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

Yasukazu Yamada, Yutaka Natsumeda, Yasufumi Yamaji, Hiremagalur N. Jayaram, Guido J. Tricot, Ronald Hoffman, George Weber

Research output: Contribution to journalArticle

18 Scopus citations

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). Km 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 (Ki = 0.1 μM) was three orders of magnitude higher than the natural product NADH (Ki = 150 μM). These results contribute to an understanding of the mechanism of action of tiazofurin in the treatment of leukemia.

Original languageEnglish (US)
Pages (from-to)179-184
Number of pages6
JournalLeukemia Research
Volume13
Issue number2
DOIs
StatePublished - 1989

Keywords

  • IMP dehydrogenase
  • kinetics, tiazofurin, thiazole-4-carboxamide adenine dinucleotide, leukemia, chemotherapy, blast crisis of chronic granulocytic leukemia

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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    Yamada, Y., Natsumeda, Y., Yamaji, Y., Jayaram, H. N., Tricot, G. J., Hoffman, R., & Weber, G. (1989). IMP dehydrogenase: Inhibition by the anti-leukemic drug, tiazofurin. Leukemia Research, 13(2), 179-184. https://doi.org/10.1016/0145-2126(89)90143-4