Purine and pyrimidine synthesis

1. Nucleotides Synthesis
By: Sahaya Asirvatham

2. lNucleic acids consist of nucleotides that have a sugar, nitrogen base, and phosphate

3. Nitrogenous Bases

4. Base Pairs
l2,4-deoxy, 5-methyl pyridine l2,4 deoxy pyridinel2 oxy,4 amino pyridine
l6-Amino Purine
l2 -Amino,6-oxy Purine

5. Base Pairs

6. Biosynthesis

7. de
novo
synthesis
Salvage
Two pathways leading to nucleotides

8. Differences in Purine and Pyrimidine synthesis
lPurines
lSynthesis starts with PRPP, purine
ring is built step-by-step with C-1 of
PRPP as a primer
lPyrimidines
lThe pyrimidine ring is
synthetized before ribose is
added
O
O
C H 2OP
O
O
O
-
-
O H O H
P P
O
OO
O
-- O
O
-
N
NO
O
C O O
-
H

9. Purines

11. Site:
In cytosol of liver, small intestine and thymus
Characteristics:
Purines are synthesized using 5-phosphoribose(R-5-P) as the starting
material step by step
PRPP(5-phosphoribosyl-1-pyrophosphate) is active donor of R-5-P
AMP and GMP are synthesized further at the base of IMP(Inosine-5'-
Monophosphate)
De novo Synthesis

13. Starts from ribose-5-phosphate(R-5-P)
Requires 11 steps overall
Occurs primarily in the liver
Basic pathway for biosynthesis of Purine Ribonucleotides

16. STEP-I
Committed step of the pathway,
an amino group donated by
Glutamine is attached at C-1 of
PRPP resulting in
5-Phosphoribosylamine
Glutamine-PRPP
amidotransferase
Acquisition of purine atom N9

17. STEP-II
Addition of 3 atoms from glycine
An ATP is consumed to activate the
glycine carboxyl group for this
condensation reaction
GAR synthetase
acquisition of purine
atoms C4, C5, and N7

18. STEP-III
The added glycine amino
group is then formylated by
N10-formyltetrahydrofolate
GAR transformylase
•acquisition of purine atom C8

19. STEP-IV
Nitrogen is contributed by
Glutamine
FGAR amidotransferase
acquisition of purine atom N3

20. STEP-V
Dehydration and ring closure yield
the five-membered Imidazole ring
of purine nucleus, as
5-aminoimidazole Ribonucleotide
FGAM cyclase
(AIR synthetase)
•closing of the imidazole ring

21. STEP- VI VII and VIII
A rearrangement transfers the carboxylate from the
exocyclic amino group to position
4 of the imidazole ring (step 7 ).
Steps 6 and 7 are found only in bacteria and fungi.
In higher eukaryotes, including humans, 5-AIR
product of step 5 is carboxylated directly to
CAIR in one step instead of two (step 6a).
N5-CAIR synthetase
N5-CAIR mutase
SAICAR synthetase
AIR carboxylase
acquisition of C6 and N1

22. STEP- IX
Aspartate now donates its amino group in two
steps ( 8 and 9 ): formation of an amide bond,
followed by elimination of the carbon skeleton
of aspartate (as fumarate)
SAICAR lyase
elimination of fumarate

23. STEP-X
AICAR transformylase
acquisition of C2

24. STEP-XI
IMP synthase
ring closure to form IMP

25. Synthesis of
AMP and GMP
from Inosine
monophosphate(IMP)

26. Regulation of Purine Nucleotide
Biosynthesis

27. This pathway ensures the recycling of purines formed by degradation
of nucleotides
Nucleosides & deoxy-nucleosides can also be salvaged
The purines can be directly converted to the corresponding
nucleotides & this process is known as ‘salvage pathway’

34. Gout
i. Excess of uric acid in blood
(Hyperuricemia).
ii.Deposition of sodium monourate
iii.Recurring attacks of acute arthritis.

35. • Hyperuricemia is not due to increased destruction of nucleic acid.
a.Primary metabolic gout:
inherited metabolic defect in purine metabolism
X-linked recessive defects enhancing the de novo synthesis
b. Primary renal gout:
It is due to failure in uric acid excretion.

37. PYRIMIDINE METABOLISM
Pyrimidine is first synthesized .
Later, it is attached to ribose -5 phosphate

38. The synthesis of pyrimidines is a much simpler process
compared to that of purines.
Aspartate, gutamine and CO2 contribute to atoms in the
formation of pyrimidine ring.
Pyrimidine ring is first synthesized and then attached to ribose
5-phosphate.
BIOSYNTHESIS OF PYRIMIDINE RIBONUCLEOTIDES

39. Formation of carbomyl phosphate
Carbomyl phosphate is formed from ATP, GLUTAMINE and
CO2.
The reaction is catalysed by CPS –II.

43. DEGRADATION
OF
PYRIMIDINES

46. 1. Sulfonamide
They inhibit the reactions of purine nucleotide synthesis requiring folic acid ( GAR
transformylase and AICAR transformylase) Used as bacteriostatic drugs to control bacterial
infection
2. Methotrexate, Aminopterin and Trimethoprim
They inhibit the reaction requiring folic acid for purine nucleotide synthesis.
Used in t/t of cancers like leukemia
Used in the t/t of bacterial infections and UTI
3. 6-mercaptopurine
Is a structural analogue of purine bases.
It is converted to 6- thioionosine monophosphate by the enzyme HGPRT, called lethal
synthesis.
5. Thioguanine
Is a guanine analogue.
It is converted to 6-thio GMP by the enzyme HGPRT.
Inhibitors

47. Inhibitors
6. Azaserine
• Is a structural analogue of glutamine.
• Is a glutamine antagonist.
•COLCHICINE
Used in the symptomatic treatment of acute attacks of gout
•PROBENECID
A uricosuric agent inhibits the tubular reabsorption of uric acid
•ALLOPURINOL
Inhibitor of xanthine oxidase
•inhibits the metabolism of certain anticancer drugs (6-MP, azathioprine)

48. 6-mercaptopurine blocks de novo purine synthesis
blocks PRPP synthetase
Hydroxyurea inhibits ribonucleotide reductase
5-fluorouracil inhibits thymidylate synthase->
decrease dTMP
Methotrexate inhibits dihydrofolate reductase->
decreased dTMP
Trimethoprim inhibits bacterial dihydrofolate
reductase-> decreased dTMP
Ribonucleaotide reductase UDP to dUDP
pyrimidine synthesis
inhibited by hydroxyurea
Thymidylate synthase dUMP to dTMP with THF as cofactor
pyrimidine sythesis
inhibited by 5-fluorouracil