IMP dehydrogenase in human leukemic cells

概要

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We investigated the kinetic properties and the effects of thiazole -4- carboxamide adenine dinucleotide (TAD), an active metabolite of tiazofurin, on IMP dehydrogenase in leukocytes from acute myeloid leukemia (AML) patients and on the enzyme purified from MOLT 4F cells. IMP dehydrogenase activity in human leukemic cell extracts from AML patients (33.4±0.1nmol/h/mg protein) was 11-fold increased compared to normal leukocytes (3.1±0.5). Human cultured cell lines, K 562 (47.6), BALL 1 (61.0) and MOLT 4F (45.7), also had elevated activities. Km values for IMP and NAD of leukemic IMP dehydrogenase from AML patients were 22.7 and 44.0μM, respectively. XMP showed competitive inhibition with IMP and noncompetitive inhibition with NAD. NADH showed mixed type inhibition with both IMP and NAD. The inhibitory pattern of TAD was similar to that of NADH, but the affinity of TAD to the enzyme (Ki=0.10μM) was three orders of magnitude higher than NADH (Ki=150μM). IMP dehydrogenase purified from MOLT 4F cells had similar kinetic properties (Km for IMP=29; NADH=54μM) and inhibitory mechanisms by natural products (Ki for XMP=85; NADH=94μM) and by TAD (Ki=0.075μM), as the enzyme from AML patients. These results suggest the usefulness of tiazofurin in the treatment of not only AML but also lymphoid leukemia.