In addition to their central roles in nucleic acid biosynthesis, purines provide high energy molecules (ATP and GTP) that drive enzymatic reactions, as well as being components of metabolic cofactors such as NAD+, FAD+ and coenzyme A, and serving as signaling molecules operating through purinergic receptors. Purines are synthesized in one of two ways: in a de novo pathway from amino acid and other building blocks or via a salvage pathway from nucleic acid turnover. In de novo synthesis, purines
are generated as ribonucleotides, rather than as free bases, as pyrimidines are. Purine (IMP) biosynthesis is carried out in a series of eleven enzymatic steps that are conserved from bacteria to humans. IMP is the central compound of the pathway, from which AMP and GMP are generated. The mammalian pathway enzymes include one trifunctional and two bifunctional enzymes; these activities are associated with monofunctional enzymes in lower organisms. In the first step, alpha-d-ribose-5-phosphate, derived from the pentose phosphate pathway, is activated by phosoribosyl pyrophosphate synthetases (Prps1 and Prps2) using ATP to form PRPP in a highly regulated reaction. PRPP is also a precursor in pyrimidine biosynthesis and the synthesis of amino acids histidine and tryptophan. In the next step, the first reaction unique to purine biosynthesis, the enzyme phosphoribosyl pyrophosphate amidotransferase (Ppat) replaces the pyrophosphate moiety of PRPP with the amide nitrogen of glutamine, purine N9, to form PRA. This enzyme is synergistically inhibited by phosphorylated adenosine and guanosine and feedforward activated by PRPP. The third and fourth steps are performed by the GAR synthetase and GAR formyltransferase activities of the trifunctional enzyme Gart. The first Gart activity provides purine atoms C4, C5 and N7 by linking glycine via its carboxyl group to the amino group of phosphoribosylamine and hydrolyzing a molecule of ATP to yield GAR, and the second Gart activity transfers what will become purine atom C8, the formyl group of 10-formylTHF, to the free amino group of GAR, generating FGAR. In the fifth step, phosphoribosylformylglycinamidine synthase (Pfas) transfers the amide group of a second glutamine to provide atom N3 of the nascent purine ring with the hydrolysis of another molecule of ATP, producing FGAM. The third activity of trifunctional Gart closes the purine imidazole ring with the hydrolysis of ATP as the sixth pathway step. The seventh and eighth steps are carried out by the bifunctional enzyme Paics, phosphoribosylaminoimidazole carboxylase, with ATP hydrolysis to form CAIR and SAICAR, respectively, adding purine atoms C6 and N1. SAICAR is cleaved, releasing fumarate, by adenylosuccinate lyase (Adsl) in step nine to yield AICAR. The last two steps to form IMP are catalyzed by the bifunctional enzyme Atic. Its first activity adds the final purine ring C2 atom via formylation by 10-formylTHF to generate FAICAR. In the final IMP pathway reaction, ring closure with water elimination to yield IMP is catalyzed by Atic's IMP cyclohydrolase activity. The provision of C2 and C8 atoms represents one of the three transfer reactions of the folate mediated 1carbon metabolic pathway which along with the folate cycle, is part of folate metabolism. AMP is synthesized from IMP in two steps. First, adenylosuccinate synthetase (Adss, Adssl1 isomers) links the amino group of aspartate to IMP with GTP hydrolysis, yielding adenylosuccinate. Fumarate is then eliminated by Adsl to generate AMP. GMP synthesis from IMP is also a two step process. NAD+ is first reduced by IMP dehydrogenase (Impdh1, Impdh2 isomers) to dehydrogenate IMP, forming XMP. The amide nitrogen of glutamine is then transferred to XMP by GMP synthetase (Gmps) with ATP hydrolysis to yield GMP. One point of pathway regulation is the inhibition of Prps by ADP and GDP, downstream products of IMP biosynthesis. A second layer of regulation involves the branch steps from IMP, catalyzed by Adss and Impdh, which are inhibited by AMP and GMP respectively to prevent buildup of pathway products. Additional coordination exists in that ATP drives the synthesis of GMP from IMP, while GTP powers generation of AMP from IMP, balancing production of the two purine nucleotides for nucleic acid biosynthesis. The two THF-requiring steps, catalized by Atic and Gart, have been used as targets in antineoplastic therapy with antifolate drugs. Impdh catalyzes the rate-limiting step in GMP synthesis, and is therefore a cancer and transplant chemotherapy target.To see the Ontology Report for annotations, GViewer and download click here [Click here to see the ontology report for related GO term - GO:0006189, KEGG map - map00240 and entry at Reactome - REACT_73848]...(less)
