Methylmercaptopurine Ribonucleoside Toxicity in Human Fibroblasts: Inhibition of Phosphoribosylpyrophosphate Synthetase as Well as Amidophosphoribosyltransferase

Abstract

Abundant evidence has been presented to indicate that phospho-ribosylpyrophosphate (PRPP) is the rate-limiting substrate for purine synthesis de novo (for review, see ref.1). Cultured cells derived from patients with purine overproduction have increased intracellular PRPP concentrations resulting from either increased PRPP synthesis or diminished PRPP utilization in alternative pathways (2–5). PRPP synthesis is catalyzed by PRPP synthetase (E.C. 2.7.6.1). Several distinct superactive forms of this enzyme have been described in association with increased PRPP generation and increased rates of purine synthesis de novo (3–6). Among these mutant forms of PRPP synthetase are enzymes with: increased maximal velocity of the reaction but normal sensitivity to purine nucleotide inhibition of enzyme activity (7); normal maximal velocity but altered regulatory properties (3, 6); both altered catalytic and regulatory properties (8).