Cytochrome P-450scc: Enzymology, and the Regulation of Intramitochondrial Cholesterol Delivery to the Enzyme

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Abstract
The mechanism and properties of the adrenal cortex enzyme system which catalyzes the side chain cleavage of cholesterol to form pregnenolone are summarized. Cytochrome P-450scc, an integral inner mitochondrial membrane protein, interacts with its electron donor adrenodoxin via an aqueous-exposed (matrix side) site, and with its substrate cholesterol via an active site in communication with the hydrophobic phospholipid milieu. In a purified, phospholipid vesicle-reconstituted system, membrane-dissolved cholesterol interacts rapidly with and can be readily metabolized by the membrane-associated cytochrome, and thus represents a readily accessible cholesterol pool. Evidence for a rapidly metabolizable mitochondrial substrate pool (presumably that in the inner mitochondrial membrane) and the regulation by ACTH of cholesterol movement from other site(s) (presumably the outer mitochondrial membrane) into the reactive pool is reviewed; additional evidence is provided which supports the idea that the outer mitochondrial membrane/intermembrane space provides the rate-limiting block to cholesterol utilization. Possible mechanisms by which ACTH might regulate intramitochondrial cholesterol movement are discussed. ACTH has been found to regulate intramitochondrial aqueous volumes (both the matrix and the intermembrane space) in a cycloheximide-inhibitable manner, and it is proposed that these volume changes reflect an altered relationship of outer and inner membranes which may promote movement of cholesterol.