STRUCTURE ACID MECHANISM OF INOSITOL MONOPHOSPHATASE

Since lithium inhibits IMPase and modulates phosphatidylinositol (PtdI ns) cell signalling at therapeutically relevant concentrations (0.5-1. 0 mM), IMPase has attracted attention as a putative molecular target f or lithium in the treatment of manic depression. IMPase is a homodimer , with each subunit organised in an alpha beta alpha beta alpha arrang ement of alpha-helices and beta-sheets, and this type of structure see ms 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 b inding site before the phosphate group can dissociate from its interac tion 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 clinica lly useful in the treatment of manic depression.