Abstract
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.
Highlights
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
To facilitate comparison with the aforementioned studies using CL as activator lipid, we studied the influence of the branched 1,2-diacyl PCs on the enzymatic activity and other properties of P450SCC in vesicles made from mixtures of these branched PCs with DMPC and DOPC, respectively
Cytochrome P450SCC Activation by Branched Phosphatidylcholines. According to their effects on the catalytic activity of P450SCC, lipids have been divided into two groups: lipids that activate the SCC activity of P450SCC and nonactivator lipids [5]
Summary
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. 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. The present paper is aimed at the elucidation of the possible importance of such a lipid configuration for the process of cholesterol side chain cleavage activity of P450SCC. For this purpose, the ␣-branched phosphatidylcholines 1,2-di-(2Ј-hexyldecanoyl)-sn-glycero-3-phosphocholine (PC[10,6]) and 1,2-di(2Ј-octyl-dodecanoyl)-sn-glycero-phosphocholine (PC[12,8]) have been synthesized and used for reconstitution of the SCC activity of P450SCC using various phosphatidylcholine vesicle
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