ヒドラジノコハク酸によるアスパラギン酸アミノ基転移酵素の Slow-binding inhibition 及び Slow, tight-binding inhibition

概要

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Administration of isoniazid to mice induced a remarkable inhibition of liver cytosolic aspartate aminotransferase. Experimental findings indicated that the inhibitor was not isoniazid itself but probably its metabolite. DL-Hydrazinosuccinate, a model compound of the metabolite, was synthesized since the metabolite was not successfully isolated. The compound was found to be even more inhibitory. The inhibition by the compound proceeded time-dependently and was not readily released. D- and L-Hydrazinosuccinate were synthesized, respectively, for further analyses of the inhibition mechanisms. D-Hydrazinosuccinate was found to behave as a slow-binding inhibitor via a single-step reaction mechanism and gave Ki of approx. 3 nM. L-Hydrazinosuccinate was a more powerful inhibitor with Ki of approx. 0.2 nM, and was found to be a slow, tight-binding inhibitor and interact with the enzyme through consecutive reversible steps. Administration of L-hydrazinosuccinate to mice produced in vivo a potent and long lasting inhibition of cytosolic aspartate aminotransferase in the liver and kidney in a relatively specific manner. The administration of this compound also caused a remarkable accumulation of citrulline in the liver and plasma, which was explained as a result of both specific and non-specific effects of the inhibitor.
日本ビタミン学会の論文
1988-03-25