Metabolism of Purine & Pyrimidine nucleotide

1. BIOCHEMISTRY
Metabolism of Purine &
Pyrimidine Nucleotides

2. Purine biosynthesis
the process can be divided into two phases:
-synthesis aminoimidazole ribosyl-5-phosphate (VII)
from ribose 5-phosphate (I)
(through 5-phosphoribosyl-1-pyrophosphate [PRPP]);
-synthesis of inosine monophosphate (XII)
from aminoimidazole ribosyl-5-phosphate

3. Biosynthetic pathway of purine nucleotides

4. The pathway of de novo purine biosynthesis from ribose 5-phosphate
and ATP - start with transfer of pyrophosphate from ATP to C-1 of D-
ribose-5-phosphat (I) forming 5-phosphoribosyl-1-pyrophosphate (II),
which is also an intermediate in NAD+, NADP+, and pyrimidine
nucleotide biosynthesis, and in purin salvage.
[PRPP – is 5-phosphoribosyl-1-pyrophosphate]

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6. Displactment of pyrophosphate from PRPP (II) by the amide nitrogen of
glutamine forms 5-phospho-β-D-rybosylamine (III). The reaction
involves inversion of configutation at C-1, and forms what will become
the β-N-glycosidic bond. [PRPP – 5-phosphoribosyl-1-pyrophosphate]

7. Condensation of (III) with glycine forms glycinamide ribosyl-5-
phosphate (IV) [adds C-4, C-5 and N-7]

8. Transfer to (IV) of a formyl (C-1) from N5,N10-methenyl-
tetrahydrofolate forms formyl-glycinamide ribosyl-5-phosphate (V)
[adds C-8]

9. Transamidation of (V) by the amide nitrogen of a second glutamine
forms formylglycinamidine ribosyl-5-phosphate (VI) [adds N-3]

10. Elimination of water accompanied by ring closure forms
aminoimidazole ribosyl-5-phosphate (VII). The initial event is
phosphoryl group transfer from ATP to the oxo function of (VI).
Nucleophilic attack by the adjacent amino nitrogen then displaces Pi with
accompanying ring closure.

11. Addition to (VII) of CO2 requires neither ATP nor biotin andforms
aminoimidazole carboxylate ribosyl-5-phosphate (VIII) [adds C-6]

12. Reaction 8 (and 9) resemble conversion of ornithine to arginine in the
urea cycle. Condensation of aspartate with (VIII) forms aminoimidazole
succinil carboxamide ribosyl-5-phosphate (IX) [adds N-1]

13. Loss of the succinil group of (IX) as fumarate forms aminoimidazole
carboxamide ribosyl-5-phosphate (X).

14. Formylation of (X) by N10-formyl-tetrahydrofolate forms
formidoimadazole carboxamide ribosyl-5-phosphate (XI) [adds C-2]

15. Ring closure of (XI) forms the first purine nucleotide,
Inosine MonoPhosphate, IMP (XII).
Oxydation and amination of IMP forms AMP and GMP.

16. Addition of aspartate to IMP forms adenylosuccinate. The
adenylosuccinate synthase reaction, while superficially similar to
reaction 8, requires GTP and hence provides a potential focus for
regulation (feedback control) of adenine nucleotide biosynthesis.

17. Release of fumarate forming adenosine-5´-monophosphate (shown as
AMP) is catalyzed by adenylosuccinase, the same enzyme that catalyzes
reaction 9

18. Oxidation of inosine monophosphate (IMP) by NAD+, catalyzed by
IMP dehydrogenase, forms xanthosine monophosphate (XMP).

19. Transamination by the amide nitrogen of glutamine proceeds by analogy
to reaction 5

20. Adenosine monophosphate (is
sythesised through
adenilsuccinate using GTP)
and Guanosine
monophosphate (is sythesised
through
Xantosinemonophosphate
usingATP)
IMP – inosinemonophosphate
Synthesis of
Adenosine monophosphate
(AMP) and Guanosine
monophosphate (GMP)
from inosine
monophosphate (IMP).

21. Control of the rate de novo
purine nucleotide synthesis.
Solid lines represent chemical flow,
and broken lines represent feedback
inhibition by products of the
pathway.
Reactions 1 and 2 are catalyzed by
PRPP synthetase and by PRPP
glutamyl aminotransferase
respectively
PRPP – 5-phosphoribosyl-1-
pyrophosphate]
IMP – inosinemonophosphate

22. Conversion of nucleoside monophosphates to di- and
triphosphates by nucleoside monophosphate kinase and
nucleoside diphosphate kinase kinase.
NMP – nucleosidemonophosphate
NDP – nucleosidediphosphate

23. Pyrimidine biosynthesis
pathway of pyrimidine biosynthesis differ from purine
synthesis in previous pyrimidine ring synthesis
followed by ribosophosphat connection

24. Biosynthetic pathway of pyrimidine nucleotides

25. Pyrimidine biosynthesis bigins with the formation, from glutamine, ATP,
and CO2, of carbamoyl phosphate. This reaction is catalyzed be
cytosolic carbamoyl phosphate synthase, and distinct from the
mitochondrial carbamoyl phospate synthase functional in urea syntesis.
Compartmentation thus provides independent pools of carbamoyl
phosphate for each process.

26. Condensation of carbamoyl phospahate with aspartate forms carbamoyl
aspartate in a reaction catalized by aspartate transcarbamoylase

27. Ring closure via loss of water, catalyzed by dihydroorotase, forms
dihydroorotic acid

28. Abstraction of hydrogens from C5 and C6 by NAD+ introduces a double
bond, forming orotic acid, a reaction catalyzed by mitochondrial
dihydroorotate degydrogenase. All other enzymes of pyrimidene
biosynthesis are cytosolic.

29. Transfer of a ribose phosphate moiety from PRPP [5-phosphoribosyl-1-
pyrophosphate] forming orotidine monophosphate (OMP) is catalyzed by
orotate phosphoribosyltransferase. Formation of the β-N-glycosidic bond
thus is analogous to the transrybosylation reactions. Only at the
penultimate reaction of UMP synthesis is the pyrimidine ring
phosphoribosylated.

30. Decarboxylation of orotidylate forms uridine monophosphate (UMP),
the first true pyrimidine ribonucleotide.

31. Reactions (7) & (8) phosphate transfer from ATP yield uridine
diphosphate (UDP) and uridine triphosphate (UTP) in reactions
analogous to those for phosphorylation of purine nucleoside
monophosphates.

32. (8) Uridin diphosphate (UDP) → Uridine triphosphate (UTP)

33. Reaction (9) uridine triphosphate (UTP) is aminated to cytidine
monophosphate CTP by glutamine and ATP

34. Reduction of ribonucleotide diphosphates (nucleotide diphosphats
[NDPs]) to their corresponding deoxynucleotide diphosphats [dNDPs])
involves reactions analogous to the purine nucleotides.

35. dUMP may accept a phosphate from ATP forming dUTP (not shown).
Alternatively, and since the substrate for TMP synthesis is dUMP,
dUDP is dephosphorylated to dUMP.

36. Methylation of dUDP at C-5 by N5,N10-methylene-tetrahydrofolate,
catalyzed by thymidylate synthase, forms thymidine monophosphate
(TMP).

37. Adenosine and Guanosine chemical degradation
[Uric acid (allantoin) sythesis]

38. Cytosine [Uracil] and Thymine chemical degradation

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