Cytochrome substrate specificity

However, there are certain properties for which no modeling attempts have been made due to the lack of the appropriate experimental data. Cytochrome substrate specificity or phase II metabolism are two examples. 

Lewis DFV, Eddershaw PJ, Dickins M, Tarbit MH, Goldfarb PS. Structural determinants of cytochrome P450 substrate specificity, binding affinity and catalytic rate. Chem Bio Interact 1998 115 175-99. 

At least six isoforms of cytochrome P450 are present in the endoplasmic reticulum of human hver, each with wide and somewhat overlapping substrate specificities and acting on both xenobiotics and endogenous compounds. The genes for many isoforms of P450 (from both humans and animals such as the rat) have been isolated and smdied in detail in recent years. 

All cytochrome P450s are hemoproteins and generally have a wide substrate specificity, acting on many exogenous and endogenous substrates. They represent the most versatile biocatalyst known. 

Cytochrome P450-type monooxygenase systems, which have a generally low substrate specificity, are widely distributed in the species of fish used for toxicity testing (Funari et al. 1987). 

Wacher, V. J., Wu, C. Y., Benet, L. Z., Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein implications for drug delivery and activity in cancer chemotherapy, Mol. Carcinogen. 1995, 13, 129-134. 

Mast, N., Norcross, R., Andersson, U. et al. Broad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain. Biochemistry 42 14284-14292, 2003. 

ANDERSEN, M.D., M0LLER, B.L., Cytochromes P450 from Cassava (Manihot esculenta Crantz) catalyzing the first steps in the biosynthesis of the cyanogenic glucosides linamarin and lotaustralin cloning, functional expression in Pichia pastoris and substrate specificity of the isolated recombinant enzymes, J. Biol. Chem., 2000,275, 1966-1975. 

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. 

The analysis of the cytochrome crystal structures reveals extensive differences among the mammalian and the human CYPs that may reflect the structural flexibility of these enzymes and therefore the broad substrate specificity observed. In general, the secondary elements and the overall structure of the CYP are conserved. Nevertheless, it seems that in most enzymes, the most flexible regions are located between the F-G helixes and the B-C loop. For example in the CYP2B4 apoprotein (lpo5) the... 

De Rienzo, F., Fanelli, F., Menziani, M.C. and De Benedetti, P.G. (2000) Theoretical investigation of substrate specificity for cytochromes P450 IA2, P450 IID6 and P450 II IA4. Journal of Computer-Aided Molecular Design, 14, 93-116. 

The marine environment acts as a sink for a large proportion of polyaromatic hydrocarbons (PAH) and these compounds have become a major area of interest in aquatic toxicology. Mixed function oxidases (MFO) are a class of microsomal enzymes involved in oxidative transformation, the primary biochemical process in hydrocarbon detoxification as well as mutagen-carcinogen activation (1,2). The reactions carried out by these enzymes are mediated by multiple forms of cytochrome P-450 which controls the substrate specificity of the system (3). One class of MFO, the aromatic hydrocarbon hydroxylases (AHH), has received considerable attention in relation to their role in hydrocarbon hydroxylation. AHH are found in various species of fish (4) and although limited data is available it appears that these enzymes may be present in a variety of aquatic animals (5,6,7,8). 

Wacher VJ, Wu CY and Benet LZ (1995) Overlapping Substrate Specificities and Tissue Distribution of Cytochrome-P450 3a and P-Glycoprotein—Implications for Drug-Delivery and Activity in Cancer-Chemotherapy. Mol Carcinog 13 pp 129-134. 

Most oxidation reactions are catalyzed by cytochrome P450 systems (see p. 318). These monooxygenases are induced by their substrates and show wide specificity. The substrate-specific enzymes of the steroid metabolism (see p. 376) are exceptions to this. 

Dai, R., Pincus, M. R., and Friedman, F. K. (1998) Molecular modeling of cytochrome P450 2B1 mode of membrane insertion and substrate specificity. J. Protein Chem. 17, 120-129. 

Wolff, T., Distlerath, L. M., Worthington, M. T., et al. (1985) Substrate specificity of human liver cytochrome P-450 debrisoquine 4-hydroxylase probed using immunochemical inhibition and chemical modeling. Cancer Res. 45, 2116-2122. 

Lewis, D. F. V. (2000) On the recognition of mammalian microsomal cytochrome P450 substrates and their characteristics Towards the prediction of human p450 substrate specificity and metabolism. Biochem. Pharmacol. 60, 293-306. 

The flavin monooxygenases (FMOs) are a family of five enzymes (FMO 1-5) that operate in a manner analogous to the cytochrome P450 enzymes in that they oxidize the drug compound in an effort to increase its elimination. Though they possess broad substrate specificity, in general they do not play a major role in the metabolism of drugs but appear to be more involved in the metabolism of environmental chemicals and toxins. 

Substrate-specific cytochrome P450-mediated hydroxylation involves NADPH-dependent oxidation of some cyclic peptides such as cyclosporine. Hydroxylated products of cyclosporine are biologically inactive and readily cleared from the body. 

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