BIOCHEMISTRY

Metabolism of Purine &

Pyrimidine Nucleotides

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

Biosynthetic pathway of purine nucleotides

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]

Sponsored

Medical Lecture Notes – All Subjects

USMLE Exam (America) – Practice

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 becomethe β-N-glycosidic bond. [PRPP – 5-phosphoribosyl-1-pyrophosphate]

Condensation of (III) with glycine forms glycinamide ribosyl-5-

phosphate (IV) [adds C-4, C-5 and N-7]

Transfer to (IV) of a formyl (C-1) from N5,N10-methenyl-

tetrahydrofolate forms formyl-glycinamide ribosyl-5-phosphate (V)

[adds C-8]

Transamidation of (V) by the amide nitrogen of a second glutamine

forms formylglycinamidine ribosyl-5-phosphate (VI) [adds N-3]

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.

Addition to (VII) of CO2 requires neither ATP nor biotin andforms

aminoimidazole carboxylate ribosyl-5-phosphate (VIII) [adds C-6]

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]

Loss of the succinil group of (IX) as fumarate forms aminoimidazole

carboxamide ribosyl-5-phosphate (X).

Formylation of (X) by N10-formyl-tetrahydrofolate forms

formidoimadazole carboxamide ribosyl-5-phosphate (XI) [adds C-2]

Ring closure of (XI) forms the first purine nucleotide,

Inosine MonoPhosphate, IMP (XII).

Oxydation and amination of IMP forms AMP and GMP.

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.

Release of fumarate forming adenosine-5´-monophosphate (shown as

AMP) is catalyzed by adenylosuccinase, the same enzyme that catalyzes

reaction 9

Oxidation of inosine monophosphate (IMP) by NAD+, catalyzed by

IMP dehydrogenase, forms xanthosine monophosphate (XMP).

Transamination by the amide nitrogen of glutamine proceeds by analogy

to reaction 5

Adenosine monophosphate (is

sythesised through

adenilsuccinate using GTP)

and Guanosine

monophosphate (is sythesised

through

Xantosinemonophosphate

usingATP)

IMP – inosine monophosphate

Synthesis of

Adenosine monophosphate

(AMP) and Guanosine

monophosphate (GMP)

from inosine

monophosphate (IMP).

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 – inosine monophosphate

Conversion of nucleoside monophosphates to di- and

triphosphates by nucleoside monophosphate kinase and

nucleoside diphosphate kinase kinase.

NMP – nucleoside monophosphate

NDP – nucleoside diphosphate

Pyrimidine biosynthesis

pathway of pyrimidine biosynthesis differ from purine

synthesis in previous pyrimidine ring synthesis

followed by ribosophosphat connection

Biosynthetic pathway of pyrimidine nucleotides

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.

Condensation of carbamoyl phospahate with aspartate forms carbamoyl

aspartate in a reaction catalized by aspartate transcarbamoylase

Ring closure via loss of water, catalyzed by dihydroorotase, forms

dihydroorotic acid

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.

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.

Decarboxylation of orotidylate forms uridine monophosphate (UMP),

the first true pyrimidine ribonucleotide.

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.

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

Reaction (9) uridine triphosphate (UTP) is aminated to cytidine

monophosphate CTP by glutamine and ATP

Reduction of ribonucleotide diphosphates (nucleotide diphosphats

[NDPs]) to their corresponding deoxynucleotide diphosphats [dNDPs])

involves reactions analogous to the purine nucleotides.

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.

Methylation of dUDP at C-5 by N5,N10-methylene-tetrahydrofolate,

catalyzed by thymidylate synthase, forms thymidine monophosphate

(TMP).

Adenosine and Guanosine chemical degradation

[Uric acid (allantoin) sythesis]

Cytosine [Uracil] and Thymine chemical degradation

Thank YOU for ATTENTION