Kinetic Analysis of Novel Inhibitors of Inositol Polyphosphate Metabolism

The ability of the novel D- myo -inositol 1,4,5-trisphosphate [Ins(1,4,5)P 3 ] analogues, L- chiro -inositol 1,4,6-trisphosphate [L- chr Ins(1,4,6)P 3 ] and the corresponding trisphosphorothioate compound [L- chr Ins(1,4,6)PS 3 ] to inhibit soluble inositol (1,4,5)P 3 /(1,3,4,5)P 4 -polyphosphate 5-phosphatase, potently and selectively, has been investigated. L- chr Ins(1,4,6)P 3 competitively inhibited 5-phosphate specific dephosphorylation of Ins(1,4,5)P 3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P 4 ] with apparent K i values of 6.35 and 1.76 μM, respectively. L- chr Ins(1,4,6)PS 3 competitively inhibited hydrolysis of Ins(1,4,5)P 3 and noncompetitively inhibited dephosphorylation of Ins(1,3,4,5)P 4 with apparent K i values of 0.67 and 0.44 μM, respectively. L- chr Ins(1,4,6)PS 3 did not affect Ins(1,4,5)P 3 3-kinase activity. In the present investigation L- chr Ins(1,4,6)P 3 and L- chr Ins(1,4,6)PS 3 have been shown to be the most potent and selective inhibitors of inositol polyphosphate metabolism yet described.