Lecture Notes-Bioorg-2019

Shikimates and
Phenylpropanoids
CO2H

HO OH
OH

shikimic acid
Introduction
Shikimic acid is the key intermediate of a large group
aromatic natural products. The isolation of shikimic acid was
first reported from aniseed (Illicium anisatum) and the fruit of
I. religiosum, whose Japanese name was “shikimi-no-ki” (shi 
four; kimi  seasons; no  of; ki  tree, literally “tree of four
seasons”). Shikimic acid has since been found in many plants,
bacteria, yeasts and moulds.
It is estimated that this group accounts for 35%
of plant dry mass, and that one-fifth of the CO2H

carbon fixed by plants is channeled to shikimic

acid metabolites, such as the lignins.
HO OH
Shikimic acid is the precursor of three important OH
aromatic amino acids: phenylalanine, tyrosine,
shikimic acid
and tryptophan.
2
Overview glycolysis _
OP
H+
O2C _ O
phosphoenol pyruvate O2C
D-glucose
H OH H

PO H-O
pentose O OH
HO
phosphate H H H
OH
cycle
D-erythrose-4-phosphate heptulose

_ _
CO2 HO CO2
Shikimic acid is produced directly
from two D-glucose metabolites:
phosphoenol pyruvate (C3) and D- O OH O OH

OH OH
erythrose-4-phosphate (C4) condense 3-dehydroshikimate 5-dehydroquinate

to form the seven carbon heptulose.

Heptulose cyclizes to form 5- _
CO2
dehydroquinate which loses water to
form shikimic acid.
HO OH

OH
shikimate

3
 Shikimic acid is converted to 5-enolpyruvylshikimate-3-
phosphate, which loses phosphate to yield chorismic acid and
prephenic acid. Chorismic acid is the branch point to a group
of benzoic acid metabolites and tryptophan. Prephenic acid
leads to the phenyl propanoids (C6-C3) and the flavonoids
(C6-C3-C6), and the amino acids phenylalanine and tyrosine.
HOCH2

H O
OH
H
OH H H
HO
H OH

D-glucose

CH3
CO2H CO2H CO2H
O CO2H 1

benzoic acids,
EPSPS 3 5 tryptophan
HO OH PO O CO2H O CO2H
OH OH OH
shikimic acid 5-enolpyruvylshikimate chorismic acid
-3-phosphate

EPSPS: 5-enolpyruvyl phenylalanine,

shikimate-3-phosphate tyrosine
O lignans,
synthase
lignins
HO2C CO2H

+ (3 x Ac-CoA)
phenyl propanoids flavonoids

OH phenols
prephenic acid

styrenes benzoic acids 4

 polyketide aromatic compound quinone

In plants:
[O]
polyketide aromatic compound quinone

quinone
Overview of
shikimate aromatic compound
biosynthesis of + terpene
[O]
quinones. Depending quinone
on the organism, (mixed metabolite)

quinones can arise via

the polyketide or quinone from shikimate: quinones from shikimate + terpene:

shikimate pathways. OH OH O H OH

CO2H

OH OH O
homogentisic acid alkarinin

O n

ubiquinones: R = H, CH3 ; n = 4-13

5
Shikimates comprise a large group of aromatic natural products.
CO2H CO2H

NH2
R O O
phenylalanine, R=H cinnamic acid coumarin
tyrosine, R=OH

CO2H
CO2H O

phenylacetic acid benzoic acid

O

flavonoid
O

lignan

6
Shikimic acid picks up three carbons from of phosphoenol pyruvate to
form chorismic acid and prephenic acid. Chorismic acid is converted to
prephenic acid via a concerted [3,3]-sigmatropic shift.
_
_ _
CO2
CO2 CO2
H
H
H

