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Volume 271, Number 22, Issue of May 31, 1996 pp. 12840-12846
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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-Branched 1,2-Diacyl Phosphatidylcholines as Effectors of Activity of Cytochrome P450SCC (CYP11A1)
MODELING THE STRUCTURE OF THE FATTY ACYL CHAIN REGION OF CARDIOLIPIN

(Received for publication, December 7, 1995, and in revised form, March 5, 1996)

From the Max Delbrueck Centrum for Molecular Medicine, 13125 Berlin-Buch, Germany, the ^§ Institute of Bioorganic Chemistry, Academy of Sciences of Belarus, 220141 Minsk, Belarus, and the ^¶ Institute for Technical Biochemistry, University of Stuttgart, 70569 Stuttgart, Germany

Cardiolipin has been shown to be the most effective activator of cholesterol side chain cleavage activity of cytochrome P450SCC, and evidence has been provided for a lipid effector site on the enzyme. Results suggested the headgroup of cardiolipin as major determinant of lipid interaction with P450SCC (Lambeth, J. D. (1981) J. Biol. Chem. 256, 4757-4762). The role of unsaturation is contradictory and open to question (Igarashi, Y. and Kimura, T. (1986) Biochemistry 25, 6461-6466). We synthesized phosphatidylcholines with fully saturated branched fatty acyl chains substituted in the 2-positions of the main chains and studied the influence of these lipids on the activity and other properties of P450SCC in vesicle-reconstituted systems. These saturated branched lipids, with regard to the fatty acyl moiety in molecular shape similar to cardiolipin but with the headgroup of phosphatidylcholines retained, 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 process of stimulation of the activity of P450SCC. Because binding of cholesterol was increased by the branched lipids monitored optically by the fraction of P450SCC in the high spin form, it was concluded that these lipids, like cardiolipin and other lipids, exert their effects by regulating the binding of cholesterol to P450SCC. These data suggest that polymorphic lipids such as branched phosphatidylcholines and cardiolipin might influence P450SCC function by maintenance of the membrane curvature at a value optimal for activity.

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