Cytochrome regioselectivity

The aim of the present chapter is to describe a recent in silico method. It is fast, easy and computationally inexpensive, and able to predict human cytochrome regioselective metabolism using ad hoc developed 3D homology models for the enzymes and the 3D structure of the potential substrates. The method uses GRID flexible molecular interaction fields as well as the 3D structure of the potential substrates, automatically providing the site of metabolism (i.e. the place where the metabolic reactions occur) in graphical output. 

White RE, MB McCarthy, KD Egeberg, SG Sligar (1984) Regioselectivity in the cytochromes P-450 control by protein constraints and by chemical reactivities. Arch Biochem Biophys 228 493-502. 

The selective monohydroxylation of heterocyclic compounds such as piperidine derivatives1741 and the 7-lactam (19)[751 have been studied. It is also been shown that hydroxylation of phenylcyclohexane can be effected using cytochrome P450 and the regioselectivity of hydroxylation can be altered by site-directed mutagenesis of the enzyme1761. 

Paine MJ, McLaughlin LA, Flanagan JU, et al. Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. J Biol Chem 2003 278(6) 4021-4027. 

Kumar, S., Scott, E. E., Liu, Hong, and Halpert, J. (2003) A rational approach to re-engineer cytochrome P450 2B1 regioselectivity based on the crystal structure of cytochrome P450 2C5. 278, 17,178-17,184. 

Lightfoot T, Ellis SW, Mahling J, Ackland MJ, Blaney FE, Bijloo GJ, de Groot MJ, Vermeulen NPE, Blackburn GM, Lennard MS, Tucker GT (2000) Regioselective hy-droxylation of debrisoquine by cytochrome P450 2D6 implications for active site modeling. Xenobiotica 30, 219-233. 

Jones JP, Trager WF, Carlson TJ. The binding and regioselectivity of reaction of (R)-nicotine and (S)-nicotine with cytochrome-P-450cam - parallel experimental and theoretical-studies. J Am Chem Soc 1993 115 381-387. 

Gorski JC, Hall SD, Jones DR, et al. Regioselective biotransformation of midazolam by members of the human cytochrome P4503A (CYP3A) subfamily. Biochem Pharmacol 1994 47 1643-1653. 

Salaun, J.P., Weissbart, D., Helvig, C., Durst, F., and Mioskowski, C, Regioselective hydroxylation and epoxidation of lauric acid and unsaturated analogs by cytochrome P450 in Jerusalem artichoke microsomes, Plant Physiol. Biochem., 31, 285-293, 1993. 

Fretz, H. and Woggon, W.-D. (1986) Regioselectivity and deuterium isotope effects in geraniol hydroxylation by the cytochrome P450 monooxygenase from Catharanthus roseus (L.). G. Don. Helv. Chim. Acta, 69, 1959-70. 

Sheridan RP, Korzekwa KR, Torres RA, Walker MJ. Empirical regioselectivity models for human cytochromes p450 3A4, 2D6, and 2C9. J. Med. Chem. 2007 50 3173-3184. 

Aoyama, X, Korzekwa, K Nagata, K., Adesnik, M Reiss, A Lapenson, D. P, Gillette, J., Gelboin, H. V, Waxman, D. ]., and Gonzalez, F. J. (1989). Sequence Requirements for Cytochrome P-450IIB1 Catalytic Activity. Alteration of the Stereospecificity and Regioselectivity of Steroid Hydroxylation by a Simultaneous Change of Two Hydrophobic Amino Acid Residues to Phenylalanine,, Biol. Chem., 264 21,327-21,333. 

Swinney, D. C., Ryan, D, E., Thomas, E E., and Levin, W. (1987). Regioselective Progesterone Hydroxylation Catalyzed by Eleven Rat Hepatic Cytochrome P-450 Isozymes, BiodKmistiy, 26 7073-7083. 

Waxman, D. J. (1988). Interactions of Hepatic Cytochromes P-450 with Steroid Hormones. Regioselectivity and Steieospecificity of Steroid Metabolism and Hormonal Regulation of Rat P-450 Enzyme Expression, Biochem. Pharmacol., 37 71-84. 

Waxman DJ. Interactions of hepatic cytochromes P-450 with steroid hormones. Regioselectivity and stereospecificity of steroid metabolism and hormonal regulation of rat P-450 enzyme expression. Biochem Pharmacol 1988 37(1) 71-84. 

Maenpaa J, Hall SD, Ring BJ, Strom SC, Wrighton SA. 1998. Human cytochrome P450 3A (CYP3A) mediated midazolam metabolism the effect of assay conditions and regioselective stimulation by alpha-naphthoflavone, terfenadine and testosterone. Pharmacogenetics 8 137-55... 

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