1. ATP _ _
HO OH
PO O CO2 O CO2
OH 2. PEP _
PO CO 2 OH OH
shikimate
5-EPSP chorismate

_
_ _ CO2
_ 1 _
3 CO2 O2C CO2
O2C 2
_
2 3 CO2 3
1 3
3 O O 2
2 HO 3
1 _
1 [3,3]- 2
O CO2
sigmatropic 1 2 1
OH
shift OH
OH p-hydroxybenzoic acid
prephenate

o-aminobenzoic acid,
p-aminobenzoic acid
phenylpropanoids
7
 a
O _ NH2
O
_ CO2 _
O CO2 CO2H
Prephenate is O
a
the precursor of
-CO2, Pyridoxamine
phenylalanine -H2O transaminase
and tyrosine. OH
phenylalanine
prephenate

b [O]

_
_ O NH2
CO2
O2C _
CO2 CO2H
O

-CO2 Pyridoxamine
transaminase
O
OH OH
tyrosine

8
C6, C6-C1 and C6-C2
The shikimate metabolites can be grouped according to the
number of carbons atoms in the side chain.
• C6 phenols and quinones
• C6-C1 : benzoic acid derivatives, including tannins
• C6-C2 : phenyl ethyl compounds

9
A. Polyketides Hydroxybenzoic acids Benzoquinones

B. Shikimatic acid Homogentisic acid Benzoquinones C6 Metabolites

Quinones are
Chroismic acid
formed mainly from
p-Hydroxybenzoic acid Benzoquinones
Phenylalanine the polyketide and
shikimate pathways,
although other
From p-Hydroxybenzoic acid:
groups may produce
CO 2H CO 2H
1. -CO 2 quinones from
2. [O]
R= 3. O-methylation
extensive
n
from terpenes
modification. The
R MeO R
OH OH
biosynthesis of
OH
1. [O] ubiquinone, the
2. C-methylation compound which
assists in biological
O O OH
Me
electron transfer, is
Me Me
[O] shown.
MeO MeO R MeO R

O n O OH
Ubiquinone 5-Demethoxy
10
ubiquinone
C6-C1. Tannins are a group of benzoic acid plant metabolites which precipitate
proteins. The gallotanins, which are hydrolyzable tannins, contain glucose and
gallic acid joined by ester linkages.
HO
O

HO OH
O O
HO
HO O OH
OH corilagin
O
HO OO
O OH OH
O
HO HO O
OH
OH
OH
O
O
OH
OH
HO O
O
OH
HO O
O OH
O

HO O O
HO OH
OH
O O
O
HO OH

HO Turkish tannin

HO OH

11
Two benzoic acid derivatives of some interest are gallic acid and ellagic acid.
Gallic acid and ellagic acid are constituents of hydrolyzable tannins but these are
found in many other natural products. These compounds are natural antioxidant
in aqueous and micellar environments. Ellagic acid is also a naturally-occuring
phytochemical pesticide and antimicrobial.

OH OH
HO
O
OH HO
HO
HO OH
O
OH O
HO O
O HO
O
O
Gallic acid OH
HO
OH

HO OH
Ellagic acid

12
 OH
Ellagitannins are hydrolyzable
HO OH
tannins which are formed from OH

the condensation of a sugar OH

core and ellagic acid units. R1 R2

Ellagitannis from banaba, HO

O H O O
OH
Lagerstroemia speciosa, were O H O OH
shown to increase uptake of HO
H O OH
adipocytes in rats, and could be HO H O
O
responsible for lowering the HO
CH2 OH
blood glucose level. (Hayashi, et O
O
O
HO
al., “Ellagitannins from Lagerstroemia
speciosa as Activators of Glucose HO
HO
Transport in Fat Cells,” Planta Med.,
O
2002, 68, 173-5.) O

