IMP dehydrogenase: inhibition by the anti-leukemic drug, tiazofurin.
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). Km values for IMP and NAD+ of leukemic IMP dehydrogenase were 22.7 and 44.0 microM, 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 (Ki = 0.1 microM) was three orders of magnitude higher than the natural product NADH (Ki = 150 microM). These results contribute to an understanding of the mechanism of action of tiazofurin in the treatment of leukemia.
Yamada
Y
Y
Laboratory for Experimental Oncology, Indiana University School of Medicine, Indianapolis 46223.
Natsumeda
Y
Y
Yamaji
Y
Y
Jayaram
H N
HN
Tricot
G J
GJ
Hoffman
R
R
Weber
G
G
D000227:Adenine Nucleotides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001752:Blast Crisis / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000097:blood; D007658:Ketone Oxidoreductases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy / Q000201:enzymology*; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D012263:Ribonucleosides / Q000494:pharmacology*
D000227:Adenine Nucleotides; D000970:Antineoplastic Agents; D012263:Ribonucleosides; D012254:Ribavirin; D009249:NADP; C038167:thiazole-4-carboxamide adenine dinucleotide; D007168:IMP Dehydrogenase; D007658:Ketone Oxidoreductases; C033706:tiazofurin