Cytochromes P450 as versatile biocatalysts

Bernhardt, Rita

doi:10.1016/j.jbiotec.2006.01.026

Cited by 766 publications

(524 citation statements)

References 130 publications

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“…As mentioned previously, P450s are well known for their exceptional ability to selectively oxidize a large variety of substrates [2,3,17,18]. This provides them with two attributes that are highly sought in a catalyst: scope and selectivity.…”

Section: P450 Biocatalystsmentioning

confidence: 98%

“…As an example, human P450s can be credited for being involved in the metabolism of approximately 75% of all clinical drugs [17]. Their impressive ability to selectively discern unactivated methylene bonds among many electronically and sterically similar groups is obvious when looking at the structure of drug metabolites [2,3,17,18]. In addition, P450s have the ability to oxidize C-H bonds of varying strength, from methine to methyl groups, often without over-oxidation to the ketone.…”

Section: P450 Biocatalystsmentioning

confidence: 99%

“…Most mammalian P450 enzymes show unequalled substrate promiscuity among P450s [2,20,66,67]. This is an attractive quality for a useful and versatile biocatalyst, and can eliminate the need for protein mutagenesis to expand the substrate scope.…”

Section: Mammalian P450smentioning

confidence: 99%

“…In bacteria, P450s are involved typically in the biosynthesis of secondary metabolites, while in mammals they are responsible largely for the metabolism of xenobiotics (foreign compounds) such as drugs, carcinogens and environmental pollutants, as well as the biosynthesis and metabolism of endogenous or naturally-occurring bioactive compounds such as eicosanoids (eicosanoic acids, leukotrienes, prostaglandins), fatty acids, steroids and vitamins [1]. One attribute that allows P450s to perform such diverse roles is their ability to oxidize unactivated C-H bonds of substrates with remarkable regio-and stereoselectivity [1][2][3][4]. It is this feature that has caught the attention of synthetic chemists.…”

Section: Introductionmentioning

confidence: 99%

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Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Auclair

Polic

2015

Advances in Experimental Medicine and Biology

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Cytochrome P450 enzymes (P450s) have the ability to oxidize unactivated C-H bonds of substrates with remarkable regio-and stereoselectivity. Comparable selectivity for chemical oxidizing agents is typically difficult to achieve. Hence, there is an interest in exploiting P450s as potential biocatalysts. Despite their impressive attributes, the current use of P450s as biocatalysts is limited. While bacterial P450 enzymes typically show higher activity, they tend to be highly selective for one or a few substrates. On the other hand, mammalian P450s, especially the drugmetabolizing enzymes, display astonishing substrate promiscuity. However, product prediction continues to be challenging. This review discusses the use of small molecules for controlling P450 substrate specificity and product selectivity. The focus will be on two approaches in the area: (1) the use of decoy molecules, and (2) the application of substrate engineering to control oxidation by the enzyme.

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Section: P450 Biocatalystsmentioning

confidence: 98%

Section: P450 Biocatalystsmentioning

confidence: 99%

Section: Mammalian P450smentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Auclair

Polic

2015

Advances in Experimental Medicine and Biology

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“…However, subsequent P450 steps were made more complicated for several reasons. First, these enzymes are membrane associated with the endoplasmic reticulum of native hosts (Bernhardt 2006). Approximating this membrane localization in E. coli will clearly be challenging.…”

Section: Challenges and Options Associated With The Heterologous Implmentioning

confidence: 99%

Downstream reactions and engineering in the microbially reconstituted pathway for Taxol

Jiang

Stephanopoulos

Pfeifer

2012

Appl Microbiol Biotechnol

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Investigating the roles of T224 and T232 in the oxidation of cinnamaldehyde catalyzed by myxobacterial CYP260B1

et al. 2016

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Although the oxidation of aldehydes to carboxylic acids is mainly catalyzed by aldehyde dehydrogenases in nature, cytochromes P450 are also able to perform such reactions. In this study, we demonstrate the oxidation of cinnamaldehyde to cinnamic acid by the myxobacterial CYP260B1. Following our docking studies of the aldehyde, we generated T224A and T234A mutants of CYP260B1 by site-directed mutagenesis to disrupt the substrate positioning and proton delivery, respectively. Furthermore, we used the kinetic solvent isotope effect on the steady-state turnover of the substrate to investigate the reactive intermediate capable of performing the catalysis. Our results suggest that the aldehyde oxidation occurs via a nucleophilic attack of the ferric peroxoanion.

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Cytochromes P450 as versatile biocatalysts

Cited by 766 publications

References 130 publications

Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Use of Chemical Auxiliaries to Control P450 Enzymes for Predictable Oxidations at Unactivated C-H Bonds of Substrates

Downstream reactions and engineering in the microbially reconstituted pathway for Taxol

Investigating the roles of T224 and T232 in the oxidation of cinnamaldehyde catalyzed by myxobacterial CYP260B1

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