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-S(p)-myo-inositol [(17)O]-thiophosphate in the presence of H(2)(18)O gave inorganic R(p)-[(16)O,(17)O,(18)O]-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.
Fauroux
Christine M-J
CM
School of Pharmacy and Pharmaceutical Sciences, Manchester University, Oxford Road, M13 9PL, United Kingdom.
Lee
Michael
M
Cullis
Paul M
PM
Douglas
Kenneth T
KT
Gore
Michael G
MG
Freeman
Sally
S
D001714:Bipolar Disorder / Q000188:drug therapy; D002384:Catalysis; D008094:Lithium / Q000009:adverse effects / Q000627:therapeutic use*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010710:Phosphates / Q000737:chemistry; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry*; D010758:Phosphorus / Q000737:chemistry*; D011487:Protein Conformation; D013237:Stereoisomerism
D010710:Phosphates; D010758:Phosphorus; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; C035638:thiophosphoric acid