Gout and the regulation of purine biosynthesis.
Overproduction of purine nucleotides de novo is the cause of hyperuricemia in a substantial portion of the gouty population. Specific enzyme abnormalities--deficiency of hypoxanthine-guanine phosphoribosyltransferase (an enzyme of the purine "salvage" pathway) and overactivity of 5- phosphoribosyl-1-pyrophosphate (PP-ribose-P) synthetase--result in hyperuricemia, and are associated with increased de novo purine synthesis and increased intracellular concentrations of PP-ribose-P. The latter is a common substrate for the first enzyme of the de novo pathway (phosphoribosyl amidotransferase) and the purine base salvage enzymes. Studies in cultured cells from patients, and in mutant cells derived from normal cell lines in vitro, suggest that elevated intracellular PP-ribose-P concentrations may increase the rate of de novo purine biosynthesis. This regulation can be explained in terms of the normal intracellular concentration of PP-ribose-P which is lower tthan the Km for the amidotransferase,  and by allosteric activation of this enzyme by PP-ribose-P. Feedback inhibition of the first step in the de novo pathway by exogenous purines can be explained either by end-product (nucleotide) inhibition of the amidotransferase, or by competition for PP-ribose-P by the salvage enzymes which have lower Km's for this substrate, or by a combination of these effects. Evidence for and against these mechanisms is discussed. Evidence is presented which suggests that exogenous purines exert a feedback effect, not only on the first step of the de novo pathway, but also at the distal branch point  in the pathway. Several potential regulatory mechanisms which might lead to excessive production of uric acid are discussed.
D000225:Adenine / Q000378:metabolism; D000582:Amidophosphoribosyltransferase / Q000378:metabolism; D002460:Cell Line; D006073:Gout / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism; D006801:Humans; D007042:Hypoxanthines / Q000378:metabolism; D007700:Kinetics; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D011685:Purine Nucleotides / Q000096:biosynthesis; D011687:Purines / Q000096:biosynthesis*
D007042:Hypoxanthines; D011685:Purine Nucleotides; D011687:Purines; D006147:Guanine; D010754:Phosphoribosyl Pyrophosphate; D000582:Amidophosphoribosyltransferase; D000225:Adenine