysis, Figure
10:373,374 however, later studies reported an anion
bound in the active site as a four-coordinate groundstate analogue.375 The report of the ground-state
vanadate bound in the active site of ribonuclease375
did not decrease efforts on designing and characterizing model systems of the potent inhibitory V-

Figure 10. The vanadate-ribonuclease complex showing

the five-coordinate vanadate-nucleoside bound in the active
site of the protein. Reproduced with permission from ref
112. Copyright 1997 International Union of Crystallography (http://journals.iucr.org/).

Chemical Reviews, 2004, Vol. 104, No. 2 867

complex. The investigators recognized the fact that

the ribonuclease binding vanadate as a ground-state
analogue did not rule out the binding of a transition
state analogue to ribonuclease. The most recent
vanadate-nucleoside investigation reported contained a five-coordinate vanadate-nucleoside shown
in Figure 10.112
Investigations into the structure of the V-transition
state analogue of the ribonuclease reaction have
unraveled many of the coordinational preferences of
vanadium alkoxides and related compounds in general (see above and below), and should be useful in
probing the mechanism of V2O5-P2O5 catalytic conversions of organic substrates. Pinacol was the 1,2diol used in the first structurally characterized model
system and the VO2 unit was replaced by a VOCl unit
(53).87 Another model system that contained a VO2
unit was used and the diol system was substituted
with an R-carboxylic acid (54).376 Several other model
systems were also reported showing that mononuclear complexes with five-coordinate V(V) are very
stable once a properly designed stabilizing ligand has
been used (55, 57, 58).355,363,364 In 1995, the problem
of disorder in the vanadate-adenosine crystals was
overcome, and the X-ray structure of the dinuclear
complex was reported (56).377 All the model studies
can be summarized as follows: the vanadium atom
favors a five-coordinate transition state structure
and is likely to bind tightly to ribonuclease, with
either ribonuclease or an external ligand such as
water being the fifth ligand around the vanadium
atom.

4.2.2. Characterization of the Nucleoside-Vanadate

Complexes that Form in Solution and Inhibit
Ribonuclease
Investigations into the structure and formation of
the complexes that form in solution between vanadate and nucleosides have continued for more than
a decade. The initial studies were carried out using
51V NMR spectroscopy and correctly identified the
major species as a 2:2 complex.106 Due to an initial
controversy with regard to identification of the major
complexes in solution and the need to determine
precisely what the concentration of the 1:1 species
was, many studies focused on the speciation of these
systems.102,106,378-381 Identification and quantification
of the 1:1 species that was actually bound to ribonuclease was not trivial379-381 since even under conditions in which this species can be observed, the 51V
NMR signal of the 1:1 species overlaps with that of
the 2:2 species.
Structural studies characterizing the geometry of
the 2:2 species existing in solution were also controversial with several options under consideration (59,
60, 61, 62, 63). Spectroscopic,307,382,383 theoretical,96,384
and solid-state model studies87,355,363,364,376,377 were key
in confirming that the vanadium atom was fivecoordinate.307,383 Although this ruled out suggestions
of four- and six-coordinate derivatives, three fivecoordinate structures remained. The specific structure of the solution complexes were investigated
using 1H, 13C, 51V, and 17O NMR spectroscopy,102,307,377,379-381,383 IR spectroscopy,307 Raman spec-

868 Chemical Reviews, 2004, Vol. 104, No. 2

troscopy,307 UV-visible spectroscopy,307,382 circular

dichroism,382 magnetic circular dichroism,382 potentiometry,102,381 and stereochemical considerations.307,383
By 1H NMR spectroscopy, the major 2:2 uridine
complex could be identified in solution (63).307,383
Minor, but structurally similar with respect to ligand
coordination, species exist and can undergo exchange
to form the one major complex in aqueous solution;
in the case of adenosine, the kinetics are less conducive for observation, and low-temperature studies are
necessary to reach the analogous conclusion for this
system.

4.2.3. Vanadium-Nucleoside Complexes: Functional

Inhibitors of Ribonuclease
The concept of transition analogues for this system
was recognized early on in a seminal study by
Lienhard and co-workers369 who documented the
inhibition of ribonuclease A with a mixture of vanadate and uracil. In these studies, the inhibition was
illustrated using both V(IV) and V(V) precursors and
thus suggesting that both V(IV)- and V(V)-complexes
are potent inhibitors of ribonuclease. Originally the
V(IV)-nucleoside inhibitor complex was prepared in
situ;370 however, at neutral pH any free V(IV) will
oxidize to V(V), which can form a complex with free
nucleosides and generate a second inhibitor complex.
Biochemical investigations were undertaken to define
the structure of the enzyme and the binding of the
vanadium-nucleoside complex.373,374,385,386 Initial structural studies of the V-protein complex were also
reported;373,374 however, the initial structures were
based on a low occupancy of the vanadate-nucleoside
adduct in the active site, and coordinates were never
deposited in the Protein Data Bank. Recently, the
structure of the five-coordinate vanadate-nucleoside
complex inside the ribonuclease was elucidated and
coordinates are now available.112,387
How good a transition state analogue the vanadate-nucleoside complex is depends on whether one
expects it to be perfect. If the RNA hydrolysis
reaction strictly requires that the transition state
have truly trigonal-bipyramidal vanadium geometry, then the vanadium-nucleoside complex will not
be a perfect transition state analogue. Indeed, neither
the model structures nor the vanadate-adenosine
structure (56) contains a complex with a vanadium
atom in a purely trigonal-bipyramidal geometry.
Furthermore, a theoretical investigation examining
the electronic properties of V-O and P-O bonds
found that dramatic differences exist with regard to
bond polarities suggesting that the electronic analogy

Crans et al.

is not ideal either.384 From the point of view of

inorganic chemistry, one would thus not anticipate
vanadate or vanadate derivatives to be perfect transition state analogues.
A reinvestigation of the inhibition constants for
binding of the vanadate-uridine complex to ribonuclease A resulted in a submicromolar binding constant49 that was 100-fold less than originally reported.369 Using these data to calculate a binding
energy, only about 40% of that expected, based on a
perfect trigonal-bipyramidal transition state geometry, was obtained.49 Recently, the potency of the
vanadate-nucleoside complex was investigated with
several mutants of ribonuclease and these investigators confirmed the conclusion that the vanadiumnucleoside is not a true and perfect transition
analogue.50 Although small structural differences
existing in the mutants were not considered, which
could diminish the observed potency of the vanadate-nucleoside complex as an inhibitor, the fact
that vanadate-nucleosides are likely to be potent,
but not perfect, transition state analogues is likely
to be confirmed. Indeed, considerations regarding
what types of phosphorylase reactions V-complexes
may be most effective against have been extensively
considered.307,388
Of the large number of ribonuclease transition
state analogues or model compounds reported, most
are based on some type of V-complex. Recently, a
rhenium-based complex was reported,389 and documented that other transition metal ions could also
be used as transition state analogues. However, these
compounds had 10-100 micromolar inhibition constants389 and thus showed poorer affinity for ribonuclease compared to that of the vanadium-nucleoside
complexes. Although the pendulum has swung from
describing the vanadium-nucleoside analogue as a
potent inhibitor of ribonuclease to a poor transition
state analogue, it remains to be seen if any other
inhibitors can withstand this level of scrutiny. From
our point of view any complex that produces half of
what would be theoretically expected is a good
transition state analogue.

4.3. Other Phosphorylases

Many examples of applications of vanadate as a
general inhibitor of phosphorylases other than phosphatases and ribonuclease exist and go beyond the
scope of this review. Briefly, the enzymes catalyzing
the hydrolysis of a phosphoester bond on a substrate
containing one phosphoester bond are formally categorized as phosphomonoesterases and are referred
to as phosphatases. When the substrate contains one
ester bond and one phosphoranhydride bond, the
enzymes are referred to as ribonucleases. For substrates that contain two phosphoester bonds, it is a
diphosphoesterase. If the enzyme catalyzes the transfer of a phosphate group from one hydroxyl in a
substrate to another hydroxyl group the enzyme is
referred to as a phosphomutase. Recent developments
will briefly be highlighted here for the enzymes
classified as phosphodiesterases and phosphomutases.
Tyrosyl-DNA phosphodiesterase is a member of the
phospholipase D superfamily. It functions as a DNA

Chemistry and Biochemistry of Vanadium

repair enzyme by hydrolyzing the bond between a

tyrosine side chain and a DNA 3-phosphate.114,390
This enzyme will facilitate the removal of stalled
topoisomerase I-DNA complexes from the DNA strand.
Despite the complexity of this enzyme system, when
vanadate was used as a substrate, a quaternary
complex could be structurally characterized. This
phosphodiesterase linked human tyrosyl-DNA phosphodiesterase, a tyrosine-containing peptide, and a
single-stranded DNA oligonucleotide into a quaternary complex that mimics the transition state for the
first step of the catalytic reaction containing a fivecoordinate vanadium.114,390 The V-complex has a
trigonal-bipyramidal geometry, whereas the corresponding tungstate complex shows a six-coordinate
metal ion geometry.114
The crystal structure of the semi-reduced form of
a cyclic nucleotide phosphodiesterase from Arabidopsis thaliana has been solved by molecular replacement and refined at a resolution of 1.8 .391 The cyclic
nucleotide phosphoesterase converts an ADP-ribose
to a 1,2-cyclic phosphate. The crystal structure of
the native form of this enzyme contains six cysteine
residues, four of which are involved in forming two
intramolecular disulfide bridges. The bridge between
Cys-104 and Cys-110 is opened in the semi-reduced
enzyme while the other bridge remains intact; the
semi-reduced state of this enzyme was cocrystallized
with the inhibitor 2,3,-cyclic uridine vanadate. The
ligand is bound within the active site, and the mode
of binding is in agreement with the previously
proposed enzymatic mechanism involving a trigonalbipyramidal vanadium atom.391
The effects of vanadate on phosphoglucomutase
have been investigated in detail. Phosphoglucomutase catalyzes the conversion of glucose-6-phosphate
to fructose-6-phosphate, and the dephosphoform is
potently inhibited by glucose-6-phosphate and glucose1-phosphate in the presence of vanadate.392 The
inhibition is attributed to the formation of 1-phosphoglucose-6-vanadate and 1-vanadofructose-6-phosphate, which forms a stable complex with the protein.
The inhibition constant for 1-phosphoglucose-6-vanadate at pH 7.4 was determined from steady-state
kinetic measurements to be 2 10-12 M.393 Calculations of the binding energy of the vanadate complex
in phosphoglucomutase revealed an excess of binding
energy, over the analogous phosphate derivative, of
about 25 kJ/mol and represents about 40% of that
expected to be available for a trigonal-bipyramidal
transition state.49
The effects of vanadate on phosphoglycerate mutase have also been studied. Equilibrium constants
for the formation of the two 2,3-bisphosphate analogues were estimated as 2.5 M-1 for 2-vanadio-3phosphoglycerate and 0.2 M-1 for 2-phospho-3vanadioglycerate.394 The results of the binding study
were fully consistent with noncooperative binding of
vanadiophosphoglycerate to the two active sites of
phosphoglycerate mutase. 2-Vanadio-3-phosphoglycerate was found to bind to the dephospho form of
phosphoglycerate mutase with a dissociation constant
of approximately 1 10-11 M at pH 7 and 7 10-11
M at pH 8.394 The two forms of phosphoglycerate

Chemical Reviews, 2004, Vol. 104, No. 2 869

mutase present in mammals, the 2,3-phosphoglycerate-dependent and 2,3-phosphoglycerate-independent forms, show differential affinities for vanadate
with the cofactor dependent form responding most
potently to vanadate.395 Cofactor-independent forms
of phosphoglycerate mutases are not inhibited by
vanadate at the 0.1 mM level, whereas the reversible
competitive inhibition yields an apparent Ki value of
15 nM for the cofactor-dependent phosphoglycerate
mutase from E. coli. The structure of E. coli cofactordependent phosphoglycerate mutase, complexed with
vanadate, has been determined to a resolution of 1.30
.396 Vanadate is bound in the active site, principally
as a vanadate trimer and not as monomeric vanadate
as reported previously.120,397 These phosphomutases
systems, like those of ribonucleases, provide ample
evidence for the applications of vanadate derivatives
in enzymology. Some mechanistic investigations in
these systems are at a level of detail analyzing the
minor differences between a vanadate-protein complex and that of the true transition state complex of
phosphoglucomutase.

4.4. ATPases
ATPases hydrolyze phosphate-anhydride bonds
and have many important roles in biology in cellular
energy metabolism. Since there are many different types of ATPases, a wide range of affinities for vanadate can be anticipated and are
observed.2,6,12,60,398,399 The effect of vanadate on some
ATPases is very dramatic with a nanomolar inhibition constant having been reported for the Na+, K+
ATPases, compared to the millimolar inhibition
constants for F1-ATPases.398 The ATPase enzymes
include many membrane enzymes, and although
many details are known with regard to the biochemical mechanisms of some ATPases, inhibitory studies
assume that vanadate acts as a phosphate analogue
and presumably inhibits the enzymes as a transition
state analogue for the phosphoryl group transfer.400-402
Information on the formation of stable protein-ViMgADP complexes similar to the protein-Pi-ADP
transition state has been described in detail elsewhere.60 Often transport inhibition in the presence
of vanadate is interpreted as an effect on an ATPase
and is used as a test of how a biological system
responds to an ATPase inhibitor.400-402 The reader
is referred to the general literature and reviews
articles for more information on this topic.2,6,12,60,399

4.4.1. Structural Precedence for the Vanadate-Phosphate

Anhydride Unit: Five- or Six-Coordinate Vanadium
Heteronuclear adducts of vanadate with phosphate
(22, 64, 65) have been studied extensively and have
a greater number of applications in biology as would
be anticipated for substrate analogues for ATPases.
The vanadate-phosphate or vanadyl-phosphate bond
is also of interest in industry since successful catalysts for the large scale preparation of maleic anhydride use V2O5 mixed with a phosphorus-oxide catalyst.403,404 Although few model studies have focused
on this unit, structural characterization exists for a
range of materials that contain a moiety that can be
classified as a vanadate-phosphate anhydride (22,

870 Chemical Reviews, 2004, Vol. 104, No. 2

64, 65). When the vanadium has a coordination

number of four (VO4), the (O)3POVO3 unit results
(22). For vanadium with a coordination number of
five (VO5), the (O)3POVO4 unit results (64, 67).405-408
If the vanadium has a coordination number of six
(VO6) the (O)3POVO5 unit results (66, 68).409-412 An
isolated O3POVO3 unit (22) has not yet been reported;
however, it has been observed as part of simple
complexes,408,413,414 larger clusters,406,407,409,410,415 and
polymeric materials.405,411,416 Many of these materials
were prepared by hydrothermal synthesis, but others
were prepared using more common synthetic approaches, and a number of these systems have been
structurally characterized. Three representative structures are shown (66),411 (67),408 and (68)410 to illustrate the diversity of these complexes, clusters,
and polymeric materials in which this type of moiety
has been reported.

In the smaller V-P containing complexes, the

anhydride unit is supported by an amine ligand413,414
or a hydroxyl ligand (67),408 and in all these cases
the two vanadium atoms are joined through a {(OV)2(-O)2} diamond core motif (53, 54), common in
dinuclear vanadium alkoxide structures. Significant
structural deviations from the bonding for the anticipated simple vanadate-phosphate anhydride system (22) are found in all these complexes.405-412 Since
the vanadium engages in additional bonding, the O3POVO4 unit (64) and the O3POVO5 unit (65) are those
observed. In one case, an amine served to stabilize
the polar vanadate-phosphate clusters within a
polymer.416 In general, these structures support a
VdO group; however, one example showed a complex
with six V-O bonds.415 These types of non-VdO
complexes are rare among high oxidation state Vcompounds and are typically seen only in systems
with highly stabilizing ligands. In some of the
systems, an anhydride linkage is protonated (66, 68).
The proton usually resides on an O atom coordinated
to two V atoms,410,411 although two cases were reported with the proton on a phosphate O atom.412,416
The fact that the O3POVO3 unit was observed in
20 different structures, and the (O)POV(O) unit was
observed in 42 structures testifies to the interest in
materials containing these types of moieties and their
bonding patterns. Interestingly, none of these studies
were carried out because of the importance of the
vanadate-phosphate anhydride in biology.

Crans et al.

4.4.2. Vanadate as a Photocleavage Agent for ATPases

In addition to the biological applications of vanadate to probe ATPases, one area of biomimetic
chemistry of great interest to the bioinorganic chemist is the vanadate-induced photolytic cleavage of
V-protein complexes. The initial studies were carried
out with dynein and myosin, which are ATPases
providing energy for intracellular transport and
found to cleave at one specific amino acid when
exposed to UV light.7,417-419 This finding was particularly remarkable considering dynein is comprised
of two or three heavy chains each of 428 kDa
(referred to as R, , and chains), three medium
chains at 70-120 kDa, and approximately four light
chains of 15-25 kDa to give a total of about 1500
kDa.420 Since this early discovery, the photolytic
cleavage of dynein, myosin, and adenosine kinase has
been extensively studied, providing information on
the phosphate-vanadate binding site in the presence
of free or bound nucleotides.7,418,419,421
The oligomeric form of vanadate was found to affect
the site of the photocleavage. In the initial study with
dynein, photocleavage occurs with a t1/2 of about 7
min at the major cleavage site, the V1 site, resulting
in fragments of 200 and 228 kDa. Upon closer
scrutiny some nonspecific cleavage was found, however, increasing the wavelength from 254 to 365 nm
results in cleavage only at the V1 site. Increasing the
wavelength to above 400 nm resulted in no observable cleavage since vanadate no longer absorbs light
at those wavelengths.422 The presence of Cr2+, Mn2+,
Fe2+, or Co2+ also prevents photocleavage and is
interpreted to mean that these metal ions bind close
to the vanadate binding site.422 Detailed mechanistic
studies have investigated the cleavage products and
found the cleaved peptide is in the phosphate binding
loop with the sequence G-X1-X2-X3-X4-G-K-G/T
where X2 corresponds to the amino acid cleaved.423,424
Homologous sequences for ATP binding proteins have
shown that different amino acids occupy the cleavage
site: an alanine in dynein and ATP synthase, a
serine in myosin, a proline in adenylate kinase, and
an arginine in R ATP synthase.417,424-426 Interestingly,
it is the location of the amino acid that determines
the cleavage and not the nature of the amino acid.
Adding 0.05-0.1 mM vanadate to the dynein heavy
chains427 or the S1 fragment of myosin421 results in
photocleavage at two distinct sites independent of
ADP concentration. These sites include the V1 and
V2 sites on dynein. The V2 site can also be accessed
by binding Vi-Co2+ATP or Vi-Mn2+ATP which quenches
cleavage at the V1 site.427 On the basis of EPR studies
showing that in the presence of tris buffer photocleavage is proportional to the development of an
EPR signal, it is believed that the process involves
formation of a V(IV) species.421,427 The studies suggested that an oligomeric species is responsible for
this reaction, and both a trinuclear427,428 and tetranuclear V(V) species have been implicated.421 Since
51V NMR studies have shown that the tetramer binds
most strongly to myosin421 and tetramer is present
in higher concentrations in solution, this is the
species most likely responsible for this cleavage
product. Photocatalyzed cleavage of dynein by Fe(III)

Chemistry and Biochemistry of Vanadium

and Rh(III) resulted in different cleavage products,429

consistent with the increasing number of reports of
metal complexes that are competent to cleave peptides.430
The recent applications of photoinduced cleavage
by vanadate/vanadate-nucleotides continue to be
very successful in studies of very complex protein
systems. Here we describe studies with the F1 ATP
synthase that probe the chemical mechanism by
which F1 ATP synthases catalyze the synthesis of
ATP using vanadate and provide critical information
on the conformation at the catalytic site of each
-subunit in the transition state. The MgADP-V-F1
complex was formed in the presence of Mg2+, ADP,
vanadate, and protein.431 Using the photoreactivity
of the trigonal-bipyramidal analogue at the -P of
ATP-site in the presence of UV light and O2 the
MgADP-V-F1 complex was cleaved within the P-loop
(GGAGVGKT) of a single -subunit at Ala158. These
results implicate Ala158 to be near the -P of ATP in
the transition state. ADP, although facilitating transition state formation, is not essential for the reaction
and cleavage was also observed at Ala158.432 These
findings indicate that Mg2+ plays a pivotal role in
transition state formation during ATP synthesis
catalyzed by ATP synthases, a role that involves both
its preferential coordination with phosphate and the
repositioning of the P-loop to bring the nonpolar
Ala158 into the catalytic pocket.432 Other applications
of the vanadate-induced photolytic cleavage include
protein systems such as the ATP-binding cassette
(ABC) transporter,433 the human P-glycoprotein,434
other ATPases,435 as well as continuing work on
myosin.436-438 The readers are referred to the current
literature for more information on this topic.

Chemical Reviews, 2004, Vol. 104, No. 2 871

of this ligand are the hydroxylamido and carboxylate

groups (69). The Amanita mushrooms are among the
few organisms in the biosphere that accumulate high
levels of vanadium (see also the sections on tunicates
and the polychaete worm). Common plants and
animals that have absorbed vanadium-rich fluids or
food will accumulate high levels of vanadium, but
these organisms, in contrast to Amanita mushrooms
and tunicates, do not biosynthesize a vanadiumcontaining natural product. The recent investigations
into molybdenum, niobium, and other metal complexes have shown the amavadine ligand to form
complexes with these metal ions; structural and
chemical properties similar to the amavadine complex are observed.441-444 More information on the
properties of these complexes is needed to evaluate
if the H3hidpa ligand is specific for vanadium accumulation only, or whether other abundant metal
ions such as molybdenum and iron are sequestered
by this ligand. There is, however, no doubt that if
vanadium is to be effectively accumulated by an
organism, a mechanism for chelating V(IV) must be
in place. At neutral pH, V(IV) generates a variety of
insoluble hydroxides as described above and generally makes the V(IV) unavailable unless a chelating
agent solubilizes the metal ion.

5. Amavadine and Siderophores

Many types of ligands that exist in nature are
capable of sequestering vanadium. Most of these
chelating agents, commonly referred to as siderophores, are primarily produced to bind other metal
ions, such as iron.439 Iron bioavailability is controlled
by these siderophores which can solubilize environmental iron hydroxides. Siderophores commonly are
formed in bacteria, microorganisms, aquatic plants,
and yeast, and it is their role to transport metal ions
into and out of cells depending on the cellular need.
However, such siderophores are not the exclusive
chelating agents that are produced in biology and one
chelating agent of particular interest is the ligand
S,S-2,2-hydroxyiminodipropionic acid (H3hidpa) (69)
found in the natural product amavadine (70), which
is produced in some species of the mushroom genus
Amanita.7,440

5.1. Amavadine
Amavadine is a metal complex that contains two
equivalents of ligand and one equivalent of vanadium. The H3hidpa ligand binds V(IV) to form amavadine ([V(hidpa)2]2-) (70),7,440 which is currently the
only documented siderophore-like ligand that binds
vanadium with greater affinity than any other metal
ion (log K2 ) 23).57 The coordinating functionalities

5.1.1. Amavadine: Structure

The discovery of high levels of vanadium from the
mushroom Amanita muscaria was first made in
1931,445 but it was not until 1972 that the natural
product was first isolated by Bayer and Kneifel.446
Since then studies have taken place with regard to
investigating the structure of the natural
product,447-451 determining the products properties
and role,448-455 identifying new species where this
derivative is formed,456,457 examining its biology,456,457
and recently, investigating the properties of other
metal complexes441-444 with H3hidpa (69).
The structural elucidation of amavadine was initially controversial because the V(IV) is in an unusual
dodecahedral geometry (70) which at the time of the
isolation of amavadine was unprecedented. Accordingly, in the initial report in which the organic ligand
was identified, an alternative structure (71) was
proposed in which amavadine contained a squarepyramidal oxovanadium(IV) chelated to two ,-Nhydroxyimino-R,R-dipropionic acid (H3hidpa) moieties (69).446,448 This proposed structure was based
on the known coordination chemistry of V(IV), an

872 Chemical Reviews, 2004, Vol. 104, No. 2

Crans et al.

types of amavadine crystals isolated from Am. muscaria have been grown in the presence of phosphoric
acid and Ca2+ ions, respectively (Figure 11).467 These
structures were solved and not only confirmed the
proposed structure but also documented the chirality
of the amavadine structure both in the neutral and
in the anionic form. Amavadine possesses five chiral
centers: four chiral carbons all have S configuration
and the fifth chiral center is generated by the manner
in which the ligands wrap around the vanadium.
Spectroscopic studies have shown that as isolated,
the natural product contains equal amounts of the
and the forms of amavadine.451 The crystal
structure of the vanadium(IV) complex of meso-2,2(hydroxyimino)dibutyric acid (76) was found to have
similar structural features.58
Figure 11. ORTEP view of a portion of the lattice of [Ca(H2O)5][-V((S,S)-hidpa)2]2H2O. Reproduced with permission from ref 467. Copyright 1999 Wiley-VCH.

axial EPR spectrum consistent with this type of

geometry and an absorbance in the IR spectrum at
980 cm-1 assigned as a VdO stretching frequency.
However, as synthetic model compounds449-451 and
the total synthesis of the natural product were
reported,447 data on this class of compounds began
to accumulate which was inconsistent with the
initially proposed structure.
Specifically, the much greater formation constant
of this complex did not compare well with other
square pyramidal VdO containing complexes with
aminocarboxylate ligands;452 amavadine remains one
of the more stable V-complexes. Comparing the
stability of the V(IV) amavadine complex with V(IV)
complexes of iminodipropionic acid (72) and Nhydroxyiminodipropionic acid (69) showed that the
NOH group was necessary to achieve this dramatic
stability increase. If the NOH group were needed for
high stability (log 2 ) 23),448,452,458 it is likely that it
would be directly coordinated to the metal ion.
Furthermore, the N-hydroxyiminodiacetic acid V(IV)
complex 73 did not contain the 980 cm-1 IR band that
was present in the N-hydroxyiminodipropionic acid
complex; this led to speculation that perhaps no VdO
group was present in the natural product. In addition, large-angle X-ray scattering experiments indicated that there were no V-O bond lengths less than
1.9 ,448 which might have indicated the presence of
a VdO bond (ca. 1.57-1.65 ). Finally, the Wieghardt459
(74) and Saussine groups460 (75) reported studies
with simple hydroxylamine complexes and their
proposal of side-on binding of the hydroxylamine
functionality to the vanadium was supported by
X-ray studies on these simple systems. These facts
led Bayer and co-workers to question the validity of
their original structural proposal and they revised
it in 1987.448 These studies led to the discovery of a
series of V-complexes referred to as nonoxo Vcomplexes with a variety of different types of
ligands.461-466
The structural studies were confirmed a few years
later when the crystal structures for the model
complexes bis(N-hydroxyiminodiacetate)vanadate(IV)
(73)449,450 and bis(S,S-2,2-hydroxyiminodipropionate)vanadate(IV) (70)451 were reported. Since then two

5.1.2. Amavadine: Activities and Roles

Amavadines great hydrolytic stability is accompanied by its reversible one-electron redox properties
that have been linked to its possible role in biology
as a one-electron redox mediator. The structural
properties of the complex are such that very little
structural reorganization of the vanadium coordination environment is necessary during the electrontransfer process. However, the one-electron redox
couple [V(V)/V(IV)] is very sensitive to solvent. These
dramatic solvent differences have been attributed to
solvent interaction with some free carboxylate groups
and thus explain why with a Pt electrode in water,
the potential is +0.53 V (vs SCE) and in dmso the
potential drops to +0.03 V (vs SCE).453 Whether
amavadine reacts via an inner or outer sphere
mechanism remains to be determined. The original
studies, assuming a square-pyramidal complex,
proposed an inner-sphere mechanism with the highly
exchange-labile axial position in square-pyramidal
complexes.458 Current structural information suggests 0.08, 0.067, and 0.019 changes in the V-O
(carboxylate), V-O (hydroxylamide), and V-N (hydroxylamide) bond lengths, respectively,449-451 between the V(IV)- and V(V)-complexes, which are
minor changes in complex geometry and are consistent with an outer sphere mechanism. In addition,
the complex appears to be hydrolytically intact (vide
infra). Accordingly, proposals regarding electron
transfer in this system need to be further evaluated.
Although it has been proposed that amavadine
serves as an efficient electron-transfer agent in the
mushroom, investigations of the reactivity of amavadine have been limited. Studies have shown that
amavadine can catalyze thiol oxidation in the absence
of hydrogen peroxide (referred to as a peroxidase
catalyst by the authors)468 and in the presence of
hydrogen peroxide it can perform peroxidative halogenation, hydroxylation, and oxygenation of alkyl and
aromatic substrates.469 Studies have been done demonstrating that amavadine will electrocatalytically
oxidize thiols such as cysteine, glutathione, mercaptoethanol, and a range of related thiols in acidic
solution; the catalytic cycle is depicted in Scheme 7.454
In the electrocatalytic oxidation of thiols, both amavadine and the model complexes show saturation
kinetics and thus follow Michaelis-Menton behav-

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 873

plex.441 The molybdenum complexes were also found

to have a similar structure, but showed more versatile electrochemistry.442,443 The niobium and tantalum
cations yield compounds with similar structures;
however, given the large size of these cations, these
compounds have several different features. Perhaps
the most notable are the quasi-irreversible or irreversible reductions that are observed with these
compounds.444

Scheme 7. The Reaction of Amavadine with

Thiolsa

Modified from ref 454.

ior.454 The initial step in this reaction is the oxidation

of the model complex from V(IV) to V(V), followed by
the formation of a thiol-V(V) adduct which is the
accumulating species. The V(IV) is regenerated by a
one-electron oxidation which then releases the oxidized disulfide. Given the coordination environment
of the vanadium, the nature of the amavadine-sulfur
adduct is not obvious. Should a covalently coordinated complex be required for this reaction, part of
the amavadine ligand must dissociate, perhaps only
temporarily, for such a reaction to occur. Such a
proposal would seem unlikely given the high stability
of the complex and its reported inertness in solution.
However, the fact that this reaction takes place
documents the ability of this complex to convert
biologically important substrates and hints at some
potential participation in metabolic processes.
Recently, Frausto da Silva, Pombeiro, and coworkers reported that amavadine could convert
methane into acetic acid in the presence of a peroxodisulfate salt and trifluoroacetic acid (eq 9).455 The
latter components are necessary for the reaction,
whereas the amavadine can be replaced by other
V-complexes such as triethanolamine oxovanadium(V) and [VO(malto)2]. In contrast, V(IV)-complexes
with ligands such as bicine (N,N-bis(2-hydroxyethyl)glycine) and heida (bis(2-hydroxyethyl)N,N-iminodiacetic acid) in the presence of peroxodisulfate salt and
trifluoroacetic acid exhibited much lower reactivity.
Using other metal derivatives as well as substituting
CF3COOH with acetonitrile also failed to support the
reaction.455 The authors propose the formation of a
methyl radical, which abstracts hydrogen from CH4
and then undergoes a one-electron oxidation by a VVoxo or VV-peroxo species. Understanding this reaction
under such mild conditions will be a major breakthrough and this class of catalyst begs further
development.
vanadium catalyst

CH4 9
8 CH3CO2H
K S O ,HOTf
2 2

(9)

The Garner group is seeking an increased understanding of the amavadine system by investigating
other related metal ion complexes with disubstituted
hydroxylimino ligands. As a result, a number of
different metal complexes have been reported, of
which the titanium,441,470 molybdenum,442,443,471 niobium,444 and tantalum444 systems will be briefly
described here. The titanium system was found to
have a structure similar to amavadine; however,
allowing a solution of the complex to stand for 2
weeks resulted in changes in the NMR spectrum; this
result indicates that solvent molecules do interact
with the hydrophilic equatorial surface of the com-

5.2. Siderophores
Siderophores provide a number of different coordination environments and a wide range of formation
constants with Fe(II) and Fe(III) as well as the
accompanying changes in complex lability.439 The fact
that Fe(III) is bound more tightly and that the Fe(II)
siderophore complex is more labile can explain how
the Fe(III) form can be taken up, the Fe(III)-complex
recognized and transported inside the cell where a
redox switch is used to release the Fe(II) inside the
cell.439 Despite the obvious biological implications if
vanadium is taken up in the place of iron by siderophores, most of the studies have focused on the
characterization of new types of V-complexes with
siderophores and little quantitative information is
available. At this time, the biological role may be
explored by examining the effects of V-compounds on
siderophore mediated-iron transport and has therefore been described in this review.

