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)PS3 to inhibit soluble inositol (1,4,5)P-3/(1,3,4,5)P-4-polyphos phate 5-phosphatase, potently and selectively, has been investigated. L-chr Ins(1,4,6)P-3 competitively inhibited 5-phosphate specific depho sphorylation 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 mu M, respe ctively. L-chr Ins(1,4,6)PS3 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 mu M, respectively. L-chr Ins(1,4,6)PS3 did not affect Ins(1,4,5)P-3 3-kinase activity. I n 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 in ositol polyphosphate metabolism yet described. (C) 1994 Academic Press , Inc.