Purine Synthesis


Purines are nitrogenous bases that form part of the nucleotides, which are the building blocks of nucleic acids such as DNA and RNA. Purines also have important roles in energy metabolism, signal transduction, and coenzyme functions. The two major purines in nucleic acids are adenine and guanine.

Purines can be synthesized in the cells either by de novo synthesis or by salvage pathways. De novo synthesis means that the purines are made from simple molecules such as amino acids, carbon dioxide, and tetrahydrofolate derivatives. Salvage pathways mean that the purines are recycled from the degradation of nucleic acids or from dietary sources.

The de novo synthesis of purine nucleotides occurs in a complex pathway that involves 11 enzymatic reactions and requires energy input from ATP. The pathway starts with the activation of ribose-5-phosphate, a product of the pentose phosphate pathway, to form 5-phosphoribosyl-1-pyrophosphate (PRPP). PRPP then reacts with glutamine to form 5-phosphoribosyl-1-amine, which is the first committed step in purine synthesis. This step is regulated by feedback inhibition by the end products AMP and GMP.

The next nine steps involve the sequential addition of atoms from various sources to build up the purine ring on the ribose sugar. The sources of atoms are:

  • N1: aspartate
  • C2 and C8: N10-formyltetrahydrofolate
  • N3 and N9: glutamine
  • C4, C5, and N7: glycine
  • C6: carbon dioxide

The final product of the de novo purine synthesis pathway is inosine monophosphate (IMP), which contains the base hypoxanthine. IMP can then be converted to either AMP or GMP by two separate pathways that require ATP or GTP, respectively. AMP and GMP can then be phosphorylated to form ADP, ATP, GDP, and GTP, which are the active forms of purine nucleotides in the cell.

The following code block shows a summary of the de novo purine synthesis pathway:

Ribose-5-phosphate + ATP -> PRPP + AMP (PRPP synthetase)
PRPP + glutamine -> 5-phosphoribosyl-1-amine + glutamate + PPi (glutamine PRPP amidotransferase)
5-phosphoribosyl-1-amine + glycine + ATP -> glycinamide ribonucleotide + ADP + Pi (glycinamide ribonucleotide synthetase)
glycinamide ribonucleotide + N10-formyltetrahydrofolate -> N2-formylglycinamide ribonucleotide + tetrahydrofolate (glycinamide ribonucleotide transformylase)
N2-formylglycinamide ribonucleotide + glutamine + ATP -> formylglycinamidine ribonucleotide + glutamate + ADP + Pi (formylglycinamidine ribonucleotide synthetase)
formylglycinamidine ribonucleotide -> aminoimidazole carboxamide ribonucleotide + H2O (formylglycinamidine ribonucleotide cyclase)
aminoimidazole carboxamide ribonucleotide + CO2 -> carboxyaminoimidazole ribonucleotide (aminoimidazole carboxamide ribonucleotide transformylase)
carboxyaminoimidazole ribonucleotide + aspartate -> 5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide + fumarate (SAICAR synthetase)
5-aminoimidazole-4-(N-succinylcarboxamide) ribonucleotide -> 5-aminoimidazole-4-carboxamide ribonucleotide + succinate (SAICAR lyase)
5-aminoimidazole-4-carboxamide ribonucleotide + N10-formyltetrahydrofolate -> 5-formamidoimidazole-4-carboxamide ribonucleotide + tetrahydrofolate (AICAR transformylase)
5-formamidoimidazole-4-carboxamide ribonucleotide -> IMP + H2O (AICAR cyclase)
IMP + aspartate + GTP -> adenylosuccinate + GDP + Pi (adenylosuccinate synthetase)
adenylosuccinate -> AMP + fumarate (adenylosuccinate lyase)
IMP + H2O -> xanthosine monophosphate (IMP dehydrogenase)
xanthosine monophosphate + glutamine -> GMP + glutamate (GMP synthetase)
AMP + ATP -> 2 ADP (adenylate kinase)
ADP + ATP -> 2 ATP (nucleoside diphosphate kinase)
GMP + ATP -> GDP + ADP (guanylate kinase)
GDP + ATP -> GTP + ADP (nucleoside diphosphate kinase)

The following image shows a schematic representation of the de novo purine synthesis pathway: