ALPHA-BRANCHED 1,2-DIACYL PHOSPHATIDYLCHOLINES AS EFFECTORS OF ACTIVITY OF CYTOCHROME P450SCC (CYP11A1) - MODELING THE STRUCTURE OF THE FATTY ACYL-CHAIN REGION OF CARDIOLIPLN

Cardiolipin has been shown to be the most effective activator of chole sterol side chain cleavage activity of cytochrome P450SCC, and evidenc e has been provided for a lipid effector site on the enzyme. Results s uggested the headgroup of cardiolipin as major determinant of lipid in teraction with P450SCC (Lambeth, J. D. (1981) J. Biol. Chem. 258, 4757 -4762). The role of unsaturation is contradictory and open to question (Igarashi, Y. and Kimura, T. (1986) Biochemistry 25, 6461-6466). We s ynthesized phosphatidylcholines with fully saturated branched fatty ac yl chains substituted in the 2-positions of the main chains and studie d the influence of these lipids on the activity and other properties o f P450SCC in vesicle-reconstituted systems. These saturated branched l ipids, with regard to the fatty acyl moiety in molecular shape similar to cardiolipin but with the headgroup of phosphatidylcholines retaine d, showed a stimulatory efficiency higher than any other phospholipid and at least comparable to cardiolipin. Activation is sensitive to the acyl chain structure and composition. Results suggest that the shape of the molecule at least partially plays an important role in the proc ess of stimulation of the activity of P450SCC. Because binding of chol esterol was increased by the branched lipids monitored optically by th e fraction of P450SCC in the high spin form, it was concluded that the se lipids, like cardiolipin and other lipids, exert their effects by r egulating the binding of cholesterol to P450SCC. These data suggest th at polymorphic lipids such as branched phosphatidylcholines and cardio lipin might influence P450SCC function by maintenance of the membrane curvature at a value optimal for activity.