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Stereochemistry at phosphorus of the reaction catalyzed by myo-inositol monophosphatase

Fauroux, C.M.J., Lee, M., Cullis, P.M., Douglas, K.T., Gore, M.G. and Freeman, S. (2002) Stereochemistry at phosphorus of the reaction catalyzed by myo-inositol monophosphatase Journal of Medicinal Chemistry, 45, (6), pp. 1363-1373. (doi:10.1021/jm011056m).

Record type: Article


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.

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Published date: 13 February 2002


Local EPrints ID: 56316
ISSN: 0022-2623
PURE UUID: 97a24918-5de4-4003-b2b8-25c18da425e2

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Date deposited: 08 Aug 2008
Last modified: 17 Jul 2017 14:31

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Author: C.M.J. Fauroux
Author: M. Lee
Author: P.M. Cullis
Author: K.T. Douglas
Author: M.G. Gore
Author: S. Freeman

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