5.2.1. The Effects of Vanadium on Siderophore-Mediated

Iron Transport
A study was recently reported with Pseudomonas
aeruginosa showing that VOSO4 inhibits the growth
of these Gram-negative bacteria.472 The effects on Feuptake were enhanced in the presence of Fe(III)chelators. Similar observations were made when
examining the iron uptake from desferrioxamine B
(77) and rhodotorulic acid (78) by Chlorella vulgaris.473 Protochelin accumulates in the presence of
vanadate in Azotobacter vinelandii and vanadate
inhibits uptake of 55Fe-protochelin and 55Fe-azotochelin complexes.474 Pyoverdine-deficient P. aeruginosa
mutants were more sensitive to VOSO4 than wildtype; however, the addition of pyoverdine to the
media did not reverse the effect.472 The pyochelin (79)
deficient mutants were more resistant to VOSO4 than
wild-type cells, and studies were carried out to link
the effects of the V-compound to superoxide formation. Exposure of the cells to paraquat, a compound
known to generate a superoxide, increased the resistance to VOSO4 and conversely, exposure to VOSO4
induced resistance to paraquat.472 The authors suggested that vanadium compromised the utilization
of pyoverdine and that the formation of the Vpyochelin can result in Fenton-type reactions and the
generation of superoxide.
These results are of interest on several counts.
First the interference with Fe transport implies that
V can be transported, or at the very least, partially
substitute for Fe in siderophore complexes in biology.
Since this was observed in several microorganisms
and plants, this effect may be general. Second, the
observations that one siderophore protected, whereas

874 Chemical Reviews, 2004, Vol. 104, No. 2

the other did not, shows that variable effects can be

observed in a biological system. These studies support the expectation that vanadium may affect iron
uptake as anticipated based on the chemical similarities of vanadyl cations and iron cations (i.e., their
tendencies toward the formation of oligo- and polymeric aqueous ions and their aqueous redox activity).

Crans et al.

UV-vis spectroscopy to bind with both V(V) and

V(IV).479

5.2.3. Vanadium Citrate Complexes: Structure and

Speciation
Citrate (83) is known as a siderophore that can
complex, in addition to iron, vanadate, and vanadyl
ions in aqueous solutions. Citrate is also an important metabolite in mammals where it also serves as
a metal chelator. Several bonding modes for V(IV)and (V)-citrate complexes have been observed
(84-90).219 The first vanadium-citrate complex,
[V2O4(H2cit)2]2-, was structurally characterized in
1995 (84). Citrate utilized the hydroxyl and central
carboxylate oxygens in the chelate, while the terminal carboxylates remained protonated; only the hydroxylate oxygen atoms bridge the V atoms. Addition
of hydrogen peroxide led to the formation of structurally similar diperoxo complexes, [(VO)2(O2)2(H2cit)2]2(85).218,219 By increasing the pH, further deprotonated
V(V)-complexes, albeit still with bidentate chelation,
have been obtained: [V2O4(Hcit)2]4- (86)480,481 and
[V2O4(cit)2]6- (87).482 Typical bond lengths in V(V)citrate complexes are 1.60-1.64 and 1.96-2.02
for VdO and V-O, respectively.218,219,480-484

5.2.2. Characterization of Vanadium-Siderophore

Complexes and Model Complexes
The crystal structure of the triscatecholamide
siderophore, enterobactin (80), with V(IV) was determined.475 In this complex, the catecholate groups
were found to be the coordinating functionalities as
in the simplest geometrically unrestricted model
complex with three N-ethyl-3,4-dihydroxybenzamide
ligands (81). Spectroscopic characterization showed
the stability and chirality of the complex originating from the preferential conformation of the triserine
backbone.475 For additional information on catechol
chemistry, we refer the reader to the section on
tunicate chemistry.
V(IV)- and V(V)-complexes were reported to form
between pyoverdine (1:1 stoichiometry) and pyochelin
(79) (1:1 and 1:2 stoichiometry).472 Below pH 1,
V(IV) was shown to form a stronger complex with
desferrioxamine B (77) than iron; however, by pH 4
the formation constant for iron was 7 orders of
magnitude greater than that of the vanadyl cation.476,477 Speciation studies of V(IV) and V(V) with
desferrioxamine B (77) indicated that at very low pH,
nonoxo V(IV)- and (V)-complexes were generated in
which the three hydroxamate functional groups occupied the six coordination sites on the vanadium.478
Upon increasing the pH, the oxo group(s) were
restored and the vanadium was complexed by one or
two hydroxamate functional groups. Rhizoferrin (82),
an amino/carboxylate/hydroxy ligand, was shown by

The V(IV)-citrate complexes generally have either

tri- or tetradentate citrate ligands. An example of a
tridentate bonding mode is found in [V2O2(Hcit)(cit)]3(88)485 in which one citrate ligand is monoprotonated
while the other is fully deprotonated. For complexes
in which the citrate ligands are fully deprotonated,
the most common binding mode is tetradentate,
which is found for complex anions with the general
stoichiometry [V2O2(cit)2]4- (89).482,485-487 A complex
with a mixed tridentate/tetradentate bonding mode,
albeit with 2:2 stoichiometry (88),485 has also been
isolated (90).488 Typical bond lengths in V(IV)-citrate
complexes are 1.58-1.61 and 1.95-2.23 for VdO
and V-O, respectively.482,485-488 The predominant

Chemistry and Biochemistry of Vanadium

features in all of these 2:2 complexes is the diamondcore [V-O-V-O] motif predominant in V(V) alkoxide
chemistry. The V(V)-citrate complexes tend to be fivecoordinate, with the exception of the six-coordinate
peroxo citrate complexes, while the V(IV)-complexes
are generally six-coordinate. Changes in pH did not
significantly affect the structure of the complex ion,
aside from the protonation state(s) of the terminal
carboxylates, in either the V(V)480- or V(IV)485-citrate
complexes. However, some of these complexes were
found to convert to each other in solution when the
pH was changed.480
Aqueous speciation studies of the vanadate(V)citrate found primarily 2:1 complexes.489 In light of
the structural results and the closeness of the fit, one
species, assumed to be a 1:1 complex, may be a 2:2
species.489 The vanadyl(IV)-citrate speciation system
indicated the presence of primarily 2:2 complexes,
although below pH 4.5 1:1 species were detected
while 1:2 (metal:ligand) species could be detected
above pH 8.
A close relative of citrate, homocitrate, is a component of the cofactor in the nitrogenases (Nases),
including V-nitrogenase (vide infra). Only one structure has been crystallographically determined for a
V(V)-complex with homocitrate (91).490 Discussion of
Nase and model compounds is presented below in the
section on low-valent vanadium chemistry.

5.2.4. V(V) and V(IV) Hydroxamate Complexes

Hydroxamic acids have the general formula RC(dO)N(R)OH, and their deprotonation and binding
modes are depicted in Scheme 8. Hydroxamates
readily deprotonate to monoanions followed by binding to the metal ion in a bidentate fashion through
the deprotonated hydroxy oxygen and the neutral
carbonyl oxygen atoms, respectively. When R is H,
two deprotonation steps result in a dianionic ligand
which has two resonance forms. This anion is generally referred to as a hydroximate due to the CdN
resonance form.491 Hydroxamate complexes have
been widely used in spectrophotometric determinations of vanadium due to the intense color of the
resulting complexes.492,493 Desferrioxamine B (77), an
abundant hydroxamate-containing siderophore that
forms complexes with both V(IV) and V(V),478,494 and
has sparked renewed interest in the study of vanadium-hydroxamate interactions.
V(V) hydroxamates are far more common due to
the tendency of V(III) and V(IV)-complexes to abstract oxygen from hydroxamic acids.495 At submillimolar concentrations, aryl hydroxamates form 1:1
five- or six-coordinate complexes at pH 7.5 as determined by 51V NMR spectroscopy; at higher concentrations the 1:2 complex predominates.496 For the 1:1

Chemical Reviews, 2004, Vol. 104, No. 2 875

complexes, 15N NMR spectra suggest the hydroxamate to be monoanionic and 13C NMR spectra indicate
that the carbonyl oxygen is weakly coordinated. The
log Kf values obtained (ca. 1-4)496 were much lower
than those obtained in more acidic solutions.497,498
Speciation studies on alkylhydroxamic acid-vanadate complexes give log Kf values on the order of
7-38 depending on the pH.499,500 Cinnamoylhydroxamate was shown to form 1:1 and 1:2 complexes with
V(V) at 1.8 M HCl in 2-methyl-4-pentanone; the
stepwise formation constants were given and an
octahedral coordination geometry was suggested.501
The first structurally characterized V-hydroxamate
complexes were the V(V)-complexes of benzohydroxamic acid (92),502 the dihydroxamate N,N-dihydroxyN,N-diisopropylheptanediamide,502 and N-phenylbenzohydroxamic acid (93).503 All the complexes are
six-coordinate and the ligands are monoanionic; the
benzohydroxamate and N-phenylbenzohydroxamate
complexes are monomeric, while the dihydroxamate
ligand yielded a 2:2 complex. A series of salicylhydroxamate V(V)-complexes with tridentate ternary
ligands were prepared; the derivative with N(salicylideneaminato)-N-(2-hydroxyethyl)ethylenediamine was crystallized (94).246 This complex and
its congeners contain a dianionic salicylhydroxamate
ligand (i.e., a hydroximate), and a strong hydrogen
bond was observed between the phenolic hydroxyl
group and the deprotonated imino nitrogen.246 A
trinuclear vanadium(V) complex, [VO(shi)(OCH3)]3
(95), was prepared from VO(acac)2 or VCl3, salicylhydroxamic acid, and NaOCH3 in methanol and
structurally characterized. Each trianionic ligand is
tetradentate with two donor atoms bound to each
vanadium center to generate a metallocrown structure.504 Similar metallocrown structures have also
been prepared from modified salicylhydroxamic acids.505 The first mixed hydroxamate/hydrazone V(V)complex contained a monoanionic salicylhydroxamate
ligand.506 Other structurally characterized V(V) ternary complexes include 4-(2-(salicylideneamino)ethyl)-imidazole/salicylhydroximate,250 benzohydroxamic acids/N-salicylideneglycine and N-(2-carboxyphenyl)salicylideneamine,507 and N-phenylbenzohydroxamic acid/acetylacetone benzoylhydrazonato and
salicylidene-L-alaninato.508

Scheme 8. Deprotonation Products and Binding

Modes of Hydroxamates

To date, no crystallographic data for V(IV) hydroxamate complexes are available, although solution
studies indicate that V(IV) hydroxamate complexes

876 Chemical Reviews, 2004, Vol. 104, No. 2

Chart 1. Hydroxamate and Pseudohydroxamate
Vanadyl Complexes

are present in some solutions.478,491,494 This is likely

due to the instability of the hydroxamate ligand
which can be readily reduced via oxygen abstraction
by V(IV) or V(III).495 Nonetheless, in solution desferrioxamine B (77) has been shown to complex with
both V(IV)478,494 and V(V).478 EPR studies show the
formation of nonoxo complexes of these metal ions
at low pH; when the pH is gradually increased the
oxo ligands are restored. Stability constants (log )
for the V(IV)-desferrioxamine were on the order of
30-40.478 A rhodotorulic acid (78) V(IV)-complex has
been prepared both as the vanadyl complex and as a
nonoxo complex; elemental analysis of the nonoxo
complex, however, showed a ratio of 3:2.2 (metal:
ligand).502 Reversible V4+/V3+ reductions were observed for both the vanadyl and nonoxo V(IV)complexes.502
A series of hydroxamate and pseudohydroxamate
vanadyl complexes were prepared, and EPR spectroscopy was used to conduct a speciation study
(Chart 1).491 For the aceto- and benzohydroxamic acid
complexes a variety of species were observed. At
acidic pH, 1:1 complexes predominate with a neutral
1:2 species present in minor concentrations. In basic
conditions, 1:2 complexes are found and at 100-fold
excess ligand, the nonoxo trihydroxamate complex is
observed between pH 7.5 and 9.5. The N-phenylbenzohydroxamic acid and 2-hydroxypyridine-N-oxide,
which only have one ionizable proton, form the 1:1
and 1:2 species, respectively. In very acidic conditions
with excess ligand, a trihydroxamate complex is
formed.491
Biological studies focusing on applications of hydroxamate V-complexes encompass a variety of areas.
A number of dihydroxamate complexes of V(IV) and
V(V) were found to stimulate glucose metabolism in
rat adipocytes.509 Interestingly, the hydrophobic dihydroxamate ligand complexes were more effective
at stimulating glucose metabolism, and it was suggested that the hydroxamates are acting like ionophores by facilitating vanadium transport into the
cells.509 ESEEM spectroscopic was undertaken to
examine the coordination environment in Shechters
complexes, and the hydroxamates were found to have
a cis orientation and to occupy a plane roughly

Crans et al.

perpendicular (within 20) to the VdO axis (96).510

V(IV)- and (V)-complexes of glutamine- and aspartate-derivatized hydroxamate ligands have also been
found to exhibit insulin-enhancing activity and activate lipogenesis.328,511 A distamycin-linked dihydroxamate complex of V(IV) in the presence of
hydrogen peroxide was shown to selectively cleave
DNA depending on the length of the linker group and
the AT sequences.512 Aryl and alkyl hydroxamate
V(V)-complexes were found to be inhibitors of the
class C -lactamase in Enterobacter cloacae P99.513,514
For the -lactamase, the largest Ki value obtained
was 0.48 mM; the association/dissociation rate constants and other studies implicate strong binding of
the V-complex in the active site.513,514 Other enzymes
inhibited by vanadate-hydroxamate complexes include serine amidohydrolase, chymotrypsin, and
elastase.514
Synthetic applications for vanadium-hydroxamates have extended this area to metal extraction
processes and asymmetric epoxidations.515-518 The
possibility of diastereomeric intermediate formation
may limit the achievable enantiomeric purity.518

6. Tunicates and the Polychaete Fan Worm

Although high concentrations of vanadium have
often been found in various tissues or organs of living
organisms, few organisms in the animal kingdom are
actually known to accumulate vanadium. Recently,
it has been reported that in addition to the high levels
of vanadium in ascidians,4,7 the fan worm Pseudopotamilla occelata also accumulates vanadium.519-521

6.1. Tunicates
Tunicates (ascidians or sea squirts) are invertebrate marine organisms and, depending on the species, accumulate vanadium in their blood. The V-containing species were first discovered in 1911 by
Henze,4,7,522 and since then, bioinorganic chemists
and biological scientists have been interested in these
animals that can concentrate vanadium from seawater (10-8 M) in various cells of the tunicate (Table
2). Bioinorganic chemists have investigated the form
and storage of vanadium in these organisms, its
redox conversion from V(V) in seawater to V(IV) and
V(III), and also how and why vanadium is accumulated. Although much is known about most of
Table 2. Concentration of Vanadium (M) in Ascidian
Tissuesa
species
Ascidia gemmata
A. ahodori
A. sydneiensis
Phallusia
mammillata
Ciona intestinalis
Styela plicata
Halocynthia roretzi
H. aurantium
a

serum

blood
cells

ND
1000
50
ND

347 200
59 900
12 800
19 300

700

600

Stolidobranchia
5
1
1
10
1
4
2
2
2

3
1
ND

3
7
4

tunic mantle

branchial

Phlebobranchia
ND
ND
ND
2400 11 200 12 900
60
700
1.400
30
900
2.900
3

700

Data taken from ref 10. b ND, not determined.

