Possible involvement of nonbilayer lipids in the stimulation of the activity of cytochrome P450SCC (CYP11A1) and its propensity to induce vesicle aggregation

Schwarz, Dieter; Kisselev, Pyotr; Wessel, Ralf; Pisch, Sandra; Bornscheuer, Uwe T.; Schmid, Rolf D.

doi:10.1016/s0009-3084(96)02642-4

Cited by 8 publications

(7 citation statements)

References 28 publications

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“…Moreover, it should be considered that CL together with PE, another nonbilayer lipid, comprise more than 50% of phospholipid of the inner mitochondrial membrane. We further found that P450SCC induces specific vesicle aggregation critically dependent on CL, which also might be connected with the formation or predisposition of formation of nonbilayer phases (Schwarz et al, 1994(Schwarz et al, , 1997.…”

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confidence: 59%

Evidence That Nonbilayer Phase Propensity of the Membrane Is Important for the Side Chain Cleavage Activity of Cytochrome P450SCC (CYP11A1)

et al. 1997

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To analyze whether specific protein-lipid interactions or physical features of the membrane contribute to cytochrome P450SCC (CYP11A1) activation by lipids, dimyristoylphosphatidylcholine/cardiolipin and dimyristoylphosphatidylcholine/branched phosphatidylcholine vesicles of defined acyl chain structure were studied for their ability to stimulate the side chain cleavage activity of the enzyme. Activation was found to increase with the mole percent of nonbilayer lipids in the system and the chain lengths of both the branched and main fatty acyl chains of the activator lipid. Unsaturation provided by dioleoylphosphatidylcholine as host lipid leads to a further increase in the potency of the branched phosphatidylcholines to activate the enzyme. The observed activation can be qualitatively interpreted in terms of the effect of these lipids on the hydrophobic volume of the membrane. Using differential scanning calorimetry, we showed that the branched phosphatidylcholines perturb the bilayer membrane structure of dimyristoylphosphatidylcholine and lower the bilayer to hexagonal phase transition temperature of dielaidoylphosphatidylethanolamine, i.e., promote hexagonal phase formation. We also examined the effect of eicosane on both the cytochrome P450SCC activity and the lipid polymorphism and found that eicosane increases both the activity and the hexagonal phase propensity of the vesicle membrane. Because of these correlations, we conclude that the nonbilayer phase propensity of the membrane rather than specific binding of activator lipids to the enzyme explains best the observed activation of enzymatic activity by the lipids.

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confidence: 59%

Evidence That Nonbilayer Phase Propensity of the Membrane Is Important for the Side Chain Cleavage Activity of Cytochrome P450SCC (CYP11A1)

et al. 1997

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“…In contrast, high levels of unsaturated fatty acids typically accumulate in cytoplasmic lipid droplets, a storage depot (25). The incorporation of branched-chain saturated fatty acids into membranes induces the formation of abnormal, inverted nonbilayer phases (79) and increases membrane fluidity (17,21,43). Both factors may contribute significantly to altered membrane functions (43).…”

Section: Discussionmentioning

confidence: 99%

Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts

Atshaves¹,

Storey²,

Petrescu³

et al. 2002

American Journal of Physiology-Cell Physiology

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High levels of saturated, branched-chain fatty acids are deleterious to cells and animals, resulting in lipid accumulation and cytotoxicity. Although fatty acid binding proteins (FABPs) are thought to be protective, this hypothesis has not previously been examined. Phytanic acid (branched chain, 16-carbon backbone) induced lipid accumulation in L cell fibroblasts similar to that observed with palmitic acid (unbranched, C16): triacylglycerol ≫ free fatty acid > cholesterol > cholesteryl ester ≫ phospholipid. Although expression of sterol carrier protein (SCP)-2, SCP-x, or liver FABP (L-FABP) in transfected L cells reduced [3H]phytanic acid uptake (57–87%) and lipid accumulation (21–27%), nevertheless [3H]phytanic acid oxidation was inhibited (74–100%) and phytanic acid toxicity was enhanced in the order L-FABP ≫ SCP-x > SCP-2. These effects differed markedly from those of [3H]palmitic acid, whose uptake, oxidation, and induction of lipid accumulation were not reduced by L-FABP, SCP-2, or SCP-x expression. Furthermore, these proteins did not enhance the cytotoxicity of palmitic acid. In summary, intracellular FABPs reduce lipid accumulation induced by high levels of branched-chain but not straight-chain saturated fatty acids. These beneficial effects were offset by inhibition of branched-chain fatty acid oxidation that correlated with the enhanced toxicity of high levels of branched-chain fatty acid.

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“…This would lead to a more negative curvature of the membrane and would generate nonlamellar phases in the purified form (Luzzati and Husson, 1962). These nonlamellar-forming lipids affect the fluidity of the membrane and have been reported to modulate the activities of numerous proteins, including rhodopsin (Epand, 1998), protein kinase C (Epand, 1987), and CYP11A1 (Schwarz et al, 1997), as a few examples.…”

Section: Phosphatidylcholinementioning

confidence: 99%

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

Brignac‐Huber¹,

Park²,

Reed³

et al. 2016

Drug Metabolism and Disposition

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Cytochrome P450s (P450s) comprise a superfamily of proteins that catalyze numerous monooxygenase reactions in animals, plants, and bacteria. In eukaryotic organisms, these proteins not only carry out reactions necessary for the metabolism of endogenous compounds, but they are also important in the oxidation of exogenous drugs and other foreign compounds. Eukaryotic P450 system proteins generally reside in membranes, primarily the endoplasmic reticulum or the mitochondrial membrane. These membranes provide a scaffold for the P450 system proteins that facilitate interactions with their redox partners as well as other P450s. This review focuses on the ability of specific lipid components to influence P450 activities, as well as the role of the membrane in P450 function. These studies have shown that P450s and NADPH-cytochrome P450 reductase appear to selectively associate with specific phospholipids and that these lipid-protein interactions influence P450 activities. Finally, because of the heterogeneous nature of the endoplasmic reticulum as well as other biologic membranes, the phospholipids are not arranged randomly but associate to generate lipid microdomains. Together, these characteristics can affect P450 function by 1) altering the conformation of the proteins, 2) influencing the P450 interactions with their redox partners, and 3) affecting the localization of the proteins into specific membrane microdomains.

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Possible involvement of nonbilayer lipids in the stimulation of the activity of cytochrome P450SCC (CYP11A1) and its propensity to induce vesicle aggregation

Cited by 8 publications

References 28 publications

Evidence That Nonbilayer Phase Propensity of the Membrane Is Important for the Side Chain Cleavage Activity of Cytochrome P450SCC (CYP11A1)

Evidence That Nonbilayer Phase Propensity of the Membrane Is Important for the Side Chain Cleavage Activity of Cytochrome P450SCC (CYP11A1)

Expression of fatty acid binding proteins inhibits lipid accumulation and alters toxicity in L cell fibroblasts

Cytochrome P450 Organization and Function Are Modulated by Endoplasmic Reticulum Phospholipid Heterogeneity

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