IMP dehydrogenase: Inhibition by the anti-leukemic drug, tiazofurin

Abstract

Tiazofurin through its active metabolite thiazole-4-carboxamide adenine dinucleotide (TAD) inhibits IMP dehydrogenase, the rate-limiting enzyme of GTP biosynthesis. IMP dehydrogenase activity in human leukemic cell extracts (33.4 ± 0.1 nmol/h/mg protein) was increased 11-fold compared to normal leukocytes (3.1 ± 0.5). K m values for IMP and NAD + of leukemic IMP dehydrogenase were 22.7 and 44.0 μM, respectively. XMP inhibited competitively with IMP and noncompetitively with NAD +. NADH exerted mixed type inhibition with respect to both IMP and NAD +. The inhibitory pattern of TAD was quite similar to that of NADH; however, the affinity of TAD to leukemic IMP dehydrogenase ( K i = 0.1 μM) was three orders of magnitude higher than the natural product NADH ( K i = 150 μM). These results contribute to an understanding of the mechanism of action of tiazofurin in the treatment of leukemia.