Mechanisms of Purine Overproduction in Man

Abstract

Several elegant studies conducted first during the 1950s showed that a segment of the gouty population exhibited hyperuricemia as a result of an increased production of uric acid (1,2). Further investigation of this subgroup revealed that these patients also exhibited an accelerated rate of purine biosynthesis de novo. In other clinical situation, an increased production of uric acid was noted to result from an accelerated catabolism of purine nucleotides; examples of the latter included the acute leukemias and hemolytic anemias (3–5) where an accelerated turnover of cells leads to an increased degradation of purine nucleotides, thus enhancing uric acid formation. The recognition that the overproduction of uric acid was an important element in the pathophysiology of several clinical conditions provided an incentive to better define mechanisms by which purine biosynthesis was regulated in man. Indeed, the nature of this regulation is now well established and has been reviewed in an earlier paper in this volume (6). In effect, the rate of purine biosynthesis de novo (i.e., the pathway leading to the synthesis of inosinic acid from PRPP, glutamine, and other precursors) is tightly controlled by the intracellular concentration of 5-phosphoribosyl-l-pyrophosphate (PRPP) and purine nucleotides (Figure 1). For example, an elevation of the intracellular concentration of PRPP will increase the rate of purine biosynthesis de novo while a decrease of the intracellular level of PRPP will decrease the rate of purine biosynthesis de novo (7). An increase in the level of the purine nucleoside monophosphates, AMP or GMP, will decrease the rate of purine biosynthesis de novo while a decrease in the concentration of these compounds will result in a compensatory increase in purine biosynthesis de novo (2). In addition, the level of the purine nucleoside diphosphate, ADP, also appears to play an important role in that increased levels of ADP inhibit PRPP synthetase (8) (Figure 1, reaction 3) and thus reduce levels of PRPP in the cell, hence, reducing the rate of purine biosynthesis de novo. On the other hand, decreased levels of ADP in the cell lead to activation of PRPP synthetase and, thus, increased levels of PRPP in the cell and an accelerated rate of purine synthesis de novo. The molecular alterations of the enzyme PRPP amidotransferase (Figure 1, reaction 1), which nicely account for these observed changes induced by PRPP and purine nucleotides, have been published previously (9) and have been summarized in the paper by Dr. Wyngaarden in this volume (6).