The Diversity and Importance of Microbial Cytochromes P450

Kelly, Steven L.; Kelly, Diane; Jackson, C.J.; Warrilow, Andrew G. S.; Lamb, David C.

doi:10.1007/0-387-27447-2_13

Cited by 29 publications

(25 citation statements)

References 162 publications

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“…Baker's yeast S. cerevisiae has only three P450 genes: CYP51, a lanosterol demethylase; CYP57, which is responsible for synthesis of the dityrosine required in cell wall assembly; and CYP61, which has been identified by proteomic studies as a sterol 22-desaturase [28]. Fungal P450s, unlike the bacterial enzymes but like the mammalian proteins, are generally membraneassociated and their turnover is supported by a single NADPH-dependent flavoprotein reductase.…”

Section: Discussionmentioning

confidence: 99%

Functional expression and characterization of cytochrome P450 52A21 from Candida albicans

Kim

Cryle

Voss

et al. 2007

Archives of Biochemistry and Biophysics

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Candida albicans contains ten putative cytochrome P450 (CYP) genes coding for enzymes that appear to play important roles in fungal survival and virulence. Here, we report the characterization of CYP52A21, a putative alkane/fatty acid hydroxylase. The recombinant CYP52A21 protein containing a 6 × (His)-tag was expressed in Escherichia coli and was purified. The purified protein, reconstituted with rat NADPH-cytochrome P450 reductase, ω-hydroxylated dodecanoic acid to give 12-hydroxydodecanoic acid, but to a lesser extent also catalyzed (ω-1)-hydroxylation to give 11-hydroxydodecanoic acid. When 12,12,12-d 3 -dodecanoic acid was used as the substrate, there was a major shift in the oxidation from the ω-to the (ω-1)-hydroxylated product. The regioselectivity of fatty acid hydroxylation was examined with the 12-iodo-, 12-bromo-, and 12-chlorododecanoic acids. Although all three 12-halododecanoic acids bound to CYP52A21 with similar affinities, the production of 12-oxododecanoic acid decreased as the size of the terminal halide increased. The regioselectivity of CYP52A21 fatty acid oxidation is thus consistent with presentation of the terminal end of the fatty acid chain for oxidation via a narrow channel that limits access to other atoms of the fatty acid chain. This constricted access, in contrast to that proposed for the CYP4A family of enzymes, does not involve covalent binding of the heme to the protein.

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Section: Discussionmentioning

confidence: 99%

Functional expression and characterization of cytochrome P450 52A21 from Candida albicans

Kim

Cryle

Voss

et al. 2007

Archives of Biochemistry and Biophysics

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“…P450s perform a variety of heme-dependent oxidative reactions, often adding hydroxyl groups to lipophilic molecules and allowing them to serve as substrates for subsequent conversions and modifications. While this basic type of oxidative reaction is conserved across the many taxa containing P450 genes (bacteria, yeast, plants, invertebrates, and vertebrates), the functions performed differ from gene to gene and range from the biosynthesis of hormones, fatty acids, and pheromones to the detoxification of drugs, phytochemicals, and insecticides (Guengerich 2005;Kelly et al 2005;Schuler et al 2006;Li et al 2007;Mizutani and Ohta 2010;Bak et al 2011;Feyereisen 2011;Schuler 2011). With their multiple roles in development and growth, as well as in response to environmental assaults, their involvement in the initial stages of the detoxification process makes understanding their evolution important to future ecological and toxicological studies.…”

Section: Introductionmentioning

confidence: 99%

Evolutionary Toxicogenomics: Diversification of the Cyp12d1 and Cyp12d3 Genes in Drosophila Species

et al. 2012

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“…The large biodiversity of CYPs is not only found in these wood-rot fungi, but in other saprophytic organisms, e.g. Aspergillus oryzae [68], and in soil actinomycetes such as the 18 CYPs in S. coelicolor A3(2) [19] and approximately 40 in Mycobacterium smegmatis [12,69]. The ability of these organisms to biotransform xenobiotics is well known, including for instance, the ability of aspergilli in industrial steroid hydroxylation.…”

Section: Microbial Cytochromes P450 and The Environmentmentioning

confidence: 99%

“…It was found to be an essential gene for viability, a result confirming it as the target after the various biochemical correlations suggesting this. We now appreciate this CYP activity is ancient and other CYP51s are found in rstb.royalsocietypublishing.org Phil Trans R Soc B 368: 20120476 sterol-producing animals, plants, protists, but rarely in bacteria, producing 14a-demethylated sterols [69,83]. The 14a-demethylation involves three sequential monooxygenase events with release of formic acid [84][85][86].…”

Section: Food Security and Microbial Cytochromes P450mentioning

confidence: 99%

Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us?

Kelly

2013

Phil. Trans. R. Soc. B

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The first eukaryote genome revealed three yeast cytochromes P450 (CYPs), hence the subsequent realization that some microbial fungal genomes encode these proteins in 1 per cent or more of all genes (greater than 100) has been surprising. They are unique biocatalysts undertaking a wide array of stereo-and regio-specific reactions and so hold promise in many applications. Based on ancestral activities that included 14a-demethylation during sterol biosynthesis, it is now seen that CYPs are part of the genes and metabolism of most eukaryotes. In contrast, Archaea and Eubacteria often do not contain CYPs, while those that do are frequently interesting as producers of natural products undertaking their oxidative tailoring. Apart from roles in primary and secondary metabolism, microbial CYPs are actual/potential targets of drugs/agrochemicals and CYP51 in sterol biosynthesis is exhibiting evolution to resistance in the clinic and the field. Other CYP applications include the first industrial biotransformation for corticosteroid production in the 1950s, the diversion into penicillin synthesis in early mutations in fungal strain improvement and bioremediation using bacteria and fungi. The vast untapped resource of orphan CYPs in numerous genomes is being probed and new methods for discovering function and for discovering desired activities are being investigated.

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The Diversity and Importance of Microbial Cytochromes P450

Cited by 29 publications

References 162 publications

Functional expression and characterization of cytochrome P450 52A21 from Candida albicans

Functional expression and characterization of cytochrome P450 52A21 from Candida albicans

Evolutionary Toxicogenomics: Diversification of the Cyp12d1 and Cyp12d3 Genes in Drosophila Species

Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us?

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