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      Unrivalled diversity: the many roles and reactions of bacterial cytochromes P450 in secondary metabolism

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          Abstract

          This review highlights the scope of chemical transformations that cytochrome P450 enzymes catalyse within bacterial secondary metabolism.

          Abstract

          Covering: 2000 up to 2018

          The cytochromes P450 (P450s) are a superfamily of heme-containing monooxygenases that perform diverse catalytic roles in many species, including bacteria. The P450 superfamily is widely known for the hydroxylation of unactivated C–H bonds, but the diversity of reactions that P450s can perform vastly exceeds this undoubtedly impressive chemical transformation. Within bacteria, P450s play important roles in many biosynthetic and biodegradative processes that span a wide range of secondary metabolite pathways and present diverse chemical transformations. In this review, we aim to provide an overview of the range of chemical transformations that P450 enzymes can catalyse within bacterial secondary metabolism, with the intention to provide an important resource to aid in understanding of the potential roles of P450 enzymes within newly identified bacterial biosynthetic pathways.

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          Most cited references282

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          Polyketide biosynthesis: a millennium review.

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            Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis.

            Species of the genus Streptomyces are of major pharmaceutical interest because they synthesize a variety of bioactive secondary metabolites. We have determined the complete nucleotide sequence of the linear chromosome of Streptomyces avermitilis. S. avermitilis produces avermectins, a group of antiparasitic agents used in human and veterinary medicine. The genome contains 9,025,608 bases (average GC content, 70.7%) and encodes at least 7,574 potential open reading frames (ORFs). Thirty-five percent of the ORFs (2,664) constitute 721 paralogous families. Thirty gene clusters related to secondary metabolite biosynthesis were identified, corresponding to 6.6% of the genome. Comparison with Streptomyces coelicolor A3(2) revealed that an internal 6.5-Mb region in the S. avermitilis genome was highly conserved with respect to gene order and content, and contained all known essential genes but showed perfectly asymmetric structure at the oriC center. In contrast, the terminal regions were not conserved and preferentially contained nonessential genes.
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              Cytochrome P450 compound I: capture, characterization, and C-H bond activation kinetics.

              Cytochrome P450 enzymes are responsible for the phase I metabolism of approximately 75% of known pharmaceuticals. P450s perform this and other important biological functions through the controlled activation of C-H bonds. Here, we report the spectroscopic and kinetic characterization of the long-sought principal intermediate involved in this process, P450 compound I (P450-I), which we prepared in approximately 75% yield by reacting ferric CYP119 with m-chloroperbenzoic acid. The Mössbauer spectrum of CYP119-I is similar to that of chloroperoxidase compound I, although its electron paramagnetic resonance spectrum reflects an increase in |J|/D, the ratio of the exchange coupling to the zero-field splitting. CYP119-I hydroxylates the unactivated C-H bonds of lauric acid [D(C-H) ~ 100 kilocalories per mole], with an apparent second-order rate constant of k(app) = 1.1 × 10(7) per molar per second at 4°C. Direct measurements put a lower limit of k ≥ 210 per second on the rate constant for bound substrate oxidation, whereas analyses involving kinetic isotope effects predict a value in excess of 1400 per second.
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                Author and article information

                Journal
                NPRRDF
                Natural Product Reports
                Nat. Prod. Rep.
                Royal Society of Chemistry (RSC)
                0265-0568
                1460-4752
                2018
                2018
                : 35
                : 8
                : 757-791
                Affiliations
                [1 ]The Monash Biomedicine Discovery Institute
                [2 ]Department of Biochemistry and Molecular Biology
                [3 ]ARC Centre of Excellence in Advanced Molecular Imaging
                [4 ]Monash University
                [5 ]Clayton
                [6 ]School of Chemistry and Molecular Biosciences
                [7 ]University of Queensland
                [8 ]Brisbane 4072
                [9 ]Australia
                Article
                10.1039/C7NP00063D
                29667657
                8600e6d0-5090-4044-b1ec-e174bce75090
                © 2018

                http://creativecommons.org/licenses/by/3.0/

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