Purine Nucleotide Synthesis: A Comprehensive Guide, Study Guides, Projects, Research of Biochemistry

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 N1 of purine is derived from amino group of aspartate.  C2 & C8 from formate of N 10

• formyl THF.  N3 & N9 are obtained from amide group of glutamine.  C4, C5 & N7 are contributed by glycine.  C6 directly comes from CO2.

 The purines are built upon a pre-existing ribose 5 - phosphate.  Liver is the major site for purine nucleotide synthesis.  Erythrocytes, polymorphonuclear leukocytes & brain cannot produce purines.

 Ribose 5 - phosphate, of carbohydrate metabolism is the starting material for purine nucleotide synthesis.  It reacts with ATP to form phosphoribosyl pyrophosphate (PRPP).  Glutamine transfers its amide nitrogen to PRPP to replace pyrophosphate & produce 5- phosphoribosylamine.

 N

10

• Formyl tetrahydrofolate donates the formyl group & the product formed is formylglycinamide ribosyl 5 - phosphate.  The reaction is catalyzed by formyltransferase.  Glutamine transfers the second amido amino group to produce formylglycinamidine ribosyl 5 - phosphate.  The reaction is catalyzed by synthetase.

 The imidazole ring of the purine is closed in an ATP dependent reaction to yield 5- aminoimidazole ribosyl 5 - phosphate.  The reaction is catalyzed by synthetase.  Incorporation of CO2 (carboxylation) occurs to yield aminoimidazole carboxylate ribosyl 5 - phosphate.  The reaction is catalyzed by carboxylase.

 Adenosuccinate lyase cleaves off fumarate & only the amino group of aspartate is retained to yield aminoimidazole 4-carboxamide ribosyl 5 - phosphate.  N 10

• Formyl tetrahydrofolate donates a one- carbon moiety to produce 5- formaminoimidazole 4-carboxamide ribosyl 5 - phosphate.  Catalyzed by formyltransferase.

 The final reaction catalyzed by cyclohydrolase leads to ring closure with an elimination of water molecule.  The product obtained is inosine monophosphate (IMP), the parent purine nucleotide from which other purine nucleotides can be synthesized.

 Synthesis of AMP:  Ionosine monophosphate (IMP) is the immediate precursor for the formation of AMP & GMP.  Aspartate condenses with IMP in the presence of GTP to produce adenylsuccinate which, on cleavage, forms AMP.

 6 - Mercaptopurine is an inhibitor of the synthesis of AMP & GMP.  It acts on the enzyme adenylsuccinase (of AMP pathway).  IMP dehydrogenase (of GMP pathway).

 The nucleoside monophosphates (AMP & GMP) converted to the corresponding di & triphosphates.  This is achieved by the transfer of phosphate group from ATP, catalysed by nucleoside monophosphate (NMP) kinases & nucleoside diphosphate (NDP) kinases.

Nucleoside monophosphate (AMP, GMP) Nucleoside diphosphate (ADP, GDP) Nucleoside triphosphate (ATP, GTP) ATP ADP NMP kinase NDP kinase ATP ADP