Action of the active metabolites of tiazofurin and ribavirin on purified IMP dehydrogenase.
作者： Yasukazu Yamada , Yutaka Natsumeda , George Weber
DOI: 10.1021/BI00406A057
关键词:
摘要: The inhibitory mechanisms of ribavirin 5'-monophosphate (RMP) and thiazole-4-carboxamide adenine dinucleotide (TAD), the active forms antimetabolites tiazofurin, were investigated in IMP dehydrogenase purified to homogeneity from rat hepatoma 3924A. has a tetrameric structure with subunit molecular weight 60,000. For substrates NAD+, Km's 23 65 microM, respectively. Product-inhibition patterns showed an ordered Bi-Bi mechanism for enzyme reaction where binds first, followed by NAD+; NADH dissociates ternary complex first then XMP is released. interacts free competes ligand site IMP, while enzyme-XMP complex. RMP exerted same as XMP, inhibition TAD was similar that NADH. However, Ki values (0.8 microM) (0.13 orders magnitude lower than those (136 (210 microM). Thus, drugs interact higher affinities natural products, IMP-XMP site. Preincubation enhanced its effect time-dependent manner. protected this inactivation or XMP. These results provide biochemical basis combination chemotherapy tiazofurin targeted against two different sites dehydrogenase.
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