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), 1363-1373. (doi:10.1021/jm011056m).

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Original Publication URL: http://dx.doi.org/10.1021/jm011056m

Description/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.

Item Type: Article
ISSNs: 0022-2623 (print)
Related URLs:
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: University Structure - Pre August 2011 > School of Biological Sciences
ePrint ID: 56316
Date Deposited: 08 Aug 2008
Last Modified: 27 Mar 2014 18:39
URI: http://eprints.soton.ac.uk/id/eprint/56316

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