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 of either D-1 or D-3 Stereochemistry in the inositol moiety greatly influences the degree of inhibition produced by Ptdlns analogues, the stereochemistry of the glycerol moiety is of little consequence. Neither structural feature, however, makes a significant contribution to binding 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, such as in the phosphatidic acids, 24 and 26. The observation that the phosphatidylinositol 4-phosphate (Ptdlns 4P) and phosphatidic acid analogues (eg, 16 or 17, and 26 respectively) inhibit Ptdlns 4-kinase may suggest that such species have a regulatory role in Ptdlns turnover.