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

Stereochemistry at phosphorus of the reaction catalyzed by myo-inositol monophosphatase
Stereochemistry at phosphorus of the reaction catalyzed by myo-inositol monophosphatase
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.
0022-2623
1363-1373
Fauroux, C.M.J.
776e9bd5-ad55-4dd1-8a56-83c7e10315d7
Lee, M.
d04961f5-36fc-4d03-af4a-cb3047be7de1
Cullis, P.M.
16ab6b58-b2ba-4aa7-94c7-c891e647c24e
Douglas, K.T.
a13c8101-9f88-4883-807d-b7245077221d
Gore, M.G.
7bd6db4b-c5a2-4206-8666-b92208ba7979
Freeman, S.
d757fa37-f6b1-4687-82f5-7cf4a0e49661
Fauroux, C.M.J.
776e9bd5-ad55-4dd1-8a56-83c7e10315d7
Lee, M.
d04961f5-36fc-4d03-af4a-cb3047be7de1
Cullis, P.M.
16ab6b58-b2ba-4aa7-94c7-c891e647c24e
Douglas, K.T.
a13c8101-9f88-4883-807d-b7245077221d
Gore, M.G.
7bd6db4b-c5a2-4206-8666-b92208ba7979
Freeman, S.
d757fa37-f6b1-4687-82f5-7cf4a0e49661

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).

Record type: Article

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.

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Published date: 13 February 2002

Identifiers

Local EPrints ID: 56316
URI: http://eprints.soton.ac.uk/id/eprint/56316
ISSN: 0022-2623
PURE UUID: 97a24918-5de4-4003-b2b8-25c18da425e2

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Date deposited: 08 Aug 2008
Last modified: 15 Mar 2024 11:00

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Contributors

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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