Dr Tooba Ali

MBBS, M-Phil (Human Genetics)

 Describe the chemistry of purines and pyrimidines and their linkage in nucleic acid synthesis and their
metabolism.
 Discuss the organization of DNA with special reference to Watson and crick model, composition, structure,
role of Pairing.
 Describe the structural forms of DNA
 Discuss the structure of different types of RNAs with special reference to composition, linkage, functions of
RNA, micro-RNA
 Illustrate the structure and functions of various types of RNAs Describe the functions of various small
RNAs present in cell.
 Explain the structure and nomenclature of nucleotides, biomedical importance of natural and synthetic
analogues
 Interpret the role of synthetic analogues of nucleotides in medicine based on sign/symptoms and data e.g
Methotrexate, 5 Flurouracil and Allupurinol.
 Explain the higher organization of DNA. Difference between DNA, chromatid and chromosome
 Gene
 Unit of heredity which is transferred from a parent to offspring
 composed of distinct sequence of nucleotides forming part of a
chromosome

 Allele
 Each of two or more alternative forms of a gene that found at
same place on a chromosome
 The building blocks of nucleic acids (DNA, RNA)

 Composed of three subunit molecules:

 a nitrogenous base
 a five-carbon sugar (ribose or deoxyribose)
 at least one phosphate group
 Nucleic acids are required for storage and expression of genetic
information

 There are two chemically distinct types of nucleic acids:

 deoxyribonucleic acid (DNA)
 ribonucleic acid (RNA)
NUCLEOSIDE
 A nucleoside is
a nitrogenous
base and a 5-
carbon sugar.
Thus a
nucleoside plus
a phosphate
group yields a
nucleotide.
 Heterocyclic Compounds

 Purines and pyrimidines are nitrogen-containing heterocycles

 Smaller pyrimidine molecule
 Purines or pyrimidines with an ´NH2 group are weak bases (pKa values
3-4)
 The planar character of purines and pyrimidines facilitates their close
association, or “stacking,” that stabilizes double-stranded DNA
 The oxo and amino groups of purines and pyrimidines exhibit keto-
enol and amine-imine tautomerism
 Physiologic conditions strongly favor the amino and oxo forms.

 Direction of numbering of purine ring is different from that of pyrimidine ring
 But the number 5 carbon is the same in both
 The sugar in ribonucleosides is D-ribose, and in
deoxyribonucleosides is 2-deoxy-D-ribose.

 Both sugars are linked to the heterocycle by a a-N-

glycosidic bond, almost always to the N-1 of a pyrimidine
or to N-9 of a purine
Mononucleotides are nucleosides with a phosphoryl
group esterified to a hydroxyl group of the sugar
The 3′- and 5′-nucleotides are nucleosides with a
phosphoryl group on the 3′- or 5′-hydroxyl group of
the sugar, respectively
Most nucleotides are 5′
Additional
phosphoryl groups,
ligated by acid
anhydride bonds
form nucleoside
diphosphates and
triphosphates
 Occasionally found in some species of DNA and RNA
 For example, in some viral DNA, and in transfer RNA.
 Base modifications include methylation, glycosylation,
acetylation, or reduction
 Imporatnce :
 The presence of an unusual base in a nucleotide
sequence may aid in its recognition by specific enzymes,
or protect it from being degraded by nucleases
No freedom of rotation about the β-N-glycosidic
bond of nucleosides or nucleotides
Noninterconvertible syn or anti conformers Both
syn and anti conformers occur in nature, the anti
conformers predominate
Anti-form is necessary for proper positioning of
complementary purine and pyrimidine bases in
double-stranded form of DNA
5-methylcytosine of bacterial and human DNA
5-hydroxymethylcytosine of bacterial and viral
nucleic acids
mono- and the di-N-methylated adenine and
guanine of mammalian messenger RNAs that
function in oligonucleotide recognition and in
regulating the half-lives of RNAs.
Structures of
Hypoxanthine,
Xanthine, and
Uric acid
Free heterocyclic bases include hypoxanthine,
xanthine, and uric acid intermediates in the
catabolism of adenine and guanine.
Methylated heterocycles of plants include the
xanthine derivatives caffeine of coffee, theophylline
of tea, and theobromine of coco
The primary and secondary phosphoryl groups of
nucleosides have pKa values of about 1.0 and 6.2,
respectively.

The pKa values serve either as proton donors or

as proton acceptors at pH values approximately
two or more units above or below neutrality
The conjugated double bonds of purine and
pyrimidine derivatives absorb ultraviolet light.

At pH 7.0 all the common nucleotides absorb light

at a wavelength close to 260 nm.
Precursors of nucleic acids
Principal biologic transducer of free energy
The mean intracellular concentration of ATP, the most
abundant free nucleotide in mammalian cells, is about 1
mmol/L
cAMP acts as second messenger
adenosine 3′-phosphate-5′- phosphosulfate, the sulfate donor
for sulfated proteoglycans and drugs
S-adenosylmethionine acts as a methyl group donor
 GTP serves as an allosteric regulator and as an energy source for protein synthesis
 cGMP serves as a second messenger in response to nitric oxide (NO) during
relaxation of smooth muscle
 UDP-sugar derivatives participate in sugar epimerizations and in biosynthesis of
glycogen, glucosyl disaccharides, and the oligosaccharides of glycoproteins and
proteoglycans
 UDP-glucuronic acid forms the urinary glucuronide conjugates of bilirubin and of
many drugs, including aspirin.
 CTP participates in biosynthesis of phosphoglycerides, sphingomyelin, and other
substituted sphingosines
 Finally, many coenzymes incorporate nucleotides
Nucleotide triphosphates have two acid anhydride
bonds and one ester bond.
Have a high group transfer potential
ΔG0 ′ for the hydrolysis of each of the two terminal
(β and γ) phosphoryl groups of a nucleoside
triphosphate is about −7 kcal/mol (−30 kJ/mol)
 Synthetic analogs of purines, pyrimidines, nucleosides, and nucleotides modified in
the heterocyclic ring or in the sugar moiety
 5-fluoro- or 5-iodouracil,
 3-deoxyuridine,
 6-thioguanine and 6-mercaptopurine,
 5- or 6-azauridine,
 5- or 6-azacytidine,
 8-azaguanine
 CLINICAL
 SIGNIFICANCE…
 5- fluorouracil (5-FU)
Pyrimidine base that inhibits
thymine nucleotides required for
DNA replication…
 Thymine nucleotides can not be
generated and rate of tumor
proliferation is greatly reduced
Purine synthesis inhibitors
Used pharmacologically to control the spread of
cancer by interfering with the synthesis of
nucleotides and, therefore, of DNA and RNA
 Cytarabine is used in chemotherapy
of cancer

 Azathioprine, which is catabolized to

6-mercaptopurine, is employed
during organ transplantation to
suppress immunologic rejection
 Synthetic, non-hydrolyzable analogs of nucleoside triphosphates
allow investigators to distinguish the effects of nucleotides due to
phosphoryl transfer from effects mediated by occupancy of
allosteric nucleotide-binding sites on regulated enzymes

 Incapable of undergoing hydrolytic release of the terminal

phosphoryl group

 Serve as Research Tools