期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 409, 期 1, 页码 134-144出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/S0003-9861(02)00491-5
关键词
cytochrome P450c17; CYP17; 17 alpha-hydroxylase/17,20-lyase; cytochrome P450c21; CYP21; 21-hydroxylase; ent-progesterone; enzyme inhibition; molecular dynamics; type I difference spectrum
资金
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R03DK056641, K08DK002387] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [P01GM047969] Funding Source: NIH RePORTER
- NIDDK NIH HHS [R03DK56641, K08DK02387] Funding Source: Medline
- NIGMS NIH HHS [GM47969] Funding Source: Medline
Human cytochrome P450c17 (17alpha-hydroxylase, 17,20-lyase) (CYP17) and cytochrome P450c21 (21-hydroxylase) (CYP21) differ by only 14 amino acids in length and share 29% amino acid identity. Both enzymes hydroxylate progesterone at carbon atoms that lie only 2.6 Angstrom apart, but CYP17 also metabolizes other steroids and demonstrates additional catalytic activities. To probe the active site topologies of these related enzymes, we synthesized the enantiomer of progesterone and determined if ent-progesterone is a substrate or inhibitor of CYP17 and CYP21. Neither enzyme metabolizes ent-progesterone-1 however, ent-progesterone is a potent competitive inhibitor of CYP17 (K-1 = 0.2 muM). The ent-progesterone forms a type I difference spectrum with CYP17, but molecular dynamics simulations suggest different binding orientations for progesterone and its enantiomer. The ent-progesterone also inhibits CYP21, with weaker affinity than for CYP17 We conclude that CYP17 accommodates the stereochemically unnatural ent-progesterone better than CYP21. Enantiomeric steroids can be used to probe steroid binding sites, and these compounds may be effective inhibitors of steroid biosynthesis. (C) 2002 Elsevier Science (USA). All rights reserved.
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