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Title: Stereochemistry at Phosphorus of the Reaction Catalyzed by myo-Inositol Monophosphatase.
Authors: Fauroux, C. M. J.
Lee, M.
Cullis, P. M.
Douglas, K. T.
Gore, M. G.
Freeman, S.
First Published: 2002
Citation: Journal of Medicinal Chemistry, 2002, 45 (6), pp.1363-1373
Abstract: myo-Inositol monophosphatase (IMPase), the proposed target for lithium therapy for manic depression, is an important enzyme in the biosynthesis of second messengers. Earlier studies have shown that the IMPase-catalyzed hydrolysis of myo-inositol monophosphates to inorganic phosphate and myo-inositol proceeds by direct attack of water at phosphorus. However, research groups have independently proposed either an in-line displacement (with inversion of stereochemistry at phosphorus) or an adjacent attack with a pseudorotation (with retention of stereochemistry at phosphorus). Here, the elucidation of the stereochemical pathway is presented. The IMPase-catalyzed hydrolysis of d-1-Sp-myo-inositol [17O]-thiophosphate in the presence of H218O gave inorganic Rp-[16O,17O,18O]-thiophosphate, with inversion of configuration at phosphorus. This is only consistent with an in-line displacement, and it rules out the controversial adjacent/pseudorotation mechanism. This result will assist in the design of alternative inhibitors of IMPase.
DOI Link: 10.1021/jm011056m
ISSN: 0022-2623
Type: Article
Appears in Collections:Published Articles, Dept. of Chemistry

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