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)P3] and the corresponding trisphosphorothioate compound [L-chr Ins(1,4,6)PS3] to inhibit soluble inositol (1,4,5)P3/(1,3,4,5)P4-polyphosphate 5-phosphatase, potently and selectively, has been investigated. L-chr Ins(1,4,6)P3 competitively inhibited 5-phosphate specific dephosphorylation of Ins(1,4,5)P3 and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] with apparent Ki values of 6.35 and 1.76 microM, respectively. L-chr Ins(1,4,6)PS3 competitively inhibited hydrolysis of Ins(1,4,5)P3 and noncompetitively inhibited dephosphorylation of Ins(1,3,4,5)P4 with apparent Ki values of 0.67 and 0.44 microM, respectively. L-chr Ins(1,4,6)PS3 did not affect Ins(1,4,5)P3 3-kinase activity. In the present investigation L-chr Ins(1,4,6)P3 and L-chr Ins(1,4,6)PS3 have been shown to be the most potent and selective inhibitors of inositol polyphosphate metabolism yet described.