Multi-step oxidations catalyzed by cytochrome P450 enzymes: Processive vs. distributive kinetics and the issue of carbonyl oxidation in chemical mechanisms.
Catalysis of sequential oxidation reactions is not unusual in cytochrome P450 (P450) reactions, not only in steroid metabolism but also with many xenobiotics. One issue is how processive/distributive these reactions are, i.e., how much do the "intermediate" products dissociate. Our work with human P450s 2E1, 2A6, and 19A1 on this subject has revealed a mixture of systems, surprisingly with a more distributive mechanism with an endogenous substrate (P450 19A1) than for some xenobiotics (P450s 2E1, 2A6). One aspect of this research involves carbonyl intermediates, and the choice of catalytic mechanism is linked to the hydration state of the aldehyde. The non-enzymatic rates of hydration and dehydration of carbonyls are not rapid and whether P450s catalyze the reversible hydration is unknown. If carbonyl hydration and dehydration are slow, the mechanism may be set by the carbonyl hydration status.
Guengerich
F Peter
FP
Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA. f.guengerich@vanderbilt.edu
Sohl
Christal D
CD
Chowdhury
Goutam
G
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D013379:Substrate Specificity
D000447:Aldehydes; D003577:Cytochrome P-450 Enzyme System; D001141:Aromatase
Carcinogenesis. 1992 Oct;13(10):1789-94
1423839
J Biol Chem. 2006 Apr 7;281(14):9127-36
16467307
J Am Chem Soc. 1977 Mar 16;99(6):1992-3
839019
J Biol Chem. 1985 May 25;260(10):6385-93
3997827
J Biol Chem. 2010 Mar 12;285(11):8031-44
20061389
Carcinogenesis. 1993 Jun;14(6):1189-93
8508506
Biochemistry. 1998 Mar 3;37(9):2800-6
9485431
Carcinogenesis. 1990 Aug;11(8):1293-300
2117502
J Biol Chem. 2010 Jun 4;285(23):17734-43
20385561
J Am Chem Soc. 2001 Mar 7;123(9):2018-24
11456824
J Biol Chem. 1997 Nov 21;272(47):29643-51
9368031
J Biol Inorg Chem. 2007 Sep;12(7):1073-81
17661096
Biochem Pharmacol. 1985 Sep 15;34(18):3213-9
3899122
Cancer Res. 1982 Aug;42(8 Suppl):3277s-3280s
7083186
Fundam Clin Pharmacol. 2003 Feb;17(1):27-41
12588628
Biochemistry. 1998 Jun 2;37(22):8097-104
9609704
Chem Res Toxicol. 1991 Jul-Aug;4(4):413-21
1912327
Chem Res Toxicol. 2009 Feb;22(2):323-31
19138062
J Natl Cancer Inst. 1973 Jul;51(1):299-302
4720880
Chem Res Toxicol. 1991 Jul-Aug;4(4):408-13
1912326
Cancer Res. 1987 Jul 1;47(13):3373-7
3581074
Chem Res Toxicol. 1999 Jul;12(7):623-9
10409402
Chem Res Toxicol. 2001 Jun;14(6):611-50
11409933
Eur J Biochem. 2000 Jun;267(11):3243-7
10824109
Biochemistry. 1999 Aug 10;38(32):10511-8
10441147
Science. 1984 Sep 7;225(4666):1032-4
6474163
Annu Rev Physiol. 2002;64:93-127
11826265
Biochem J. 1971 Apr;122(3):327-32
5165730
J Biol Chem. 1999 Aug 20;274(34):23833-40
10446146
Arch Biochem Biophys. 1974 Jul;163(1):404-15
4152897
J Biol Chem. 2008 Mar 14;283(11):7293-308
18187423
Alcohol Clin Exp Res. 1996 Feb;20(1 Suppl):22A-24A
8659682
J Am Chem Soc. 2005 Apr 13;127(14):5224-37
15810858
Biochemistry. 1995 Aug 29;34(34):10939-45
7662675
Carcinogenesis. 1990 Aug;11(8):1329-33
2387018
J Pharm Sci. 1982 Dec;71(12):1328-34
6130140
Biochem J. 1982 Mar 1;201(3):569-80
7092812
Biochem Biophys Res Commun. 1991 Aug 30;179(1):689-94
1822117
J Med Chem. 1990 Nov;33(11):2933-42
2231592
Chem Res Toxicol. 2008 Jan;21(1):70-83
18052394
Bioorg Med Chem. 1997 Apr;5(4):641-4
9158861
Drug Metab Dispos. 1994 Jul-Aug;22(4):584-91
7956734