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Structure and mechanism of inositol monophosphatase
Author(s) -
Atack John R.,
Broughton Howard B.,
Pollack Scott J.
Publication year - 1995
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(95)00063-f
Subject(s) - lithium (medication) , chemistry , phosphatidylinositol , stereochemistry , binding site , enzyme , protein subunit , alpha (finance) , mechanism (biology) , biochemistry , signal transduction , biology , medicine , endocrinology , philosophy , epistemology , gene , construct validity , nursing , patient satisfaction
Since lithium inhibits IMPase and modulates phosphatidylinositol (PtdIns) cell signalling at therapeutically relevant concentrations (0.5–1.0 mM), IMPase has attracted attention as a putative molecular target for lithium in the treatment of manic depression. IMPase is a homodimer, with each subunit organised in an αβαβα arrangement of α‐helices and β‐sheets, and this type of structure seems crucial to the two‐metal catalysed mechanism in which an activated water molecule serves as a nucleophile. Lithium appears to inhibit the enzyme following substrate hydrolysis by occupying the second metal binding site before the phosphate group can dissociate from its interaction with the site 1 metal. The understanding of IMPase structure and the mechanism of substrate hydrolysis and lithium inhibition should be useful in the development of novel inhibitors which may prove clinically useful in the treatment of manic depression.