Metabolic defects of primary hyperuricemia and gout

Abstract

Gout is a syndrome of multiple pathogeneses rather than a single disease entity. Reviewed here are the metabolic defects of primary gout, with major emphasis upon two well characterized, although uncommon, variants due to specific enzyme abnormalities: (1) structural mutants of phosphoribosylpyrophosphate (PP-ribose-P) synthetase with increased activities, resulting in increased rates of synthesis of PP-ribose-P, a key substrate of purine biosynthesis, and (2) structural mutants of hypoxanthineguanine phosphoribosyltransferase (HGPRT) with reduced activities, resulting in reduced consumption of PP-ribose-P and therefore a surplus in the amount available for purine biosynthesis de novo. The present state of our limited knowledge of control of purine biosynthesis is also reviewed briefly, and the potential mechanisms of excessive uric acid production in idiopathic gout are discussed in terms of possible excesses of substrates (PP-ribose-P or L-glutamine) of the first specific reaction of purine biosynthesis, possible defects of control of the enzyme catalyzing this reaction, or defects in maintenance of optimal concentrations of nucleotide regulators of this reaction. It is likely that the rate of production of uric acid in man is influenced by availability of substrates, cofactors and regulatory compounds, and activities of enzymes at many reaction sites other than the first specific reaction of the purine sequence, but their influences upon the rate of purine production can be conveniently analyzed in terms of their indirect effects upon this reaction. Examples cited include glucose-6-phosphatase deficiency glycogen storage disease, in which marked hyperuricemia and purine overproduction are present, and elevated activities of hepatic xanthine oxidase in gouty patients with increased uricaciduria, perhaps occurring secondary to other factors but nevertheless contributing to the excessive purine production. The basic lesions of the more than 95 per cent of patients with primary gout who do not have abnormalities of either PP-ribose-P synthetase or HGPRT remain to be defined, but will almost certainly turn out to be multiple, complex and, in many cases, subtle deviations of metabolic control.