Substrate specificity of human glycinamide ribonucleotide transformylase

The nucleotide substrate specificity of human glycinamide ribonucleotide tr ansformylase, a chemotherapeutic target, has been examined. The enzyme acce pts the sarcosyl analog of glycinamide ribonucleotide, carbocyclic glycinam ide ribonucleotide, and two phosphonate derivatives of carbocyclic glycinam ide ribonucleotide with V/K values, relative to that obtained for beta-glyc inamide ribonucleotide, of 1, 27, 1.4, and 2.9%, respectively. Several othe r analogs of carbocyclic glycinamide ribonucleotide, namely a truncated pho sphonate and 2',3'-dideoxy- and 2',3'dideoxy-2',3'-didehydro-carbocyclic gl ycinamide ribonucleotide, were inhibitors of the enzyme, competitive agains t glycinamide ribonucleotide, with K-i values approximately 100 times highe r than the K-m for beta-glycinamide ribonucleotide. Although the results of the present study parallel those obtained previously with the avian enzyme (V.D. Antle, D. Liu, B. R. McKellar, C. A. Caperelli, M. Hua, and R. Vince (1996) J. Biol. Chem. 271, 6045-6049), quantitative differences between th e two enzyme species have been uncovered. (C) 1999 Academic Press.