Biosynthesis of

Purines &
Pyrimidines
Learning Objectives

 To identify the requirements for the synthesis of purines

 To identify the requirements for the synthesis of pyrimidines

 To describe the reactions (pathways) involved in the

synthesis of purine nucleotides

 To describe the reactions (pathways) involved in the

synthesis of pyrimidine nucleotides
 Biosynthesis of Purines & Pyrimidines

 Very little or no dietary purines and pyrimidines are

converted into nucleotides or incorporated into nucleic acids

 Dietary nucleic acids / nucleotides are converted into

purine/ pyrimidine bases which are then completely
metabolized for excretion

 Human tissues synthesize purines and pyrimidines from

amphibolic intermediates according to the physiologic need of
cell / tissue
Biosynthesis of Nucleotides

Two types of pathways:

1. De novo synthesis
Synthesis of purines and pyrimidines from small
precursor molecules

2. Salvage pathways
Recycling the free bases and nucleosides released
from the breakdown of nucleic acids
De novo Synthesis of Purine Nucleotides

 Precursors
 Amino acids (Glycine, Aspartate, Glutamine)
 CO2 (from HCO3-)
 Formyl group (from formyl-tetra-hydro-folate)
 Ribose-5-phosphate (HMP shunt & nucleosides)
 Enzymes (cytosol)
 Coenzymes and Cofactors
 Formyl-and methenyl-tetra-hydro-folate, Mg++
 ATPs
 For Energy & PRPP formation
Sources of Atoms of Purine Nucleus

6
7
5
1 8
Methenyl group
2
4 9
3
Formation of PRPP

+
-
Pi ADP & 2,3-BPG

Regulation by feed back inhibition

PRPP-synthase and PRPP-glutamyl-amido-tranferase are
inhibited by IMP, GMP & AMP
 GAR
Methenyl- H4 folate
Formyl
Transferase

PRPP Glutamyl
amidotransferase

FGAM synthetase

GAR-synthetase

AIR synthetase
AIR carboxylase
AICAR

Formyltransferase

SAICAR-synthetase
IMP Cyclohydrolase

Adenylosuccinase
Formation of other Purine Nucleotides
aspartate fumarate

ATP
ADP
ADP
Oxidative
Phosphorylation

ATP
Salvage Pathways

 Since
 De novo synthesis is expensive and

 A few cells (e.g. RBCs) lack some enzymes involved

in de novo synthesis (e.g. PRPP-amido-transferase)

 Hence cells use salvage pathway (requiring far less

energy and enzymes than de novo synthesis)
Salvage Pathway for Purine Nucleotides

Two pathways are available

a. One step pathway (phospho-ribosylation of purines)

(direct phospho-ribosylation of adenine, guanine and hypoxanthine)

Guanine
Phosphoribosyl
Tranferase
Salvage Pathway for Purine Nucleotides

b. A minor pathway is also available

(phosphorylation of nucleoside)

ATP ADP

Purine – Ribose Purine–Ribose–Phosphate

Nucleoside kinase
A or G AMP or GMP
Synthesis of Deoxy-ribonucleotide
Synthesis of Deoxy-ribonucleotide

Ribonucleotide reductase

- H2O
 Synthesis
of
Pyrimidine Nucleotides
Synthesis of Pyrimidine Nucleotides
 Precursors
 Amino acids (Aspartate, Glutamine)
 CO2 (from HCO3-)
 Methenyl-tetra-hydrofolate
 Ribose-5-phosphate (HMP shunt & nucleosides)
 Enzymes
 Coenzymes and Cofactors
 NAD+, NADPH, tetra-hydrofolate, Mg++
 ATPs
 Energy
 PRPP formation
Sources of Atoms of Pyrimidine Nucleus
 Cytosolic

Orotidine
monophosphate

Kinase

Kinase
Drugs used to inhibit
Purine / Pyrimidine Synthesis

1. Purine analogs e.g. allopurinol

2. Pyrimidine analogs e.g. fluoro-uracil

 Synthetic analogs of purine or pyrimidine or their

derivatives serve as anti-cancer drugs
 Either by inhibiting an enzyme
Or
 By being incorporated into DNA or RNA
 Drugs used to inhibit
Purine / Pyrimidine Synthesis

3. Methotrexate (Anti-folate drugs)

Blocks the reduction of di-hydro-folate to tetra-hydro-folate,
thus inhibiting the nucleotide synthesis

4. Glutamine analogs block purine nucleotide biosynthesis

Synthesis of Pyrimidine Nucleotides
Enzymes
(de novo synthesis of purine nucleodites)
1. Glutamine-PRPP amido-transferase,
2. GAR synthetase,
3. GAR transformylase (Formyl-trasferase)
4. FGAR amido-transferase,
5. FGAM cyclase (AIR synthetase),
6. AIR carboxylase,
7. SAICAR synthetase,
8. SAICAR lyase (adenylo-succinase)
9. AICAR transformylase (formyl tranferase)
10. IMP synthase (IMP cyclodydrolase)
Cytosolic

Kinase

Kinase