22-Ketocholesterol. A potent competitive inhibitor of cytochrome P-450scc-dependent side-chain cleavage of cholesterol.
22-Ketocholesterol binds with high affinity to purified, phospholipid vesicle-reconstituted cytochrome P-450scc. Binding, quantitated using reversal of cholesterol-induced absorbance changes in the Soret region of the enzyme, indicates an affinity 3-5 times greater than that for the normal substrate cholesterol. The ketosteroid cannot be hydroxylated at position 22 and thus acts as a potent inhibitor of cholesterol side-chain cleavage. Steady-state kinetics demonstrate competitive inhibition by this steroid and provide a KI value several-fold lower than the cholesterol Km. On the basis of recently proposed mechanisms for hydroxylation by cytochromes P-450, 22-ketocholesterol may exert its inhibitory effect by acting as a tightly bound analogue that resembles the enzyme-bound cholesterol from which a hydrogen has been abstracted from position 22.
D000302:Adrenal Cortex / Q000201:enzymology*; D000325:Adrenodoxin / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005287:Ferredoxin-NADP Reductase / Q000378:metabolism; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D010088:Oxidoreductases / Q000378:metabolism*; D011284:Pregnenolone / Q000096:biosynthesis; D011485:Protein Binding
D000325:Adrenodoxin; C035465:22-ketocholesterol; D011284:Pregnenolone; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D010088:Oxidoreductases; D002786:Cholesterol Side-Chain Cleavage Enzyme; D005287:Ferredoxin-NADP Reductase