Noncompetitive inhibition of inositol monophosphatase by K-76 monocarboxylic acid.
K-76COONa, a fungal product that was previously isolated for its inhibition of complement activation, was found to inhibit myo-inositol monophosphatase activity. K-76COONa was slightly more potent than lithium, with a Ki of approximately 0.5 mM. Kinetic analyses with D-myo-inositol 1-phosphate as the substrate showed that myo-inositol monophosphatase inhibition by K-76COONa was noncompetitive relative to substrate but competitive with activation by magnesium. Higher concentrations of K-76COONa were necessary to inhibit myo-[3H]inositol 1,4-bisphosphate hydrolysis by inositol 1,4-bisphosphate/inositol 1,3,4-trisphosphate 1-phosphatase (IC50 = approximately 7.5 mM). K-76COONa may be useful for further investigation of the mechanism of myo-inositol monophosphatase and for determination of whether inhibition of this enzyme plays a role in the therapeutic effectiveness of lithium in treatment of affective disorders.
Pachter
J A
JA
Schering-Plough Research, Bloomfield, New Jersey 07003.
D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D008094:Lithium / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013379:Substrate Specificity
D007295:Inositol Phosphates; D012717:Sesquiterpenes; C002647:inositol 1-phosphate; C044259:inositol 1,4-bis(phosphate); C038797:K 76 carboxylic acid; D008094:Lithium; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; C053087:inositol-1,4-bisphosphate 1-phosphatase; D008274:Magnesium