Structure and mechanism of inositol monophosphatase

FEBS Letters

Atack, John R.¹  Broughton, Howard B.¹  Pollack, Scott J.¹ 

[1] Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK

关键词: Inositol monophosphatase;    Lithium;    Enzyme inhibitor;    Enzyme structure;    Enzyme mechanism;   

DOI  :  10.1016/0014-5793(95)00063-F

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown