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Volume 270, Number 20, Issue of May 19, pp. 12075-12084, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.

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Stephen G. Ward , Stephen J. Mills , Changsheng Liu , John Westwick , Barry V. L. Potter

Several natural and unnatural inositol phosphates and analogues were analyzed for their ability to inhibit the in vitro phosphatidylinositol 3-kinase (PI 3-kinase) activity immunoprecipitated from a leukemic T cell line by a p85 monoclonal antibody. A 3-position ring-modified analogue of D-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P), L-chiro-inositol 2,3,5-trisphosphate (L-chiro-Ins(2,3,5)P) and its phosphorothioate analogue, L-chiro-inositol 2,3,5-trisphosphorothioate, as well as the analogue benzene 1,2,4-trisphosphate induced reversible inhibition of PI 3-kinase activity, which correlated with decreased V but unchanged Kvalues for PI 3-kinase. Other inositol phosphates, including D- and L-Ins(1,4,5)P, D-myo-inositol 1,3,4,5-tetrakisphosphate, the enantiomers of myo-inositol 1,3,4-trisphosphate, DL-myo-inositol 1,4,6-trisphosphate (DL-Ins(1,4,6)P), and DL-scyllo-inositol 1,2,4-trisphosphate (DL-scyllo-Ins(1,2,4)P), did not inhibit PI 3-kinase activity under identical conditions. L-chiro-Ins(2,3,5)P closely resembles Ins(1,4,5)P and D-Ins(1,4,6)P except for a difference in the orientation of a single hydroxyl group at either the equivalent 3-OH or 2-OH position of Ins(1,4,5)P, respectively. Similarly, L-chiro-Ins(2,3,5)P resembles D-scyllo-Ins(1,2,4)P, but has a different orientation of both the equivalent 3-OH and 2-OH positions. Since Ins(1,4,5)P, DL-Ins(1,4,6)P, and DL-scyllo-Ins(1,2,4)P did not inhibit PI 3-kinase activity, this suggests that the orientation of the two hydroxyl groups at the 2- and 3-positions plays a pivotal role in the inhibitory action of inositol phosphate analogues on PI 3-kinase activity. Thus, inositol phosphate analogues inter alia are shown for the first time to inhibit PI 3-kinase and may be useful tools for determining the function of PI 3-kinase and its substrate binding specificities.

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