O
O

Lagerstroemin: R1=OH; R 2=H OH

Flosin B: R1=H; R2=OH OH

13
 CO 2H CO 2H CO 2H

PAL -o xidation

NH2

The benzoic phenylalanine cinnamic acid be nzoic acid

and cinnamic [O] [O] [O]

acids are CO 2H CO 2H
-o xidation
CO 2H
TAL chorismic
biosynthesized NH2 acid
HO
in a metabolicHO

tyrosine 4-hydroxycinnamic acid

HO

p-hydroxybenzoic acid
grid. These (p-coumaric acid)

compounds [O] [O] [O]

occur widely HO CO 2H HO CO 2H
HO CO 2H
HO CO 2H
-o xidation
in plants. NH2
HO HO
HO HO
3,4-dihydroxyphenylalanine (DOPA) caffe ic acid pro tocatec huic ac id OH

de carbo xylase, gallic acid

[CH3] [CH3]
-CO2

HO CH3O CO 2H CH3O CO 2H
-o xidation
NH2
HO HO HO

do pamine ferulic acid vanillic acid

1. [O]
1. [O] 1. [O]
2. [Me]
2. [Me] 2. [Me]

OH
CH3O CO 2H CH3O CO 2H
HO
-o xidation

NH(CH3) HO HO
HO
OCH3 OCH3 14
adrenaline
sinapic acid syring ic ac id
Cyanogenic glycosides: C6-C2

• A cyanogenic glycoside has an

aglycone with a cyanide group and
an attached sugar. Cyanogenic
glycosides release the poisonous
hydrogen cyanide enzymatically.
• Cyanogenic glycosides are found in
cassava, and the fruits and wilting
leaves of the rose family (including
cherries, apples, plums, almonds,
peaches, apricots, and raspberries).
Sorghum (Sorghum bicolor)
expresses cyanogenic glycosides in
its roots and thus is resistant to pests
such as rootworms.
• The dotted arrow is a metabolic link
to aromatic glucosinolates.
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 Glucosinolates • The glucosinolates are found in
Brassicales and contain sulfur,
OH
-
nitrogen and a group derived from
OSO3
HO O glucose.
S N
HO
HO
• About 120 glucosinolates are known
in plants, where the R group is alkyl,
(R group derived from methionine, alanine,
HO
variable) leucine, or valin; aromatic, derived
from phenylalanine and tyrosine; or
indolic derived from tryptophan.
• Glucosinolates act as natural pesticides and defense against
herbivores. These substances are also responsible for the
bitter or sharp taste of many common foods such as mustard,
radish, horseradish, cress, cabbage, Brussels sprouts,
cauliflower, broccoli, and turnip.
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 Phenyl propanoids: C6-C3
• The phenylpropanoid metabolism is unique to plants.
• Many intermediates and end products of the phenylpropanoid
pathway play important roles in plants as phytoalexins,
antioxidants, antiherbivory compounds, UV protectants,
pigments, and aroma compounds. Phenylpropanoids
polymerize to form lignins, which are essential components of
the cell wall stability.
• Phenylpropanoid biosynthesis is one of the best-studied
pathways in plants. The enzymes of the phenylpropanoid
pathway are organized in multi-enzyme complexes and there
is evidence for the coordinated expression of genes and
enzymes. Genes encoding enzymes of this pathway are
developmentally and tissue-specifically regulated and may be
induced by environmental stresses such as nutrient deficiency,
exposure to cold, UV light, and pathogen attack.  17
Phenylalanine and tyrosine are deaminated by phenylalanine ammonia lyase
(PAL) or tyrosine ammonia lyase (TAL) to cinnamic acids. The cinnamic
acids (C6-C3) are the precursors to the phenyl propanoids, coumarins,
styrenes, benzoic acids, phenols, and flavonoids. A multi-enzyme complex
enables coordinated action of PAL and cinnamate-4-hydroxylase (C4H) which
control the flux of intermediates in phenylpropanoid biosynthesis.
NH2 CO2H Ar - C3: cinnamaldehydes
CO2H
cinnamyl alcohols
CO2H aryl propanes
PAL
or
TAL
Ar - C3: coumarins
C4H
R1 R3
R R R2
phenylalanine, R=H
cinnamic acids
tyrosine, R=OH + 3 x Ac
Ar - C2: styrenes
flavonoids acetophenones

