22-thio-23,24-bisnor-5-cholen-3 beta-ol: an active site-directed inhibitor of cytochrome P450scc.
The title compound (22-Thiol) was prepared from the 22-hydroxy derivative via the isothiouronium salt. Using purified enzyme components from bovine adrenocortical mitochondria, 22-Thiol was found to be a potent, competitive inhibitor (Ki = 0.7 microM) of cholesterol side chain cleavage. Spectral studies showed that binding of 22-Thiol to cytochrome P450scc produces changes characteristic of sulfur coordination to the heme-iron, suggesting that its high affinity arises from a dual interaction with the cholesterol binding site and the heme. Together with previous results obtained with 22-amino and 22-hydroxy analogues, these findings provide support for the proximity of C-22 and the heme-iron of cytochrome P450scc in the enzyme-substrate complex.
Vickery
L E
LE
Department of Physiology and Biophysics, University of California, Irvine 92717.
Singh
J
J
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000037:antagonists & inhibitors*; D006418:Heme; D007700:Kinetics; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D011283:Pregnenes / Q000494:pharmacology*; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds
D011283:Pregnenes; D013438:Sulfhydryl Compounds; C056190:22-thio-23,24-bisnor-5-cholen-3-ol; D006418:Heme; D002786:Cholesterol Side-Chain Cleavage Enzyme