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 877

these topics,3-7,9,16,59,523 the function of vanadium in

tunicates remains elusive even though many credible
hypotheses have been put forth. Other aspects of
theseanimals,includingtheirbiologyandphysiology10,11,524-531
are also important frontiers in this area. Since
tunicates have a primitive backbone (a key chordate
feature), these organisms are very suitable as a
models for genome science which has increased the
current interest in these organisms.531 In the past few
years, results have been forthcoming that put an end
to the existing controversy regarding the possible
existence of V(III) in biological systems and will be
reviewed here.

6.1.1. Location of Vanadium in Tunicate Blood Cells

The specific form of vanadium in tunicates has
been investigated since its discovery, when V(III) in
cell lysates was identified in the species Ascidia
ceratodes. The environment required to stabilize
V(III) under physiological conditions would need to
be either very acidic or make use of a powerful
coordinating ligand. Early reports that suggested the
presence of V(III) in acidic environments were met
with some skepticism. The possibilities that either
the acidity was an artifact of the isolation procedure
or that the isolated vanadium should have been in
oxidation state IV were considered and tested experimentally. These issues were compounded by
subsequent studies revealing that, depending on the
suborder of ascidian, as well as the cell type within
each species, the form of the vanadium varied.
Although some disagreement may still exist with
regard to the oxidation states of vanadium in the
blood cells of ascidians, a consensus appears to have
been reached: the Aplousobranchia suborder contains mainly V(IV) and the Phlebobranchia suborder
contains mainly V(III). Within one organism both
forms of vanadium exist depending on whether the
blood cell is a lymphocyte, stem cell, leukocyte,
pigment cell, or vacuolated cell. Although vanadium
levels are higher than the normal levels of 10-9-10-8
M in all these cells,398 the vanadium is mainly stored
in vacuolated cells. The vacuolated cells can be
divided into nine morphologically different cell types
of which three, the morula, signet ring, and compartment cells, have been the focus of many investigations. The morula cells are bright yellow mulberryshaped cells with spherical vacuoles that exhibit
orange-colored fluorescence. The signet ring cells are
greenish-gray cells containing one large vacuole and
the nucleus on one side of the cell. The compartment
cells are green and contain several vacuoles of
various sizes. Initially, it was assumed that the
vanadium accumulated in the morula cells due to
their intense color. However, studies using X-ray
microanalysis,532,533 cell fractionalization,534,535 and
various spectroscopic techniques536 (reviewed in ref
7) suggest that the signet ring cells and the compartment cells are the primary storage sites. A recent
study shows that vanadium also accumulates in
vacuolated amoebocytes in Phallousia mammillata
and Ascidia sydneiensis samea.537
The strong fluorescence and yellow color of the
morula cells is due to a material that makes up to

Figure 12. Selected examples of tunichrome ligands.8,538-540

50% of the dry weight of these cells. This material

was named tunichrome, and its isolation and identification was a tour-de-force when considering the
air sensitivity of both the free ligand and its colorful
V-complex.538,539 Tunichromes are polyphenolic tripeptides (Figure 12), and upon isolation yielded a
naturally occurring ligand that is capable of complexing V(III) and maintain it in a low oxidation
state539,540 at physiological pH. The synthesis and
possible biological roles of the various tunichromes
have been recently reviewed.8 The characterization
of tunichrome initiated a series of model studies of
vanadium catecholate complexes (vide infra); at the
time of these early model studies it was not known
that vanadium and tunichrome were located in
different cells, and that little vanadium would be
complexed to tunichrome.

6.1.2. Aqueous V(III) Chemistry

V(III) is the lowest oxidation state of vanadium
that can be reasonably stable in aqueous solution.
The aqua ion [V(H2O)6]3+ can be obtained by dissolving V2O3 into acids or by electrolytic or chemical
reduction of V(IV) or V(V) solutions. Studies of V(III)
require stringent anaerobic conditions since V(III) is
easily oxidized by air based on its standard reduction
potential value of 0.337 V (vs NHE) in strongly acidic
solutions. Experimental techniques employed for
V(III) solution studies are limited to UV-Vis spectroscopy and electrochemistry. V(III) is maintained
in aqueous solution only in an acidic pH range under
reducing conditions or in the presence of a potent
chelator.
The aqua V(III) ion is blue-green and exhibits
characteristic absorption bands in the visible region
at 400 nm ( ) 9.3) and 595 nm ( ) 6.0).541 The
simple [V(H2O)6]3+ (97) and [V(OH)(H2O)5]2+ (98)
(pKa1 ) 2.6) ions exist only in strongly acidic solutions
pH < 1 and from 1.0 to 3.5, respectively. Upon
increasing the solution pH (1.0 < pH < 3.5), V(III)

878 Chemical Reviews, 2004, Vol. 104, No. 2

dimerizes to form [V2(2-O)(H2O)10]4+ (99) (log Kd )

1.6).542 The dimer can be observed spectroscopically
at 430 nm543 with  ) 3000 ( 50 M-1 cm-1.542 The
dimer in acidic solution favors the bis(-oxo) binding
mode over the bis(-hydroxo) binding mode.544-546
Formation of the trimer [V3(OH)8(H2O)10]+ (100) and
tetramer [V4(OH)12(H2O)12] (101) are suggested at pH
> 3.5.542 And although perhaps not yet generally
accepted, the solid-state characterization of [V3(3O)]6+ and [V4(3-O)2]8+ lend credence to the existence
of trimers (100)547 and tetramers (101)548 in solution.
An insoluble solid usually referred to as {V(OH)3}n
(Ksp ) 4 10-35 M4)549,550 forms at pH > 4.5 showing
the need for strong chelation of any soluble V(III) that
exists at neutral pH.

6.1.3. Oxidation State of Vanadium in Tunicates

The Aplousobranchia and Phlebobranchia suborders of ascidians mainly accumulate V(IV) and V(III),
respectively. Most studies have focused on the latter
system, in part because of the rarity of observing such
a reducing metal ion in nature and also, in part,
because of the experimental difficulties in identifying
V(III)-containing material from biological systems. A
wide range of experimental approaches have been
used including spectroscopic551-554 and magnetic555,556
studies of isolated extracts555,556 and whole
cells551-554,557 to convincingly demonstrate that indeed
not all the observed V(III) is an experimental artifact
of either the isolation or the analysis methods used.
Since V(III) is stable in acidic environments, the
observation of V(III) was initially linked either to the
metal ion being accumulated in acidic cells or to the
metal being bound by a potent chelator. If cationic
vanadium exists in cells in high concentrations, then
large concentrations of counterions must also be
present regardless of whether the metal was complexed to a potent ligand or not. In one study, where
the V(III) in Ascidia gemmata blood cells contained
some V(IV), analysis of the Raman SO42- and VdO
stretching peak intensities suggested a SO42- to V3+
ratio of 1.47:1;558 such a value is expected for SO42being a major counterion for V3+. High concentrations
of sulfate anion were noticed in the first studies of
extracts, and have been confirmed on whole cell blood
using X-ray absorption spectroscopy,551 sulfur K-edge
EXAFS552-554 and Raman spectroscopy.558
Efforts at measuring and calculating the pH values
of the various blood cells have been crucial for
researchers in this field to elucidate the location and
form of the accumulated vanadium (reviewed in ref
7). In isolated cells, these types of studies involve

Crans et al.

using markers and then monitoring the spectroscopic

properties between species in cell vacuoles, cytoplasm, and extracellular fluids.556,559-561 The morula
cells are found to be neutral or slightly acidic since
they contain large concentrations of acid-sensitive
ligands. Most of the data for signet ring cells and
compartment cells suggest that these cells are also
neutral, leaving the vacuoles in these cells to be acidic
and thus the location of the high concentration of
vanadium. In ascidian blood cells, higher concentrations of V(III) were found to correlate with lower pH.
A recent systematic and high-resolution investigation
of solutions containing V(III) and sulfate at a variety
of pH values; the conditions that mimic those of V(III)
found in intact blood had pH values ranging from 0
to 3 depending on the sulfate content.552,562 These
studies confirm and further extend the earlier report
demonstrating that V(III) does exist in whole blood
cells.551
Recent work has focused on characterizing the
nature of the V(III)-sulfate interaction in whole
blood cells.551-554,557 Although some aliphatic sulfonate558 and low valent sulfur can be observed in
intact blood cells, only traces of sulfate ester or
sulfonate was found in washed blood cell membranes,557 leading the authors to propose that sulfonate is exclusively cytosolic. Assigning coordinated
sulfate to the lower C3v symmetry and splitting the
transition of tetrahedral SO42- into 1s f a1 and 1s
f e transitions gives spectral fits of the data which
show that chelation of sulfate to V(III) explains the
natural broadening in the A. ceratodes blood cell
sulfur K-edge XAS spectra (Figure 13).557 Model
systems have been reported showing structural precedence for monodentate and bidentate sulfate coordination as described in greater detail below.
Considering the C3v symmetry of coordinated sulfate, data from intact tunicate blood cells and extracts
have been modeled, and some resolution to the
conflicting reports on the nature of vanadium in
tunicate blood is emerging. Studies on whole cell
blood of Phallusia nigra showed that this species has
a significant fraction of the vanadium in a ligand
environment provided by catechols and thus implies
DOPA-like complexation.553,562 These findings should
be compared with the analysis of fresh unoxidized
Henze extracts from A. ceratodes where 18% of the
V(III) was found in a tris(catecholate)-like environment552 consistent with the extraction causing some
of the DOPA-like complexation with the V(III). Since
the whole blood of these specimens was also investigated and no evidence was observed for the catechol-peptide-like (DOPA-like) complex,552 it is clear
that extraction increases the fraction of these complexes measured. Extraction is presumed to mix the
contents of the morula, signet ring, and compartment
cells; therefore, future work may reveal whether
leakage of tunichrome is a beneficial event.
A recent comparison of several specimens with A.
ceratodes from two locations shows significant differences existing even within one species.554 Despite
the anticipated biological, genetic, and environmental
variability, some differences between Ascidia and
Phallusia species were identified.552,562 Importantly,

Chemistry and Biochemistry of Vanadium

Figure 13. Sulfur K-edge XAS spectra of (a) (s) the highvalent portion of the blood cell spectrum; (- - -), the fit
to the spectrum; and (- - -) the Gaussian components of the
fit to the spectrum. (b) The second derivatives of (s) the
blood cell sulfur K-edge XAS spectrum and (- - -) the fit
to the spectrum. Reprinted from ref 557. Copyright 1995
American Chemical Society.

these studies imply that future observations of

populational differences will be reported within a
species and that specific blood content will vary
among genera.

6.1.4. Uptake of Vanadate into Tunicates

The majority of the vanadium is taken up as V(V)
from seawater (Figure 14). Since the vanadium ions
inside the blood cells are in oxidation state III or IV,
the aqueous vanadium has been reduced. This is not
a simple feat since the V(V)/V(IV) and V(IV)/V(III)
redox couples, in strongly acidic solutions, are 1.00
and 0.337 V (vs NHE), respectively. Thus, the tunicate blood cells not only support accumulation of
vanadium up million-fold concentration gradients,
but since no vanadium granules are observed in the

Figure 14. A model of the pathway for the reduction and

accumulation of vanadium in ascidian vanadocytes. Reprinted with permission from ref 10. Copyright 2003
Elsevier.

Chemical Reviews, 2004, Vol. 104, No. 2 879

blood cells, the V(III) will exist in the cells in a

reduced form that is seemingly bioenergetically unfavorable and incompatible with physiological conditions. It has been suggested that reduction involves
NADPH in the tunicate. In other biological systems,
the uptake of vanadium has been linked to its
reduction.563
Uptake studies of 48V showed that vanadium is
primarily transported to the tunicates blood plasma
via the branchial sacs.564 Some additional absorption
takes place in the gastrointestinal tract. Vanadate
enters the tunicates through anionic transporters as
evidenced by the inhibition of vanadate uptake in the
presence of phosphate,565 but recently the existence
of a vanadium transporter has been suggested (Figure 14).10 Vanadium bound to vanadium-binding
proteins (vanabins) in the cytoplasm531 may facilitate
the transport and accumulation of the vanadium in
the vacuoles. The fact that vanabins bind V(IV) more
strongly than V(V) suggests that reduction does take
place before the vanadium ion binds to the protein.
51V studies show that V(V) persists in blood plasma,
but blood cells trap the vanadium and facilitate the
reduction to V(IV) and V(III).59 The reduction of V(V)
to V(IV) and V(III) has been of interest for some time,
and model systems examine the redox properties of
not only tunichrome related complexes, but other
systems that may be of relevance to this reaction
(vide infra).

6.1.5. Vanadium Binding Proteins: Vanabins

Three vanabins previously referred to as vanadiumassociated proteins (VAPs) have been isolated.527,530,531
The isolated vanabins include proteins with apparent
molecular weights of 12.5, 15, and 16 kDa. Using a
specific antibody, the proteins were shown to be
localized in the cytoplasm of vanadocytes.525,527,531,566
Two vanabins from the blood cells of A. sydneiensis
samea, vanabin1 and vanabin2, have been cloned and
characterized in great detail.527,531 The vanabin proteins are rich in cysteine residues, but distinct from
metallothioneins and other known cysteine-rich proteins.
The affinities of vanabin1 (12.5 kDa protein) and
vanabin2 (15 kDa protein) for V(IV) were determined
using a Bio-Gel P column and the Hummel-Dreyer
method.531 The affinities of the vanabins for V(IV)
were measured using a competition experiment between the relatively weak V(IV) iminodiacetic acid
complex and the proteins; dissociation constants of
2.1 10-5 and 2.3 10-5 M were obtained. Vanabin1
binds 10 vanadium atoms, whereas vanabin2 binds
20 vanadium atoms. Presumably, the differences in
sequence between these two proteins are responsible
for the difference in the number of protein-bound V
atoms.531 Neither Mg(II), MoO42-, nor WO42- affected
the binding of V(IV), whereas Cu2+ did reduce V(IV)
binding. The significance of the difference in the
number of V(IV) ions bound is not clear, and it is also
possible that vanabin1 also binds more V(IV) ions less
tightly. At this time, EPR studies suggest (Figure 15)
that the vanabins bind to the V(IV) through residues
other than the cysteines.566
Attempts to determine the affinity of the vanabins
for V(V) were not reproducible. Such reproducibility

880 Chemical Reviews, 2004, Vol. 104, No. 2

Figure 15. EPR (top) and two-pulse ESEEM spectrum

(bottom) and its time-domain data spectrum (bottom inset)
of VO2+ and vanabin2. Reprinted with permission from ref
566. Copyright 2003 American Chemical Society.

problems can be attributed to the sensitivity of the

interaction between the V(V) and a cysteine-rich
protein which can undergo redox chemistry resulting
in protein modification and reduction of V(V) at some
pH values.567 These studies did show that the affinity
of the proteins for V(V) is much less than for V(IV)
and may be at the detection limit of the method
employed.
The affinity of vanabins for vanadium rivals that
of a nickel chaperone protein (UreE), the copper
binding site of Menkes protein, and a periplasmic
molybdate-binding protein (ModA). Based in part on
the affinity of the vanabins for V(IV) and the location
of these proteins, Michibata suggested that the roles
of these vanabins are to transport the vanadium to
the vacuole as illustrated in Figure 14.10

Crans et al.

fication of tunichrome. Studies showed the effects of

ligand modification on the structure of the V-complex
and its spectroscopic and redox properties. In the
tunichrome-V-complex, it is the catechol units that
are coordinated to the vanadium. Model complexes
for tunichrome B1 analogues demonstrated that
catechol complexation is critical for high stability.568
In the reaction of tunichrome with V(V), the reduction of V(V) to V(IV) readily took place, whereas the
reduction to V(III) only happened with difficulty, if
at all, under physiological conditions.540 Details of the
ligand oxidation and the metal reduction will vary
with the specific catechol, although some generalizations can be made.568,569 Several intermediates, including semiquinones and quinones, form although
in some of these systems it is difficult to determine
the location of the unpaired electron.568,569
A range of complexes (102-108) form between
catechols and V(III), V(IV), and V(V); these complexes
have different stoichiometries, charges, structures,
nuclearities, and reactivities.568-576 The simple V(III)
catecholate and semiquinone complexes undergo a
redox reaction to form dianionic 1:3 V(IV):L complexes in organic solvents and serve as an excellent
model system for this class of complexes.568,569 The
V(III)-complexes, albeit more reactive, tend to be
mono- or binuclear, whereas the V(IV)-complexes are
often polymeric.568,569 The generation of monomeric
structures may thus require reduction to V(III)complexes. Some of these complexes contain no oxo
groups, and although nonoxo complexes are relatively
rare for complexes with vanadium in oxidation state
IV and V, they predominate in complexes of V(III).577

6.1.6. Model Complexes and Their Chemistry

Model studies have changed dramatically in the
past decade. Initially, model studies focused on
ligands that could complex V(III) and (IV), either
under physiological conditions or in organic solvents.
The identification of tunichrome led to a surge in
activity in vanadium-catechol chemistry with a
particular focus on the redox chemistry of such
systems. With the determination that tunichrome
and vanadium are found in different cellular compartments in A. ceratodes, it became clear that
tunichrome is not likely to be the main natural ligand
that maintains the vanadium in oxidation state III.
The number of investigations into this type of chemistry has since been significantly reduced. Efforts
probing the properties of this class of V-complexes
now focus on those systems mimicking the potential
function of ligand and V-complex. At this time, the
major modeling studies in this area are those related
to investigations of the properties of the vanadiumsulfate types of systems that exist in whole blood
cells.

