Studies on the mechanism of action of a bilayer stabilizing inhibitor of protein kinase C: cholesterylphosphoryldimethylethanolamine.
Cholesterylphosphoryldimethylethanolamine is a zwitterionic compound which is a good bilayer stabilizer. As has been found with many other compounds having these properties, cholesterylphosphoryldimethylethanolamine is found to be a potent inhibitor of protein kinase C in both vesicle and micelle assay systems. The kinetics of the inhibition in Triton X-100 micelles was non-competitive with respect to ATP, histone, diolein, phorbol ester and Ca2+. It has a Ki of about 30 microns. The inhibition kinetics as a function of phosphatidylserine concentration is more complex but suggestive of competitive inhibition. Cholesterylphosphoryldimethylethanolamine does not prevent the partitioning of protein kinase C into the membrane. This inhibitor lowers the Ca2+-phosphatidylserine-independent phosphorylation of protamine sulfate by protein kinase C and directly affects the catalytic segment of the enzyme generated by tryptic hydrolysis. Thus, this zwitterionic bilayer stabilizing inhibitor of protein kinase C both competes with the binding of phosphatidylserine as well as affects the active site of protein kinase C.
Epand
R M
RM
Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada.
Stafford
A R
AR
Bottega
R
R
Ball
E H
EH
D000818:Animals; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008051:Lipid Bilayers; D008823:Micelles; D008958:Models, Molecular; D010718:Phosphatidylserines; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D004983:Ethanolamines; D008051:Lipid Bilayers; D008823:Micelles; D010718:Phosphatidylserines; C061041:cholesterylphosphoryldimethylethanolamine; D002784:Cholesterol; D011493:Protein Kinase C