INHIBITION OF HUMAN ERYTHROCYTE-MEMBRANE PHOSPHATIDYLINOSITOL 4-KINASE BY PHOSPHOLIPID ANALOGS

Analogues of phosphatidylinositol (Ptdlns, 1) have been synthesized to investigate the structural requirements for inhibition of a Ptdlns 4- kinase obtained from human erythrocyte membranes. While the presence o f either D-1 or D-3 Stereochemistry in the inositol moiety greatly inf luences the degree of inhibition produced by Ptdlns analogues, the ste reochemistry of the glycerol moiety is of little consequence. Neither structural feature, however, makes a significant contribution to bindi ng affinity. Competitive inhibitory activity was found to be retained (or even enhanced) in substantially simpler analogues consisting of 1 or 2 hydrocarbon chains attached to a charged phosphate head group, su ch as in the phosphatidic acids, 24 and 26. The observation that the p hosphatidylinositol 4-phosphate (Ptdlns 4P) and phosphatidic acid anal ogues (eg, 16 or 17, and 26 respectively) inhibit Ptdlns 4-kinase may suggest that such species have a regulatory role in Ptdlns turnover.