Recent advances in the identification of enzyme abnormalities underlying excessive purine synthesis in man

Work is continuing in the attempt to increase knowledge of the regulation of the rate of purine synthesis in man by means of an analysis of biochemical alterations leading to purine overproduction among patients with gout. The authors are now assessing the frequency of kinetic mutations in enzymes whose alterations already have been associated with increased purine synthesis. Efforts in this regard have been rewarded by the identification of a new form of alteration leading to partial deficiency of HGPRT and a kinetic variant of PRPP synthetase with increased affinity for ribose-5-phosphate. In order to identify new forms of enzyme abnormalities associated with excessive purine synthesis, the value of a proposed classification scheme requiring measurement of PRPP and ribose-5-phosphate concentration and generation is being assessed in cultured fibroblasts. It is hoped that the results of these measurements will lead to the identification of additional kinetic variants of presently known enzyme abnormalities and will help to identify new classes of mutants in the regulation of human purine metabolism. The excessive purine synthesis that underlies the hyperuricemia of a substantial number of patients with gouty arthritis reflects alterations in the normal mechanism regulating the rate of purine nucleotide synthesis. The study of such purine "overproducers" has provided insight into the nature of this regulatory mechanism and has underscored the diversity of specific genetic and biochemical aberrations affecting it. Despite these advances, however, less than 10% of all patients with gout and excessive purine production can presently be accounted for by known enzyme abnormalities (1). Recognition that current knowledge of the regulation of the rate of purine nucleotide synthesis in man is incomplete has provided the authors impetus leading to the studies described here, which are preceded by a brief review of background.