BIOCHEMICAL AND MOLECULAR-PROPERTIES OF LITHIUM-SENSITIVE MYOINOSITOLMONOPHOSPHATASE

Myo-inositol monophosphatase is a pivotal enzyme of the inositol secon d messenger system which is specifically inhibited by therapeutic leve ls of lithium salts, implicating inhibition of this enzyme as a potent ial site of its action in bipolar disease. This enzyme has a native mo lecular weight of 59,000, and has traditionally been found in the cyto solic fraction, although a membrane-bound form has also been identifie d. Possessing two identical subunits, this enzyme hydrolyzes those mon ophosphates which are equatorially located within the inositol ring, a nd several nucleoside monophosphates phosphorylated at the 2-position. Each subunit of the native enzyme contains an active site with unusua lly large caverns as revealed by crystallographic studies, which may e xplain the accommodation of these structurally unrelated substrates. W e have suggested that the uncompetitive inhibition of this phosphatase by lithium ions may prevent the formation of an enzyme-bound non-isom eric (meso) intermediate, Mg2+-inositol 1,3 or 4,6 cyclic monophosphat e when this enzyme hydrolyzes its respective isomeric substrates.