Cytochrome-P450 mono-oxygenase

Cytochrome P450 (CYP) Cytochrome P450 isozymes Cytochrome P450 mono-oxygenases Mixed function oxidases... 

FIG. 21 Schematic diagram of cytochrome P450 mono-oxygenase reaction with substrate RH and product ROH. 

Pisatin (6.23) is an isoflavonoid phytoalexin that is synthesized by pea (Pisum sativum L.) as a response to infection (Preisig et al., 1989). Subsequently, it was shown that pathogens capable of demethylating pisatin were tolerant of this phytoalexin. The enzyme responsible for demethylation is a specific cytochrome P450 mono-oxygenase released by the fungus Nectria haematococca (Delserone et al., 1999). 

In companion papers, Renton and Mannering29 and Leeson et al.30 described the decrease in activity of the hepatic cytochrome P450 mono-oxygenase system following... 

Yu J, Chang P-K, Ehrlich KC, Cary JW, Montalbano B, Dyer JM, Bhatnagar D, Cleveland TE Characterization of the critical amino acids of an Aspergillus parasiticus cytochrome P450 mono-oxygenase encoded by ordA that is involved in the biosynthesis of aflatoxins Bj, Gj, Bj and G2. Appl Environ Microbiol 1998 64 4834-4841. 

Siminszky, B., Gavilano, L., Brown, S.W., Dewey, R.E. (2005) Conversion of nicotine to nornicotine in Nicotiana tabacum is mediated by CYP82E4, a cytochrome P450 mono-oxygenase. Proc. Natl. Acad. Sci. USA, 102,14919-24. 

In B. napus, the enzyme which is responsible for fhe hydroxylafion of 3-butenylglucosinolate to yield 2-hydroxy-3-butenylgIucosinoIate is thought to be a cytochrome P450 mono-oxygenase (Rossiter et al, 1990). 

Oxidative reactions catalysed by non-microsomal enzymes are less varied than those mediated by cytochrome P450 mono-oxygenases but are important in the metabolism of some drugs (e.g. isoproterenol, methylxanthines, methimazole, ethanol, chloral hydrate), endogenous substances (adrenalin, histamine) and naturally occurring compounds (vitamin A). Theophylline and caffeine (methylxanthines) simultaneously undergo microsomal cytochrome... 

For the enantioselective preparations of chiral synthons, the most interesting oxidations are the hydroxylations of unactivated saturated carbons or carbon-carbon double bonds in alkene and arene systems, together with the oxidative transformations of various chemical functions. Of special interest is the enzymatic generation of enantiopure epoxides. This can be achieved by epoxidation of double bonds with cytochrome P450 mono-oxygenases, w-hydroxylases, or biotransformation with whole micro-organisms. Alternative approaches include the microbial reduction of a-haloketones, or the use of haloperoxi-dases and halohydrine epoxidases [128]. The enantioselective hydrolysis of several types of epoxides can be achieved with epoxide hydrolases (a relatively new class of enzymes). These enzymes give access to enantiopure epoxides and chiral diols by enantioselective hydrolysis of racemic epoxides or by stereoselective hydrolysis of meso-epoxides [128,129]. 

Iley, J., L. Constantino, F. Norberto, and E. Rosa (1990). Oxidation of the methyl groups of N,N-dimethylbenzamides by a cytochrome P450 mono-oxygenase model system. Tetrahedron Lett. 31,4921 922. 

Fig. 19.13. Cytochrome P450 mono-oxygenases. Electrons are donated by NADPH to O2 and the substrate. The flavin coenzymes FAD and FMN in one subunit transfer single electrons to cytochrome P450, which is an Fe-heme containing protein that absorbs hght at a wavelength of 450 nm. The enzyme is embedded in a membrane, usually the endoplasmic reticulum.

Once absorbed from the intestine, flavonoids will be subjected to metabolism involving phase I or phase II enzymes. Hydroxylation and demethylation are examples of cytochrome P450 mono-oxygenase-dependent (phase I) activities that may be involved in the metabolism of flavonoids. Nielsen et al. [24] showed that microsomes prepared from normal and Aroclor-treated rats were capable of hydroxylating certain flavonols and... 

The initial description of biological activities of arachidonic acid metabolites arising from cytochrome P450 mono-oxygenases reveals similarities to prostanoids, i.e. they can act as secretagogues and local modulators of circulating hormones and their principal activity is circumscribed to the... 

Sultana, N., Schenkman, J.B., and Rusling, J.F. 2005. Protein film electro chemistry of microsomes genetically enriched in human cytochrome P450 mono oxygenases. J. Am. Chem. Soc. 127 13460-13461. 

McLean KJ, Marshall KR, Richmond A, Hunter IS, Fowler K, Kieser T, Gurcha SS, Besra GS, Munro AW (2002) Azole antifungals are potent inhibitors of cytochrome P450 mono-oxygenases and bacterial growth in mycobacteria and streptomycetes. Microbiology-Sgm 148 2937-2949... 

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