6.1.7. Catechol-Based Model Chemistry

The development and studies of model compounds
flourished after the isolation and structural identi-

Fundamental studies of the reaction of V(V)

with the simple catechols and substituted catechols
are crucial for a detailed understanding of this
rich redox chemistry568,570,578-580 and have been reviewed.246,250,540,581,582 V(V) catechol complexes have
been reported in solution578,579 and in the solid
state.461 Speciation studies have been carried out
showing the formation of 1:1 (105), 1:2 (106), and 1:3
(107) species in various protonation states.570-572
Although modification of the catechol does not seem
to affect the formation constants of the system,571,572
the electronic structure is affected as evidenced by
the significant changes in the EPR spectrum.583,584
Ternary complexes containing catecholate and bipyridine have many properties analogous to pure catecholate complexes.585,586 A structurally interesting
compound is the nonoxo V-complex with bipyridine

Chemistry and Biochemistry of Vanadium

and phenanthroline as the auxiliary ligands (103).461

Model compounds designed to mimic the tunichrome
complex that replaced the peptide functionality failed
to be as efficient in complexing vanadium.576 However, the resulting complexes showed, as in the case
of the parent tunichrome, that the catechol unit was
critical for V-complex formation and dictated the
properties of the parent and model systems. Recent
studies with intact whole blood cells indicate that
some DOPA-like ligands are coordinated to a minor
fraction of the vanadium in intact blood cells, and
approximately one-third of the vanadium can be
attributed to these type of complexes in the Ph. nigra
ascidians.553 Model studies on a range of vanadium
catechol and catechol-derived complexes show that
when V(V) reacts with a catechol, the ligand undergoes oxidation.246,250,540,581,582 The resulting vanadium
catechol complexes contain vanadium in either oxidation states III or IV with the structures shown as
in (102-104). The ligand-metal electron-transfer
reaction varies depending on the solvent. Evidence
for the oxidized metal/reduced quinone form is obtained in polar solvents, whereas solid-state studies
support the reduced metal/oxidized ligand formulation.170,575,577,587 Similar ligand-based redox processes
were reported with other simple catechol ligands.575,588
An important question to consider is, how can
V(III)-compounds be formed and exist under physiological conditions? Whether V(III)-complex formation is possible has been debated for some time.
3,5-Di-tert-butylcatechol was shown to react with
[VO(acac)2] under an inert atmosphere in an organic
solvent to yield a V(III) tris(semiquinone) complex.573
1,8-Hydroxyquinoline reduces [VOCl2(thf)2] in the
presence of Et3N to yield [VIII(quin)3] (109).574 Disproportionation reactions (and enzymatically catalyzed reactions) are known to facilitate processes that
may otherwise be difficult; such disproportionation
reactions have been observed in vanadium-salen
complexes (eqs 10 and 11). This reaction needs to be
considered in detail since there has been some
concern as to whether physiologically relevant reducing agents such as glutathione, NADH, and NADPH
are competent to reduce V(IV)-complexes to V(III).7
Initial results obtained by EPR spectroscopy suggested that the Molgula manhattensis tunichrome
reduces, in vitro, V(V) and V(IV) to V(III).540 However, further reexamination by means of a calorimetric V(III) assay revealed that both M. manhattenis
and Ascidia nigra tunichromes failed to produce
detectable amounts of V(III) in either acidic (pH 2)
or neutral (pH 7) media.582 The possibility that A.
nigra tunichrome assayed with V(V) at pH 7 generated low levels of V(III) was, however, not ruled
out.582 Interestingly, a cysteine methyl ester was
recently shown to be able to reduce V(IV) to V(III) in
the presence of aminopolycarboxylates.589 The search
for a natural reductant of V(IV) to yield V(III)
continues. The difficulties experienced in designing
such systems provides fuel to the controversy regarding the reductive power of tunichrome-type
ligands540,582 and other ligand systems.589
New complexes of vanadium with catechols and
similar units continue to be reported,306,478,571,572,590

Chemical Reviews, 2004, Vol. 104, No. 2 881

2VIVO(salen) + 4H+ f
VVO(salen)+ + VIII(H2salen) + H2O (10)
VVO(salen)+ + VIII(H2salen) + 4Cl- f
VIVO(salen) + VIVCl2(salen) + 2HCl (11)
including a dinuclear V(V) catecholate complex [Et3NH]2[VO2(3,5-dtbc)]2 (110).574,575 Because of their rich
properties, these systems have versatile reactivity
patterns, some of which will be described as model
systems for the nitrogenase reaction.591-594

6.1.8. Vanadium Sulfate Complexes

The structural and functional properties of vanadium-sulfate model compounds have been of increasing interest to better understand the nature of the
vanadium in the blood cells of these animals. The
recent interpretations of the XAS spectra (Figure 13)
suggest that the presence of the sulfate is responsible
for the line broadening observed,557 and begged the
need for comparison with spectra from complexes also
characterized in the solid state by X-ray crystallography.

Representative examples of structurally characterized vanadium-sulfate compounds are shown (111117). Most of the structural studies of vanadium-

882 Chemical Reviews, 2004, Vol. 104, No. 2

sulfate interactions have focused on V(IV) presumably

due to the oxygen sensitivity of V(III) and the lower
affinity of sulfate for V(V). The structural information
summarized here is mainly based on crystallographic
information although a symmetry analysis of IR
bands suggests that a distinction between bridging
and chelating sulfate groups can be made in many
cases.595 Sulfate can interact in a variety of ways with
vanadium. Structural information is available on
monodentate (111-114), bidentate (115-117), and
several bridging coordination modes to two (118123), three (124), and even six (125) vanadium

centers; even a mixed bidentate/bridging coordination

mode (126, 127) has been observed. There are additional examples of purely inorganic crystal structures containing vanadium-sulfate interactions. Most
of these compounds are obtained from hydrothermal
syntheses, and their structures contain sulfate-bound
vanadium in oxidation states V, IV, III, and II with
bonding patterns similar to those summarized above.
Representative examples are shown of these purely
inorganic structures model industrial catalysts in
sulfuric acid productions (111, 120, 125, and 126).

Crans et al.

Many of these interactions will not remain intact in

solution.
An aqueous vanadyl complex with sulfate anion,
[VO(H2O)4(SO4)], was prepared via hydrothermal
synthesis and contained layers of complex, sulfate,
and piperazinium ions (111).596 In many sulfatebound V(IV) structures, pyridyl-type ligands are
effective stabilizing ligands,597-601 although other
ligands can be used. A monomeric vanadyl complex
with bidentate sulfate, [VO(terpy)SO4] was structurally characterized (115).597 A density functional theory
(DFT) analysis indicated that in the gas phase [VO(terpy)]2+ unit favors coordination with SO42- over
coordination with two water molecules by 350 kcal/
mol.597 A series of neutral phenanthroline oxovanadium(IV) complexes with monodentate sulfate ligands
have been structurally characterized (112); the integrity of these complexes under physiological conditions was not discussed even though anti-leukemic
activity was reported.598
Bi- and polydentate sulfate-containing ligands have
been used as stabilizing agents in several studies to
generate binuclear complexes. Vanadyl-sulfate complexes (113),602,603 sulfate-bridged divanadyl complexes (118),602,604 and vanadyl-heterometallic sulfate complexes602,604 are among this class of complexes
that have been isolated and characterized. A tetraoxo-tetravanadium(IV) cluster with a tri(hydroxy)alkyl ligand and a bridging sulfate605 and a related
(6-SO4) polyoxometalate cluster (125) were synthesized from an aqueous solution of V2O5 and -alanine.606 A range of polymeric chains expressed as
{[VIVO(SO4)(bipy)]}, (124),599 {[VIV2O2(-OH)2(bipy)2]-SO4-[VIV2O2(-OH)2(bipy)2]}, (119),600 {[(VIVO)2(OH)2(SO4)2]2-}, (120),607 and {[VIVO(H2O)(SO4)2]2-},
(126)607 were all prepared by hydrothermal syntheses
and have been structurally characterized. In {[VIVO(H2O)(SO4)2]2-}, (126), the vanadyl group is bound
by a bidentate sulfate group and a bridging sulfate
group;607 in {[VIVO(SO4)(bipy)]}, (124), the sulfate
acts as a tridentate bridge.599
There are fewer structures containing V(III) in line
with the greater air sensitivity of this oxidation state
and the fact that sulfate fails to stabilize the reduced
vanadium sufficiently. A coordination polymer of
sulfate-bridged dioxalatovanadate(III), trans-K3[V(ox)2(SO4)]n, (121) was structurally characterized in contrast to a monomeric complex trans-K5[V(ox)2(SO4)2]
that was only characterized by IR and Raman
spectroscopy.608 Using the N,N,N,N-tetrakis(2-pyridylmethyl)ethylenediamine ligand, (tpen), a hexacoordinate V(III)-complex with a bidentate sulfate
group was isolated (116) and was found to be stable
in aqueous solution.601 If N,N-bis(2-pyridylmethyl)ethylenediamine, (bispicen), was used instead, a
dimeric, heptacoordinate V(III)-complex with a bridging sulfate was isolated (127).601 The latter of the two
complexes is hydrolytically unstable and forms [V2Cl2(-O)(bispicen)2]Cl2 in aqueous solutions.601 A
potentially octadentate polypyridyl ligand binds two
vanadyl cations, which are further linked by a
bridging sulfate anion (122).609 An oxo-bridged V(III)
dimer, {[V(phen)2(SO4)]2O}, prepared from a hydrothermal reaction of V(V), contains monodentate

Chemistry and Biochemistry of Vanadium

sulfate coordinated to the vanadium centers (114).610

A polymeric material with repeating [VIII(OH)(SO4)2]2units has also been recently obtained (123).607 Other
inorganic V(III) sulfate complexes have been structurally and spectroscopically characterized,611-615
including the anhydrous V2(SO4)3 salt.616

While V(II)-compounds are not likely to exist in

biology, they are discussed briefly for completeness
and for comparison with V(III)-compounds. One
organic V(II) sulfate complex, [V(bipy)2(SO4)], has
been crystallographically characterized and shows a
bidentate sulfate ligand (117).617 The corresponding
[V(py)4SO4] compound was also synthesized. However, only a small number of inorganic V(II) sulfate
compounds have been structurally characterized.618,619
V(IV) rapidly forms a 1:1 complex with sulfate (Kf
) 300 M-1.620 V(III) in contrast to V(IV) has a modest
affinity for sulfate ions in aqueous solutions. V(III)
speciation studies have been carried out using spectrophotometry, redox measurements, and potentiometry.542 The 1:1 ([V(SO4)(H2O)5]+, K 30 M-1) and
1:2 species ([V(SO4)2(H2O)4]-, K 2-3 M-2) have
reasonable stability at acidic pH, although at mildly
acidic pH their hydrolysis products ([V(OH)(SO4)(H2O)4], pKa1 ) 3.2 and [V(OH)2(SO4)(H2O)4]-, pKa2
) 4.6) form.
Structural features of V-sulfate complexes can be
summarized as follows. Complexes in which the
sulfate is monodentate contain a VdO group. When
sulfate coordinates in a bidentate manner, the vanadium can contain a VdO group or be a nonoxo
vanadium depending on the ternary ligand bound to
the vanadium. In cases in which the bidentate sulfate
group bridges two vanadium atoms, the vanadium
contains the VdO unit. Such dinuclear structures can
be discrete molecules or part of an extended network
that may support extensive hydrogen bonding. Triply
bridging sulfate is more rare and includes structures
in which the vanadium atoms are bound to more than
one type of sulfate. These structures are relatively
inorganic in nature and are consistent with an
inorganic coordination environment inside the tunicate vacuoles. Any organic ligand to vanadium that
might be present in the vacuoles should be able to
withstand acidic environments, have low pKa values,
and be able to effectively compete with sulfate
complexation; pyridyl-containing biomolecules are
potential ligands.597

Chemical Reviews, 2004, Vol. 104, No. 2 883

6.2. Fan Worm Pseudopotamilla Occelata

The fan worm Ps. occelata of the Polychaeta class
was reported to contain high levels of vanadium in
1993.519 The vanadium concentration is highest in the
bipinnate radiole, the epidermis covering the radioles. Little vanadium was found in the muscular,
connecting, and supporting tissues or in the blood
plasma, whereas vanadium accumulation on the
vacuolar membranes and in intravacuolar and cytoplasmic electron-dense inclusions were observed.
Most of the vanadium is believed to be in oxidation
state III and a high level of sulfate is found in the
vanadium-containing cells.520,521 Although the vanadocytes are quite different between ascidians and this
fan worm, it is presumably significant that the
storage locale and form seem to be the same in these
animals.520,521 The role of vanadium in these animals
is not known. Proposals include roles in the regulation of oxidation-reduction reactions at the surface
of the radiole, in the absorption of O2, and in
detoxification mechanisms. The possibility that the
action of V-compounds occurs prior to their accumulation in the vanadocytes was suggested.520

7. Vanadium Nitrogenase
7.1. Nitrogenases
The bacterial enzyme nitrogenase (Nase) is capable
of catalyzing the reduction of atmospheric N2 to NH3
and is responsible for cycling about 108 tons of N per
year from the atmosphere to the soil.27 Nase is a
metalloprotein containing Mo and Fe, V, and Fe or
Fe only as the metal cofactors. The enzymatic N2
fixation occurs at ambient temperature and 0.8 atm
N2 pressure; modeling this process remains one of the
great challenges for bioinorganic chemists. The fascination with this protein can be explained, in part,
because of the several protein and inorganic components, and in part because of the complex chemical
reaction that is catalyzed by this enzyme. The overall
reaction of the common molybdenum-containing Nase
is currently believed to be as shown in eq 12. Some
variation in the stoichiometry of e-, H+, and MgATPs
and the overall products of the reaction exists depending on the specific conditions under which the
reaction occurs and which Nase is used. A greater
amount of H2 is generated for each NH3 produced and
more ATP is consumed during the reduction of N2
by the vanadium nitrogenase (V-Nase) (eq 13) as
compared to the molybdenum nitrogenase (MoNase) (eq 12).27 Whether the exact number of MgATP
required for the V-Nase reaction is 4027,30 or 2428-30
can presumably be traced to the difficulties in the
preparation and purification of the enzyme. The
enzymes carry out their function under anaerobic
conditions and have developed elaborate protection
mechanisms to exclude oxygen from the active site
and the redox active cofactors.

N2 + 8e- + 8H+ + 16MgATP f

2NH3 + H2 + 16MgADP + 16Pi (12)
N2 + 12e- + 14H+ + 40 (or 24) MgATP f
2NH3 + 3H2 + 40 (or 24) MgADP +
40 (or 24) Pi (13)

884 Chemical Reviews, 2004, Vol. 104, No. 2

Figure 16. Schematic representation of V-Nase and the

possible structure of vanadium in FeVco. Redrawn from
ref 28. Copyright 2000 Elsevier.

Three classes of Nases exist and all of them are

comprised of Fe-S-cluster-containing subunits, but
differences exist with regard to the heterometalcontaining protein cofactor. The V-Nase is comprised
of an Fe protein and a V-Fe protein, and this enzyme
is the focus of this review. The other Nases, which
have been described in detail elsewhere,7,27,51,621 will
only be discussed when illuminating the function or
properties of the V-Nase. Studies on V-Nase have
been plagued by the recognition that apparent homogeneous mixtures of protein preparations have in
fact been mixtures, and have hindered mechanistic
and structural studies.27
The largest class of Nases is the nif-encoded Nase,
which contains molybdenum and iron in the heterometal cofactor. This type of Nase is expressed under
normal conditions, and is referred to as Mo-Nase.
The second largest class of Nases is the vnf-encoded
Nase. This Nase contains vanadium and iron in the
heterometal cofactor, and is referred to as V-Nase.
Although V-Nase is widely distributed, it is only
expressed when Mo is a limiting nutrient. The third
Nase is the anf-encoded Nase that only contains iron
in its active site and in the Fe-S-cluster cofactors.
This Nase is the most difficult one to access and is
only expressed under molybdenum and vanadium
starvation conditions in some microorganisms. This
Nase is referred to as the Fe-Nase. Although VNase
is a distinct enzyme, its heterometal-based active site
is structurally analogous to that of Mo-Nase.

7.2. Biochemistry of Nitrogenase

The Nases contain two major protein components,
and each of them is comprised of multiple subunits
and/or metal clusters (Figure 16). One protein complex is an iron-containing protein, and another is the
heterometallic protein containing molybdenum (MoFe),
vanadium (VFe), or iron (FeFe). Specifically, in the
V-Nases, the homodimeric Fe protein has a MW of
64 kDa and the VFe protein has a MW of 240 kDa.622
The heterometal-containing subunit has two different
types of inorganic clusters, a P cluster (Fe8S7) and
an MFe-cofactor (Fe7S9M, M ) Mo, V, Fe). The V
form is exclusively observed in the V-Nase and the
Fe form is exclusively observed in the Fe-Nase.
The iron protein component contains two R subunits, which are bridged by a [Fe4S4] cluster and

Crans et al.

incorporates two binding sites for MgATP. A schematic illustration of functional aspects of the complex
is shown in Figure 16. Investigations into the enzymology of this process have recently been reexamined
using ATP-analogues after it was recognized that this
protein contains the peptide fold common for nucleotide binding proteins.623,624
The FeV component has a R222 subunit structure,
and contains two P clusters at the R and subunit
interface. The P cluster is believed to transfer electrons to the FeM-cluster in all three Nases. The M
cluster in the V-Nase is commonly referred to as
FeVco and is the proposed binding site for N2. Two
FeVco clusters are located in the R subunits (Figure
16). The FeVco cluster can be described as the
catalytic cofactor since it is responsible for the
conversion of N2 to NH3 (vide infra). The exact
structure of the VFe protein is still not known, but
all studies so far strongly suggest that it is analogous
to the Mo-Nase.625 A second V-Nase has been found
in Az. vinelandii, which lacks the R subunit and half
of the P cluster, but is active nonetheless.626,627 Thus
far, all the clusters have only been assembled by
biosynthesis.
In the absence of a crystal structure of a VFe
protein, the detail of the environment of the Vbinding site has been provided from EXAFS studies
of proteins isolated from Azotobacter chroococcum
(Ac1v)628 and Az. vinelandii (Av1v).629 The V-atom was
in an environment similar to that observed for the
V-atom in the model compound [Me4N][VFe3S4Cl3(dmf)3] (129).630,631 XANES and EXAFS studies of
thionine-oxidized and dithionite-reduced forms of the
Az. chroococcum Nase suggest a vanadium oxidation
state between +II and +IV.628,632 EPR studies in
reduced Az. vinelandii V-Nase give g ) 5.5, which
corresponds to an overall S ) 3/2 spin for the cluster
in the protein.51,633
Temperature has been shown to play a role not
only with regard to the activity of the Nases, but also
in the expression of the enzymes themselves. Upon
increasing the temperature from 30 to 40 C, the
amount of N2H4 produced by the Az. chroococcum
V-Nase increased by a factor of 15, whereas the
amount of NH3 produced remained constant.634 Increasing the temperature to 50 C resulted in a
further 3-fold increase in N2H4 production and a
7-fold decrease in NH3 production.635 These reversible
effects were interpreted as temperature-induced conformational changes, which at high temperatures,
may allow FeVco to reduce N2 to N2H4, but not to
NH3.51,634 In the same system, V-Nase was shown
to have 10 times the activity of the Mo-Nase when
the temperature was lowered to 5 C.636 In the Az.
vinelandii enzyme system, at 30 C, Mo was found
to repress both the vnf and anf operons, less so at 20
C, and not at all at 14 C.637 Furthermore, vanadium
was shown to repress the anf operon at 30 C, but
not at 20 C; this suggests that Az. vinelandii can
produce all three Nases between 14 and 20 C,
depending on the availability of Mo and V. These
results suggest that Nases found in cooler climates
may favor the presence of V-Nases.

Chemistry and Biochemistry of Vanadium

Figure 17. Structure of the FeMo-cofactor of dithionitereduced A. vinelandii MoFe-protein. Redrawn from ref 641.
Copyright 2002 American Association for the Advancement
of Science.

Chemical Reviews, 2004, Vol. 104, No. 2 885

obtained in a reduced and oxidized form: the PN

cluster being the two-electron reduced form of the POX
cluster.646-649
The active site in the Mo-Nase cofactor is a
MoFe7S9N cluster (Figure 17). A corresponding partial structure has been proposed for the FeVco (128
in Figure 16) and is supported by vanadium EXAFS
and other investigations.625,628,632 Such a proposal
must now consider the presence of an interstitial
nitrogen atom.641 These studies and interpretations
implicate coordination by sulfides, homocitrate hydroxylate and carboxylate groups, and a histidyl
imidazole group (128 in Figure 16). The heterometal
cubane-type clusters with [MFe3S4]z- cores (for example, 129) have been useful precursors in assembling synthetic analogues of the FeMoco and
FeVco clusters of the Nase cofactors.650 For example,
the reduced cores with the framework [VFe3S4]2+ are
topological analogues of the reduced clusters of Nase
and are effective in demonstrating the redox properties of these types of clusters and the analogous Mocontaining clusters.646-649

7.3. Clusters in Nitrogenase and Model Systems:

Structure and Reactivity
The P and FeMoco clusters have been structurally
characterized for the Mo-Nase;53,638-640 however,
recently the MoFe-protein was investigated at 1.16
resolution and an interstitial atom located within
the Fe6 core (Figure 17) was discovered.641 This new
structure has provided information on which all
previous data needs reconsideration, given the role
and effect such a trapped element would have.
Calculations have been carried out and provide
support for the expectation that a nitrogen atom is
the best candidate.52,642 ESEEM spectroscopy showed
that the trapped element did not exchange with
labeled N2 during catalysis,643 suggesting that the
cluster remains intact and does not exchange with
N2 during catalysis. Although less likely, the possibility that exchange did not take place because the
interstitial element is something other than nitrogen
has not yet been ruled out. Discovery of a trapped
nitrogen atom is directly relevant to the heterometal
core in FeVco because of its structural analogy to the
heterometal core of FeMoco.27,51,625 Model calculations
investigating the structure and reactivity of the
active site Nase cofactor cluster, MFe7S9, were carried
out. The studies indicated that the size of the cofactor
cluster is dependent on the nature of the heterometal
and increases in the order FeMoco < FeVco <
FeFeco.644
The P cluster in Mo-nitrogenease has a stoichiometry of Fe8S7 and is closely related to the ironmolybdenum (FeMoco) and iron-vanadium (FeVco)
clusters containing an MFe7S9 structure with a
heterometal and two cysteine residues added to the
P cluster geometry. The P cluster can also be represented in combination with two nearby cysteine
residues from the protein to become a cluster with
an Fe8S9 structure. Recently, synthetic clusters of this
system have been characterized in detail based on
synthetic methodology developed for the preparation
of the MFe4S6 cluster.645-649 The P cluster can be

The first vanadium-containing model system reported,theVFe3S4-cluster[(dmf)3VFe3S4Cl3]-,(129),630,651

illustrated the stability of the [VFe3S4]2+ unit, since
it formed in cluster self-assembly and remained
intact in the presence of excess ligand. A series of
clusters, (130-136), related to this cluster were
subsequently reported and the structures and reactivity of these species investigated in detail.631,651-653
Important new clusters that have been reported
include two vanadium clusters with the VS3O2N
coordination unit, [(Meida)VFe3S4Cl3]3- (137) and
[(Meida)VFe3S4(O-p-C6H4CH3)3]3- (138),650 (Meida )
N-methyliminodiacetic acid) as well as the first
synthetic cluster with the exact core composition as
FeMoco, {[(Meida)MoFe3S4Cl2)](2-S)(Fe4S4Cl3)}4-.650

886 Chemical Reviews, 2004, Vol. 104, No. 2

When V(III) is incorporated into an iron-sulfur

cluster as [VFe3S4]2+ a different charge distribution
results [V3+Fe3+Fe2+2S4]2+(Fe2.33+).649 Examples of
such clusters, [(dmf)3VFe3S4Cl3]- (130), [(dmf)2(PEt3)VFe3S4Cl3]- (131), and [(dmf)(bipy)VFe3S4Cl3]- (132),
are capable of catalyzing the reduction of hydrazine
by cobaltocene/lutidine hydrochloride.651,653-655 Reduction of hydrazine to NH3 is commonly used to
document the reactivity of these clusters and for the
cuboidal clusters (130-135); the coordination of the
hydrazine to the V-atom appears to be critical to its
reduction.630,651,653,655 In contrast to the complexes
(129-135) described above, [(HBpz)3VFe3S4Cl3]2(136)653 does not catalyze hydrazine reduction. The
inactivity of this complex is consistent with the
interpretation that the catalytic reduction rate of
hydrazine of these complexes in general depends on
the terminal ligands coordinated to vanadium. That
is, fewer labile solvent molecules coordinated to the
V-atom lead to lower rates of hydrazine reduction.
A new class of clusters containing the MFe4S6-unit
was reported and represents a new topological system
slightly closer to the FeVco cluster.645 The [VFe4S6(PEt3)4Cl] complex (139) was compared in detail to
the corresponding Mo-system, and due to the large
cavity size in this cluster, greater differences were
observed between the different heteroatom-containing systems. The openness of this structure is in
dramatic contrast to the recently discovered interstitial nitrogen atom in FeMoco, and may explain the
reactivity of (139), which is distinct from that observed with the VFe4S6-unit.

These clusters also catalyze the reduction of phenylhydrazine to NH3 and aniline. Attempts to characterize intermediates by the isolation and characterization of complexes with hydrazine have led to
the report of the hydrazine vanadium single cubane
complex (Me4N)[(PhHNNH2)(bpy)VFe3S4Cl4] (140).655
A related cluster (141) reacts to form (142) and
subsequently (143).648,649 The S-bridged structure of
[(Bpz)2V2Fe6S9(SH)2]4- (143) has crystallographically
imposed C2 symmetry. The core exhibits a bridging
pattern [V2Fe6(2-S)2(3-S)6(6-S)], which reduces to
two cuboidal VFe3(3-S)3 fragments that share a
common bridging atom (the 6-S atom) and are
externally bridged by two 2-S atoms. Cyclic voltammetry experiments on the [VFe3S4]2+ cluster,
[(HBpz)3VFe3S4(LS3)]2- (136), demonstrated the stability of this system by reversible conversion among
the 1+, 2+, and 3+ oxidation states of the clusters.
Double-cubane clusters such as [V2Fe6S8Cl4(C2H4S2)2]4- (135)652 have been reported and their
reactivity investigated. When this cluster reacts with
HSCH2CH2SH in dmso, a single cubane-cluster was
formed (133). Single and double cubane clusters in
multiple oxidation states were isolated from [(HBpz)3-

Crans et al.

VFe3S4(LS3)]2-. The [VFe3S4]3+ unit with the formal

charge distribution of [V3+Fe3+2Fe2+S4]3+, (Fe2.67+),649
was obtained from the double-cubane cluster [V2Fe6S8(SEt)9]3- 656 and the single cubane cluster [VFe3S4(Et2dtc)4]-.283 Recently, new edge-bridged double cubane clusters [(HBpz3)2V2Fe6S8(PEt3)4] (142), and
(Et4N)4[(HBpz3)2V2Fe6S8Cl4],648,649 were characterized.
This study allows the transformations (136) f (141)
f (142) f (143) to be monitored and document the
feasibility of reversible redox changes in the clusters.648,649 These observations support the recent
findings that the P cluster may change during
enzyme catalysis.648,649

7.4. Structural Model Complexes of the VFe

Cofactor Binding Site
In the V-Nase, the coordination sphere of the
FeVco cofactor contains three sulfur atoms from
Fe-S cluster, one N-atom from His-421, and two
O-atoms from (R)-homocitrate (128). There will also
likely be three Fe-atoms near the V-center with V-Fe
distance of 2.76 .27,28 Complexes have been reported
that model part of this structure. The ligands to the
V-atom in these complexes are sulfur, nitrogen, or
oxygen atoms (144-147). The valence of the V-atom
ranges from +III to +V and thus includes model
complexes that have limited air sensitivity. Complexes with a variety of bi- and tetradentate S-donor
functionalities have been prepared as model complexes for Nase.657-660 These complexes have some
structural similarities to the binding site of Nase.
However, in contrast to the isolated cofactor, they fail
to convert N2 to NH3. Selected structures of this type
are shown (144-147). Additional S-coordinated vanadium coordination compounds from V(II) to V(V)
have been described in previous reviews.9,16,28 V(III)
and V(V) complexes of tris(2-thiolatoethyl)amine
N(CH2CH2S)33- (NS3) (148) and bis(2-thiolatoethyl)ether O(CH2CH2S)22- (149) are representative of

Chemistry and Biochemistry of Vanadium

Chemical Reviews, 2004, Vol. 104, No. 2 887

complexes coordinated to a coligand and may be

related to the nitrogen fixation process.661,662 These
coligands can be hydrazine, hydrazide, imide, amine,
organic cyanide, and isocyanide. Since none of these
can convert N2 to NH3, these complexes serve only
as structural models.16,28

7.5. Homocitrate
Homocitrate is a noncovalent cofactor and a structural component of FeMoco. It is presumably also a
component of FeVco and the iron-iron (FeFeco)
clusters, because nifV is required for full functionality
of all three Nases.663 A 49V labeled study showed that
homocitrate is required for the V-precursor transfer
of FeVco from VnfX to nif-apodinitrogenase.664 The
dinuclear V(V) species [K2(H2O)5][(VO2)2(R,Shomocitrate)2]H2O represents the first synthetic and
structural characterization of a transition metal
homocitrate complex and may in fact be an early
precursor in the biosynthesis of FeVco.490
For comparison, several V(V)-citrate complexes
have been reported.480,483,490 The dinuclear V(V)citrate complex, K2[V(O)2(C6H6O7)]24H2O, demonstrated the coordination mode found in the Nase
cofactor.483 See the siderophore section of this review
for additional details on V-citrate complexes.

