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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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 |
| Item ID: | 56316 |
| Date Deposited: | 08 Aug 2008 |
| Last Modified: | 12 May 2013 01:13 |
| Contributors: | Fauroux, C.M.J. (Author) Lee, M. (Author) Cullis, P.M. (Author) Douglas, K.T. (Author) Gore, M.G. (Author) Freeman, S. (Author) |
| Date: | 13 February 2002 |
| Status: | Published |
| URI: | http://eprints.soton.ac.uk/id/eprint/56316 |
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