Ar - C1: benzoic acids

Ar: phenols
benzyl aldehydes
quinones
benzyl alcohols
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 HO CO2H
Examples of 3-caffeoylquinic acid (chlorogenic acid).
First isolated in 1846 from coffee, it has since
O
cinnamic acids OH
been found to be a common plant compound.
It functions as an allelopathic substance in
HO O sunflower.
and the C6-C3 OH
derivatives. OH

Cinnamic acids HO
OH

themselves do O O
CH3O
not usually HO OH OH

occur in the HO
OC OH
RO

free form but O

coniferyl alcohol, R=H
coniferin, R=glucosyl
are isolated as 2-caffeoylarbutin

glycosides. CH3O

Cinnamic acids eugenol

Eugenol and saffrole are well-known
are precursors HO
constituents of flavor and spice plants.
They are precursors to lignins and lignans.
of lignans and O
lignins. saffrole
O

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Examples of cinnamic acids and the C6-C3 derivatives. Rosmarinic acid is
a dimer of two different C6-C3 units.

CO2H
HO CO2H
O
NH2
HO OH
HO O
tyrosine
caffeic acid HO CH2 CH CO2H
OH

HO
HO CO2H
CO2H rosmarinic acid

NH 2 OH Rosmarinic acid is a naturally-occurring

HO
anti-histamine compound from
phenylalanine tsaang gubat (Ehretia macrophylla).

Coumarins are aromatic lactone C6-C3 derivatives. They are widely

distributed in plants, particularly the Umbelliferae and Rutacea families.
CO2H CO2H CO2H
[O] glucose
RO RO OH RO O-glu

E Z
R1 R2
umbelliferone H H R2
herniarin CH3 H 5 4
6 3
skimmin glu H
7 1 2
aesculetin H OH 8 CO2H
scopoletin CH3 OCH3 R1O O O RO O-glu 20
Examples of coumarin compounds.
O HO
O-H O O
CO2H C
H H

OH O O O O

O-H

O O

Some microorganisms (such as Aspergillus fumigatus ) O O

CH2
transform coumarin from plants (such as grass)
to produce dicoumarol. Dicoumarol is a powerful
blood anticoagulant and can cause fatal hemmorages
in cattle that eat the hay.
O O O O
dicoumarol

OH HO
O H O Furobinordenatin is a coumarin from Citrus plants.
H
O O

O HH O

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Lignans are phenylpropanoid dimers. They can be rationalized by formation by
coupling of resonance-stabilized by radicals with the assistance of “dirigent” proteins.
OH

oxidase only oxidase with guiding (dirigent) protein

OCH3

OH

OH O
. OH
CH3O
HO
CH 3O
OH H
O .
O OH
H
OCH3
OCH3
Proposed coupling intermediate
(+/-)-Dehydrodiconiferyl alcohols

+
OCH3
OCH3
OH
OH
O
O

H H

O
O
HO
HO
OCH3
(+/-)-Pinoresinols OCH3
(+)-Pinoresinol
+ Other dimers
(N.G. Lewis, et al. in Science, 275, 362 (1997);
Plant Physiol., 123, 453 (2000); Chem. Biol., 6, 143 (1999))

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The diversity of lignan structures can be rationalized by bond formation via
different radical sites.
CH 2OH CH2OH CH2OH
CH3O CH 2OH
.

[O] O CH 2OH

CH 3O CH 3O CH3O
OH O. O OCH 3

H+ O

O
[H]
HO
OCH3
OCH 3
CH 3O CH 2OH

HO CH 2OH
HO
OH
O O

OCH3
O
OCH 3 H+
OCH3
O
HO
H+
(+)pinoresinol CH 3O CH2OH

HO CH2OH

OCH 3
OH
(+)isolariciresinol

23
The diversity of lignan structures can be rationalized by bond formation via
different radical sites.

H
.

CH3O CH3O
. O O
OCH3 OCH3
CH3O O HO
O
O licarin A
OCH3 H+

(from eugenol)

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