7.6. Activation of Nitrogen

Given the inertness of N2, the formation of molecular nitrogen coordination compounds is a key step
in nitrogen fixation. The ability of V(II) to reduce N2
to NH3 and/or hydrazine was shown more than 30
years ago.665-667 Shilov demonstrated that N2 is
reduced in alkaline solution in the presence of mixed
V(II) and Mg(II) gels667 and in alkaline V(II)-pyrocatechol solution.666 Although many transition metal
nitrogen complexes have been synthesized, (150159), most of these such as [V(CO)5N2]- (160) are only
stable in solution below -53 C.668 Bioinorganic
chemists are far from their goal of generating catalytically competent complexes for nitrogen fixation
that are stable at ambient temperature.
The activation of N2, by forming bridging (150154) or end-on (155-161) N2 adducts in dinuclear
and mononuclear metal complexes, has been reported
and characterized.668,669 This type of reaction works
best with octahedral complexes of V(II) and V(III),

which tend to have high spin states of the dinuclear

metal complexes, thus favoring interactions between
the nitrogen 1g and the metal d orbitals.670,671 The
activation of N2 can range from poor to strong
depending on the charge of the complex, the presence
of alkali atoms and the spin state of the complex.670,671
Ab initio calculations show dinuclear complexes with
the V-N-N-V motif exhibiting considerable V-N
interactions, with V(II)-complexes being more stable
than V(III)-complexes.670,671 The preparation and
characterization of a bridging complex, with the unit
V(III)-N2-V(III) (151), has however, been reported.669
In mononuclear V(II)- and V(III)-complexes, the V-N
interaction is less stable due to the weak nitrogen
antibonding 1g interactions with the appropriate
metal d orbital. Not surprisingly, no mononuclear
V(III)-N2 complexes have been prepared; however,
mononuclear V(-I)-complexes exist (155-161).
The series of V(-I)-complexes expand the known
systems to include a class of complexes with monodentate (156, 160, 161), bidentate (155, 157, 159),
and tetradentate (158) phosphine ligands.672 In complexes with more than one N2 functionality, the N2
unit can be cis or trans. The cis isomers generally
are the kinetic products, while the trans isomers are
typically the thermodynamic products. Inspection of
the spectroscopic data indicates an ion-pair interaction of the type V-NdNM+.672 Results from computational studies on the model complex [V(PH3)4(N2)2]- (156) suggest that the anionic vanadium
center favors metal-to-ligand -back-bonding while
hampering ligand-to-metal donation.673 This is
consistent with observations of the reductive protonation of these complexes to form NH4+ 672,674,675 and

888 Chemical Reviews, 2004, Vol. 104, No. 2

Crans et al.

the ability of CO and isocyanides to easily displace

coordinated N2.672 Amides and amidinate ligands
(RNC(R)NR-) have been employed as versatile precursors for dinuclear compounds with metal-metal
bonds such as the N2 bridged dinuclear V-complexes
shown in 150-154.676 The diazenido(2-)-bridged complex in 150 has V-N and N-N bond lengths of 1.76
and 1.24 , respectively, but these dinuclear complexes cleave upon the addition of thf. Coordination
of other donor ligands, such as thf, results in the
release of N2 gas and the formation of a monomeric
complex with the formula [V(RNC(R)NR)2(thf)2].676

complexes, the organometallic [V2N2(mes)6] (168)

complex was investigated683 and found to produce
NH4+ and/or N2H5+ with protic reagents. V-Nase
also exhibits an alkyne reductase activity as shown
in eq 15.684,685 Isocyanide reductase activity has also
been reported (eq 16).686

-CtC- + 2H+ + 2e- f -CdCRNC + 6H+ + 6e- f CH4 + RNH2

(15)
(16)

8. Additional Focus Areas in Biomimetic

Vanadium Chemistry

Documenting the precedence for organometallic

complexes such as 162 and 163 are important to the
goal of developing catalysts that fix N2. The mononuclear V(III)-complex with (dimethylamino)methylphenyl (162) was prepared.677 The dinuclear precursor complex [V(Me3Si)N{CH2CH2N(SiMe3)}2)Cl]2
(164) was used to generate the doubly nitrido-bridged
V(V)-V(V) and V(V)-V(IV) dimers (163, 165,
166).678,679

7.7. Formation of Hydrazine and Other Reduced

Compounds
The Nase from Az. chroococcum produces NH3 and
trace amounts of N2H4 (eq 14).634 The formation of
N2H4 prompted investigations into the properties of
V(III)-complexes with N2H4 and their derivatives.

N2 + 4H+ + 4e- f N2H4

(14)

Substituted hydrazines form dinuclear V(III)complexes in which the hydrazine bridges the two
V-atoms (164).680 In mononuclear complexes 167171, the two hydrazine groups are generally coordinated head-on in a trans configuration.680 While most
complexes have the hydrazine group coordinating
head-on (such as 171681) some are thought to coordinate side-on, 168 and 169.682 Although reactivity
studies need to be examined for many of these

A variety of enzyme activities have been observed

by V-compounds in addition to those described above.
In this section, we will briefly review reports on
activities of V-compounds as well as describe emerging systems in bioinorganic V-chemistry. We will
begin by describing the vanadium peroxidase and
catalase activities of V-compounds. Then porphyrin
derivatives and their properties and roles followed
by the insulin mimetic properties of V-complexes will
be discussed. Finally, a few additional areas of
interest will be summarized including the interaction
of serum proteins with V-compounds, and the molybdenum-free nitrate reductase.

8.1. Peroxidase Activity of Vanadium Compounds

Peroxidases catalyze the oxidation of a variety of
substrates using H2O2 as an oxidant. The activity has
been observed both with VHPOs and vanadium
model compounds6,7,38,47,687 as well as other metal
complexes.688 Although the enzyme can use acyl
peracids as an oxidant, the lower efficiency of the
enzyme with this agent results in the accumulation
of oxidized intermediates in solution.47,689 In model
systems, these donors are quite effective.162,690,691
Recently, Pecoraro and co-workers suggested that the
VHPOs may actually be vanadium peroxidases and
that the well-known halogenation reactions may
simply reflect the abundance of chloride in the
marine environment.7,38 The VHPO from As. nodosum can oxidize pseudohalides such as cyanide6,47
and thiocyanate.47,687 The number of substrates converted by this class of enzymes is constantly increasing and is of interest, in part, because such reactions
provide information relevant to understanding the
role of these enzymes and because of the synthetic
utility of the reactions.7,38,46,146,170,181,691 Electron-rich

Chemistry and Biochemistry of Vanadium

substrates that can be accepted by the enzyme are

prime candidates for electrophilic oxidation.
The sulfide oxidation reaction has been the subject
of many investigations using both enzyme and model
compounds as catalysts. The stereoselectivity of this
reaction has been a key aspect of these studies, and
reactions yielding stereoselective oxidations have now
been reported.38,46,146,162,170,258,264 The oxidation of thiol
groups has been implicated as being relevant to the
proposed mechanism of the peroxovanadate interaction with insulin receptors to induce the receptor
stimulated protein phosphorylation.7,319 Recently,
mononuclear model systems were found to be competent to oxidize sulfides to sulfoxides in the presence
of one equivalent of acid.257,692 Evidence for a hypobromite-like vanadium intermediate, [VO(OH2)(OH)(OBr)]+, has been obtained using electrospray mass
spectrometry on the vandate/H2O2/Br- system.231
Model compounds such as 28-31 did not react with
styrene or cyclooctene when tested, presumably
because more electron-rich substrates were needed
for the reaction to take place.257,692

8.2. Catalase Activity of Vanadium Compounds

The Fe-heme containing haloperoxidases catalyze
the disproportionation of H2O2 into singlet excitedstate oxygen;139 however, the VHPOs can catalyze
this reaction only in the presence of Br- or I-.693 This
catalase reaction is favored at higher pH values than
the haloperoxidase reaction which is favored at lower
pH values.139 Studies with model compounds 28-31
in the absence of an organic substrate will generate
dioxygen with the addition of a single equivalent of
both H2O2 and base. The reaction does not occur in
acidic solution, presumably due to the formation of
HOBr. In organic solvents, the disproportionation of
H2O2 is stoichiometric; however, sequential addition
of H2O2, acid, and base can produce one more cycle
of the reaction.7,38,189 Several Schiff base metal complexes with catalase activities are currently under
investigation and specifically the Mn complex holds
promise as a potential pharmaceutical agent for the
treatment of strokes and other life-threatening problems.694

8.3. Vanadium Porphyrins

Porphyrins form very stable complexes, in particular with VO2+, and often function as a thermodynamic sink in the biosphere. VO-porphyrins represent a substantial fraction in crude petroleum695 and
coal;696 a significant byproduct of refining is vanadium sulfide. Synthetic and structural studies tend
to focus on V(IV) porphyrin derivatives,697,698 but a
few V(II)699,700 and V(III)701 porphyrins structures
have been reported. Homo-702,703 and heterodimers703
could be observed by EPR spectroscopy at -193 C.
Vanadyl porphyrins provide a convenient model
system for the more reactive oxoiron(IV) porphyrinate intermediate in oxygen atom transfers.704-707 In
nonaqueous media, multiple oxidation and/or reduction steps are common,708-710 and redox reactions
take place both in the porphyrin ring and on the
metal center. EPR studies show that in the solid

Chemical Reviews, 2004, Vol. 104, No. 2 889

vanadium octaethylporphyrin complex, [VO(OEP)],

the unpaired electron resides in the metal b2(dxy)
orbital. Upon oxidation, an electron is removed from
the porphyrin ring rather than from the metal
center.706,707 Reduction with one electron places the
electron in a porphyrin orbital rather than in the
metal d orbital711 analogous to the redox processes
observed in oxoiron(IV) porphyrinates.712
The heme environment in V-containing myoglobin
and horseradish peroxidases was synthesized and
investigated using EPR spectroscopy.713 V(IV) porphyrins were characterized by both vibrational and
electronic spectroscopy,714 and ESEEM spectroscopy.715,716 An anomalously polarized resonance line
in the Raman spectrum suggested that V(IV) is
located out of the porphyrin plane as is also the case
with the Fe(III) ion.717 As anticipated, the V-O
stretching Raman frequency was sensitive to the
axial ligands -donor characteristics.718 Changes in
Raman spectra of porphyrin cation radicals provided
additional insights for heme porphyrin intermediates.704 EPR spectroscopy indicates that an unpaired
vanadium electron resides in a relatively pure dxy
orbital. Axial interaction of vanadyltetraphenylporphyrin VO(TPP) with Lewis bases was found to be
weak (K < 2) and sterically hindered.719
V(IV) porphyrin intercalation complexes with DNA
were reported, and these complexes are being considered as anticancer agents.720-722

8.4. Insulin-Like Effect of Vanadium Compounds

The insulin-like effect of vanadium salts on
cells723,724 and diabetic animals725-731 has been known
since the 1980s. Diabetic patients frequently have
both abnormal glucose and lipid metabolism, which
can be normalized by treatment with insulin. Although glucose levels in blood and serum were the
original methods for monitoring the symptoms of
diabetes, the correction of abnormal lipid metabolism
in the diabetic state is now also accepted as important in the management of this disease. Recent work
in understanding the pathophysiology of diabetes has
included studies of both glucose and lipid metabolism.732 Studies testing compounds in animal model
systems726-731 and in human beings733-736 show that
simple vanadium salts and V-complexes alleviate the
symptoms of diabetes. The STZ-induced diabetic
Wistar rat is the most common animal model used
for evaluating the insulin-like effect of metal complexes. V-compound treated diabetic Wistar rats can
be divided into responding and nonresponding groups
with respect to the lowering of diabetic hyperglycemia presumably due to genetic variation in the
animals.330,727 Initially, the vanadium salts were
believed to be able to substitute for insulin; however,
currently their effects are most commonly attributed
to enhancing insulin action.737
Peroxovanadium(V) complexes were the first group
of compounds showing significantly higher activity
than the simple inorganic vanadium salts.174,175,277
These compounds are of particular interest because
of their extraordinary (and still unsurpassed) potency
in stimulating the phosphorylation of the insulin
receptor (IR) in in vitro assays.174,175,738,739 The effects

890 Chemical Reviews, 2004, Vol. 104, No. 2

of simple vanadium salts and peroxovanadium compounds on protein tyrosine phosphatases and insulin
receptor phosphorylation have been useful agents in
studies probing the phosphorylated insulin receptor.319 These studies were important because they
demonstrated that hydrolysis of the peroxovanadium
compound did not explain the observed effects observed in cells or in animal model systems. A large
class of compounds based on V(IV) chelate complexes726,740 have been extensively studied mainly by
the Sakurai and Orvig/McNeill groups, respectively.64,729,740,741 The effects of bis(picolinato)oxovanadium(IV)740,742 and the effects of bis(maltolato)oxovanadium(IV),727 have been described in great
detail and have also been reviewed.64 In addition,
recent reports have documented the effects of certain
V(V)-complexes in animals.66,67,743 One class of V(V)complexes are the dipicolinate vanadate complexes,
and the chemistry of these V-complexes have been
examined in detail.66,67 Another class of V(V)-complexes are formed with hydroxamate ligands, and
these compounds have been prepared in situ.743 These
studies counter earlier reports of inactive V(V)complexes derived from maltol.728 A few insulin
enhancing V(III)-complexes have been reported68
suggesting that the vanadium oxidation state does
not seem to be as critical as previously believed.
Reviews describing the effects of a number of Vcompounds tested in animals show how the number
of compounds is rapidly increasing.64,737 The insulin
mimetic effect of V-complexes has now been reported
to extend from V to other metal complexes including
Cr,744 Zn,745-747 and Co complexes.748
Because the insulin signaling system is exceptionally complex, we have yet to understand all of its
intricate details. As such, it is not reasonable to
expect the action of effective insulin-enhancing agents
to be readily understood. Indeed, to date, no single
target can explain all the observed insulin-like effects
of V-compounds.323,327,749-751 The insulin-like effect of
V-compounds likely involves a protein tyrosine phosphatase.13,175,751 Specifically, vanadate is generally
believed to exert its insulin enhancing effect through
competitive inhibition of regulatory protein phosphatases, with a major candidate being phosphatase
1B (pp1B). This phosphatase is the first phosphatase
in the insulin regulatory cascade and is particularly
sensitive to inhibition by V-compounds. Inhibition of
pp1B in a knock-out mouse led to increased insulin
sensitivity and obesity resistance752 and with antisense RNA led to increases in insulin-dependent
signaling in the ob/ob mouse.753 However, the potency
of the competitive inhibition of phosphatases by
V-compounds depends on the structure of the complex, the oxidation state of the metal ion, and the
nature of the phosphatase13,272,314,316,319,754,755 and differs by several orders of magnitude, allowing for
selectivity of V-compounds in vivo. Some V-compounds such as peroxovanadate irreversibly oxidize
the catalytic cysteine in protein phosphatases,319
while simple vanadate salts319,739 (and presumably
[VO(malto)2]) do not undergo similar redox chemistry,
which may explain their smaller effect on the autophosphorylation of the IR.175-177 It is likely that other

Crans et al.

aspects of regulation remain to be unfolded. For some

time, we have been advocating that the failure to
document a correlation between phosphatase potency
and effect in vivo is because this one variable alone
cannot explain the observed insulin-like effects of
V-compounds. We are currently conducting a multimetal compound analysis based on a Compound
Profile database. In such an analysis, correlations
between phosphatase inhibition (as well as other
selected factors) and the insulin-enhancement effect
of transition metal compounds in Wistar rats on the
lowering of elevated cholesterol levels were observed
(unpublished).
The biodistribution and transport of compounds
into cells are likely to play important roles in the
mode of action of the V-compounds. By default, the
compounds must cross lipid interfaces in cells to
reach their desired target. Studies have been done
showing that after the administration of the compound to animals, the compounds will decompose into
the metal ion and the ligand after a certain amount
of time.756,757 Since the metal ion and ligand do not
remain intact, the hypothesis that the adsorption and
transport of the compounds would involve the loss
of organic ligands has been put forward.756,757 The
interaction of vanadyl cation with transferrin was
characterized in detail several decades ago by Chasteen and co-workers,36,295 and these studies as well
as more recent studies will be described below. The
binding of V(IV) to biological ligands, in particular
to transferrin, is important because if transferrin
would bind the intact or partially intact V-complex,
responses to different metal compounds would vary.
In the event transferrin could bind V-complexes with
different affinities, the ligand could be more than a
vehicle to transport the vanadium ion across the
membrane. Indeed, recent studies306 have reported
that transferrin abstracts the vanadium from [VO(malto)2] contrary to earlier studies carried out with
[VO(malto)2]750 and [VO(acac)2],758 which reported
that species other than the vanadyl cation were
bound to the transferrin. A comparison of the transport of [VO(malto)2], [VO(acac)2], and vanadate suggests that the two former complexes, when intact, can
enter cells through passive diffusion.759 The transport
of these compounds into erythrocytes is not affected
by a phosphate anion-transport blocking agent in
contrast to the transport of vanadate, which is
inhibited.759 Additional information on the mode of
transport of these compounds across membranes and
by transferrin is critically linked to when and where
the compound falls apart into ligand and metal ion;
this will be key to determining how important
transport is to the effectiveness of these compounds.
A third mechanism gaining increasing recognition
involves effects of the metal complex on the redox
regulation of the cellular environment. Cytoplasmic
reduction of vanadate by GSH has been recognized
since 1980 and has been extensively studied.760
Cytoplasmic reduction of vanadate to V(IV) can
explain why the Na,K ATPase in vivo seemed resistant to inhibition by vanadate. V(IV) is a less potent
inhibitor of the Na,K ATPase and when vanadate is
reduced to V(IV), it cannot inhibit this enzyme at

Chemistry and Biochemistry of Vanadium

attainable in vivo concentrations of V(IV). The coordination complexes that form between V(IV) and
GSH have been described by several groups,300,301,761-764
and the specific species that form are somewhat
controversial depending on pH, and the metal-toligand ratio.300,301,761,763,764 Surprisingly, little structural information is available on metal ion-GSH
complexes,765 although one related V(IV)-complex
with cysteine methyl ester766 has been reported. A
variety of spectroscopic techniques have been used
to examine V-complexes. Depending on the conditions, eight to nine different V(IV) species have been
observed by EPR spectroscopy in the presence of 100fold excess of GSH.300,301 Because GSH forms even
weaker complexes with V(V) than with V(IV) with
GSH, and because GSH will undergo oxidation while
V(V) is reduced, this reaction is much less understood.
The role of oxidative stress in the etiology of
diabetes has recently been proposed to be involved
in both the origin of the disease and increasing
secondary complications.767 The role of oxidative
stress caused by glucose toxicity and the resulting
production of free radicals, especially in the pancreas,
has been proposed to be a major cause of the
development of insulin resistance in both type 1768
and type 2 diabetics.769-771 This is especially important in patients with diabetic complications. Since
antioxidant therapy is currently being investigated
to decrease the loss of insulin sensitivity768 it is likely
that some of the effects of metal complexes, whether
they be beneficial or toxic effects, may be due to redox
regulation. In rats with STZ-induced diabetes, vanadate administration was shown to decrease GSH
while the levels of GSH reductase and oxidized GSH
remained unchanged.772 In comparison with insulin,
vanadate was only partially able to control the
impaired antioxidation system of diabetic rats. In the
same model system, both vanadate and insulin
improved lipid metabolism as monitored by total lipid
levels, triglyceride, and lipogenic enzymes.773 In
examining different tissues, vanadate administration
was also found to have antioxidant properties when
the activities of antioxidant enzymes catalase, superoxide dismutase, and GSH peroxidase were measured.774 The above results suggest that antioxidant
effects of the oral administration of vanadate have
been established in diabetic rats and support the
hypothesis that changes in cellular GSH metabolism
are connected to the insulin-enhancing properties of
transition metal complexes.
Current recognition of both the negative and the
positive effects of oxidation-reduction reactions in
biology has led to the cellular redox state being
increasingly investigated. Various examples of protein and metabolism regulation have been described,775-778 including the proposal that cellular
oxidation mediates insulin resistance.767 Decreased
glutathione (GSH) levels have been implicated in the
lowered resistance of diabetics to oxidative stress.779
Complications of diabetes have been correlated with
reduced GSH levels, suggesting that antioxidants
such as GSH can protect against diabetic complications.780 The vanadate-stimulated NAD(P)H oxida-

Chemical Reviews, 2004, Vol. 104, No. 2 891

tion781-783 has been extensively investigated. The

possibility that this activity may be linked with the
insulin-enhancing redox-related modes of action has
not previously been proposed, presumably because
superoxide was not yet recognized as an inducer of
normal metabolic processes. However, studies have
been conducted linking vanadate-induced cell growth
regulation to reactive oxygen species.341 Vanadiuminduced Fenton781,783 and Haber-Weiss chemistry781,783
has been investigated, but the possibility that these
reactions are linked to the insulin-enhancing properties of metal complexes has not previously been
proposed. Studies of known and intact coordination
complexes combined with a speciation analysis will
be necessary in such investigations and are likely to
emerge for this and other pathways regulated by the
redox state of the cell.
With all the beneficial action of the variety of
different V-complexes, the failure to implement these
compounds in the treatment of diabetic patients can
mainly be attributed to the toxicity of the compounds.735-737,784 Although the toxic effects are initially manifested as the failure to gain weight and
gastric irritation, the fact remains that for the simple
salts the therapeutic window is too narrow for further
development.735,736,784 Although it may be possible to
dissociate the toxic effects of V-compounds from their
beneficial effects, the progress in this area has been
complicated by the desire to first understand the
mode of action of these compounds. As stated above,
diabetes is a multifaceted disease that is likely to
involve multiple pathways. These considerations may
be further exacerbated by the possibility that some
of the beneficial effects of V-compounds may in fact
involve reactive oxygen species (ROS), which were
recently recognized as important in the normal
control of metabolism by inducing certain transcription factors.785 Studies in cellular systems with a
range of compounds are becoming increasingly important as more information on the action of different
classes of V-compounds in various cellular systems
becomes available (see for example, refs 30, 312,
331-342, 731, and 786).

8.5. Affinity for Transport Proteins: Transferrin

and Serum Albumin
The affinity of serum transport proteins, particularly transferrin, became of increasing interest when
the therapeutic potential of V-compounds was recognized. Model systems to characterize the interaction of serum proteins with V-compounds continue
to be reported and both structural and spectroscopic
techniques are used to investigate the suitabilities
of these models787 to the direct studies reported with
the protein.36,788,789 The interaction of vanadyl cation
and vanadate with both transferrin and serum
albumin was investigated in detail several decades
ago by Chasteen and co-workers36,295 and more recently by others.789-793 Transferrin has an affinity for
vanadyl cation that is at least 10-fold greater than
that of serum albumin.36,790,791,793 Immunoglobins
have little if any affinity for vanadyl cation.750 Serum
albumin can associate with up to 20 molecules of
V(IV), and the resulting complex will represent a

892 Chemical Reviews, 2004, Vol. 104, No. 2

reservoir of readily accessible vanadium in, for

example, infusion solutions.790,791 Studies using CD
spectroscopy suggested a specific interaction between
VO2+ and Cys-34.793 FTIR spectroscopy and gel and
capillary electrophoresis studies suggested that the
VO2+ interacted with the histidine nitrogen atom and
the terminal R-amino groups whereas vanadate
interacted with the -amino group in Lys residues.790
At acidic pH serum albumin in the presence of H2O2
and VO2+ was found to oxidatively deaminate lysine
residues to form the corresponding aldehyde functionalities. The reaction was inhibited by EDTA and
catalase, and at no point was vanadium as effective
as the copper ion in this reaction.794
Recent studies have been carried out and demonstrated that vanadium is carried and accumulated
in transferrin isolated from animal tissue.792,795 The
V-transferrin complex is sufficiently stable to be able
to withstand electrophoresis,796 HPLC,797 or mass
spectrometry797 treatment. Although more labile
complexes may not have been isolated in such studies, complexes containing vanadium in different
oxidation states and with different conformations of
the protein have been detected.797 Few studies have
been carried out with V-complexes to answer the
question as to whether the abstraction of the vanadium ion from the complex is ligand-dependent.306,750,758
Increases in ferritin and lactoferrin expression on
treatment of respiratory epithelial cells by some
metal complexes was reported798 and confirmed studies supporting the link reported between the activation of transferrin gene expression with tyrosine
protein phosphatases.799

8.6. Newly Discovered Class of

Vanadium-Containing Enzyme
Recently, molybdenum-free nitrate reductase enzymes have been isolated from bacteria that contain
vanadium.800,801 The periplasmic nitrate reductase
isolated from Pseudomonas isachenkovii bacteria
showed a correlation between increasing nitrate
reductase activity and vanadium content.800 The
nitrate reductase from Tv. nitratireducens contains
both vanadium and a heme, possibly in the same
subunit.801 The latter enzyme also exhibits nitrite
reductase and haloperoxidase activities. An N-terminal amino acid sequence comparison using SwissProt Bank for this enzyme failed to show a relationship of this enzyme with the molybdenum-containing
nitrate reductases, nitrite reductases, and haloperoxidases.801

9. Summary
V-compounds and vanadium-containing proteins
have shown a wide range of properties and reactivities, some small-molecule based while others provide
the needed structure or function in a biomolecule.
Various aspects of this topic have been described in
more than 100 reviews over the past decade. It was
therefore beyond the scope of this review to be
comprehensive. Indeed, the readers are referred
elsewhere for more information in the various areas,
and key reviews are listed to provide the novice

Crans et al.

reader with access to excellent sources of information

in the various mature and developing areas. New
areas identified in this review include the new
vanadium-binding proteins, vanabins, isolated from
the tunicates, which are proposed to be the first
vanadium transport proteins, and represent only the
third class of proteins (VHPO, VNase and vanabins)
that bind vanadium naturally. The current developments in studies demonstrating haloperoxidase activities from other enzymes to which vanadate was
added, and the recognition that this may be a general
feature of hydrolytic enzymes which may exhibit
similar activities upon binding a metal ion open up
new areas in chemistry and biology. Since many
enzymes are found to have dual functions in biological systems, the fact that the addition of vanadium
(and perhaps other metal ions) can change the action
of a protein may have far-reaching implications for
how vanadium affects biological systems.
Of particular relevance to this review is the observation that V-compounds have been reported to
exhibit increasing numbers of enzyme activities. The
combined range of vanadium bioactivity is vast. The
vanadate-phosphate analogy places vanadate in a
central position to interact effectively with phosphorylases. Indeed, enzymologists and bioinorganic chemists have exploited this analogy for decades, and it
continues to give results in the structural arena that
are important to biologists. Although vanadate may
not be a perfect transition state analogue and may
not be able to provide the entire binding affinity
anticipated for an ideal analogue, very few alternatives exist, and certainly not any with similar high
binding affinities. However, other activities of Vcomplexes are beginning to play a role and show some
selectivities that are very promising such as that
observed in the photochemically induced cleavage of
myosin and F1 ATPase at one specific amino acid
residue by vanadate. Other activities, such as the
peroxidase and haloperoxidase activity exhibited by
amavadine, provide important information to chemists. If amavadine is truly kinetically inert, these
activities would imply outer sphere reactions and
would thus serve as a new prototype of reactivities
exerted by V-complexes. The ability of V-complexes
to act as peroxidases, catalases, and nitrogenases is
very important, and suggest, not surprisingly, that
many reactions of V-compounds include redox processes. Given that many of the compounds able to
model enzyme reactions, are under consideration as
therapeutic agents, can serve as tools in biological
investigations, and are exhibiting new types of reactivities, investigations into vanadium chemistry are
likely to grow significantly in the future.

10. Acknowledgments
DCC thanks the Institute for General Medicine at
the National Institutes of Health for funding.

11. List of Abbreviations

A. ceratodes
Az. chroococcum

Ascidia ceratodes tunicate (sea squirt)

Azotobacter chroococcum nitrogen-fixing bacterium

Chemistry and Biochemistry of Vanadium

A. gemmata
Am. muscaria
As. nodosum
A. sydneiensis
samea
Ar. thaliana
Az. vinelandii
acac
ADP
ADPV
AMP
AMPV
AMV
ATP
ATPase
B. stearothermophilus
Bicine
BMOV
bipy
bispicen
Bpz
Ca. fumago
C. inaequalis
Co. officinalis
Co. pilulifera
Ch. vulgaris
cat
CD45
DOPA
DFT
dmso
3,5-dtbc
En. cloacae P99
E. coli
EPR
ESEEM
EXAFS
FAD
FeMoco
H3hidpa
heida
HSALIMH
LAR
M. manhattensis
malto
MCDD
meida
mes
NAD
NADH
NADP
NADV
NMR
ox
OEP
P. aeruginosa
P. isachenkovii

Ascidia gemmata tunicate (sea squirt)

Amanita muscaria mushroom
Ascophyllum nodosum alga
Ascidia sydneiensis samea tunicate
(sea squirt)
Arabidopsis thaliana flowering plant
Azotobacter vinelandii nitrogen-fixing
bacterium
acetylacetonante
adenosine 5-diphosphate
adenosine 5-diphosphate vanadate
adenosine 5-monophosphate
adenosine 5-monophosphate vanadate
adenosine 5-monovanadate
adenosine 5-triphosphate
adenosine triphosphatase
Bacillus stearothermophilus bacterium
N,N-bis(2-hydroxyethyl)glycine
bis(maltolato)oxovanadium(IV)
2,2-bipyridyl
N,N-bis(2-pyridylmethyl)ethylenediamine
tris(1-pyrazolyl)borate
Caldariomyces fumago fungus
Curvularia inaequalis fungus
Corallina officinalis alga
Corallina pilulifera alga
Chlorella vulgaris alga
catechol
protein tyrosine phosphatase CD45
3-(3,4-dihydroxyphenyl)alanine
density functional theory
N,N-dimethylsulfoxide
3,5-di-tert-butylcatechol
Enterobacter cloacae P99 bacterium
Escherichia coli bacterium
electron paramagnetic resonance
electron spin-echo envelope modulation
extended X-ray absorption fine structure
flavine-adenine nucleotide
iron-molybdenum cofactor
S,S-2,2-hydroxyiminodipropionic acid
N-(2-hydroxyethyl)iminodiacetate
[4-2-(salicylideneaminato)ethyl]imidazole
leucocyte antigen related protein tyrosine phosphatase
Molgula manhattensis tunicate (sea
squirt)
maltolato
2-chloro-5,5-dimethyl-1,3-cyclohexadione
N-methyliminodiacetic acid
mesitylene
-nicotine adenine dinucleotide, oxidized form
-nicotine adenine dinucleotide, reduced form
-nicotine adenine dinucleotide phosphate
-nicotine adenine dinucleotide vanadate
nuclear magnetic resonance
oxalate
octaethylporphyrin
Pseudomonas aeruginosa Gram-negative bacterium
Pseudomonas isachenkovii bacterium

Chemical Reviews, 2004, Vol. 104, No. 2 893

Ph. mammillata

Phallousia mammillata tunicate (sea

squirt)
Ph. nigra
Phallusia nigra tunicate (sea squirt)
Ps. occelata
Pseudopotamilla occelata fan worm
pp1B
protein tyrosine phosphatase 1B
PTK
protein tyrosine kinase
PTP
protein tyrosine phosphatase
py
pyridine
BrNH2pyg
N-(2-pyridylmethyl-3-bromo-6-amino)iminodiacetic acid
quin
quinoline
shi
salicylhydroximate
STZ
streptozotocin
terpy
terpyridine
thf
tetrahydrofuran
tpen
N,N,N,N-tetrakis(2-pyridylmethyl)ethylenediamine
TPP
meso-tetraphenylporphyrin
TS
transition state
Tv. nitratireducens Thioalkalivibrio nitratireducens nitrate reducing bacterium
V-compounds
vanadium compounds
V-complexes
vanadium complexes
VAP
vanadium-associated proteins
VBPO
vanadium bromoperoxidase
VCPO
vanadium chloroperoxidase
V-P
vanadate-phosphate analogy
VHPO
vanadium haloperoxidase
VNase
vanadium nitrogenase
XANES
X-ray absorption near edge structure

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