NEW CARBOHYDRATE SUBSTRATES OF LITHIUM-SENSITIVE BOVINE BRAIN MYOINOSITOL MONOPHOSPHATASE

Myo-inositol monophosphatase (IMPase) is a crucial enzyme of the inosi tol second messenger system and it generates the inositol lipids precu rsor myo-inositol from inositol monophosphates derived from receptor-m ediated and de novo pathways. This phosphatase is inhibited by therape utic levels of lithium, and the inhibition of this enzyme has been lin ked to lithium's pharmacological action in manic-depressive disorder. During the course of our studies with IMPase, we observed that IMPase is not only capable of hydrolyzing inositol monophosphates but certain other carbohydrate monophosphates involved in carbohydrate metabolism . This property of IMPase suggests that it may play a role in both ino sitol signaling and also carbohydrate metabolism. Among several phosph ates tested, IMPase acted upon D-myo-inositol 1-phosphate = L-myo-inos itol 1-phosphate = 2'-AMP > xylulose 5-phosphate > erythrose 4-phospha te > ribose 5-phosphate > fructose 1-phosphate > fructose 6-phosphate > glucose 6-phosphate > fructose 1,6 bisphosphate. The pattern obtaine d using 3.0 mM Mg2+ (maximal stimulation) was different from the one o btained using 0.5 mM Mg2+ (physiological). Inositol 1,2 cyclic monopho sphate and several other phosphorylated carbohydrate intermediates wer e not hydrolyzed by IMPase. Considering the broad specificity of IMPas e towards several carbohydrate metabolites, it is possible that IMPase has a role in controlling multiple sites of the cell metabolism, in a ddition to its role in inositol signaling. In addition, analogues of t hese carbohydrate monophosphates might be developed as novel lithium-t ype inhibitors of IMPase.