From Genetic Diversity to Metabolic Unity: Studies on the Biosynthesis of Aurafurones and Aurafuron-like Structures in Myxobacteria and Streptomycetes

Frank, Bettina; Wenzel, Silke C.; Bode, Helge B.; Scharfe, Maren; Blöcker, Helmut; Müller, Rolf

doi:10.1016/j.jmb.2007.09.015

Cited by 60 publications

(52 citation statements)

References 60 publications

(96 reference statements)

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“…Epothilone is one of so far seven known myxobacterial compounds, the biosynthesis of which involves cytochromes P450 (15). Besides the epothilones, these are the antifungal leupyrrins (16) and the cytotoxic spirangienes (17) (also from S. cellulosum), the antibiotic myxovirescin from Myxococcus (18), the electron transport inhibitor stigmatellin (19) and the antibiotic aurafuron (20) from Stigmatella aurantiaca, and the antifungal ajudazols from Chondromyces crocatus (21).…”

Section: The [3fe-4s] or [4fe-4s] And The [3fe-4s] ϩ [4fe-4s] Or [4fementioning

confidence: 99%

Genome Mining in Sorangium cellulosum So ce56

Ewen

Hannemann

Khatri

et al. 2009

Journal of Biological Chemistry

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Myxobacteria, especially members of the genus Sorangium, are known for their biotechnological potential as producers of pharmaceutically valuable secondary metabolites. The biosynthesis of several of those myxobacterial compounds includes cytochrome P450 activity. Although class I cytochrome P450 enzymes occur wide-spread in bacteria and rely on ferredoxins and ferredoxin reductases as essential electron mediators, the study of these proteins is often neglected. Therefore, we decided to search in the Sorangium cellulosum So ce56 genome for putative interaction partners of cytochromes P450. In this work we report the investigation of eight myxobacterial ferredoxins and two ferredoxin reductases with respect to their activity in cytochrome P450 systems. Intriguingly, we found not only one, but two ferredoxins whose ability to sustain an endogenous So ce56 cytochrome P450 was demonstrated by CYP260A1-dependent conversion of nootkatone. Moreover, we could demonstrate that the two ferredoxins were able to receive electrons from both ferredoxin reductases. These findings indicate that S. cellulosum can alternate between different electron transport pathways to sustain cytochrome P450 activity. The cytochrome P450 (CYP)2 enzymes constitute a superfamily of external monooxygenases. The catalytic versatility of the family members explains their involvement in such diverse biological processes as biosynthesis of steroid hormones, carbon source assimilation, and metabolism of xenobiotics. In addition, cytochrome P450 enzymes have been reported to be involved in the biosynthesis of many pharmaceutically interesting secondary metabolites from a variety of microorganisms (1-4). Cytochromes P450 are usually dependent on an external electron donor. With respect to their electron transport system they can be divided into several classes, with class I (the mitochondrial/bacterial cytochrome P450 systems) being the predominant form in prokaryotes (5). In this system the electrons required for the enzymatic reaction originate from NAD(P)H and are delivered to the cytochrome P450 via a ferredoxin reductase and a ferredoxin. In a number of examples, the heterologous reconstitution of the electron transfer chain has been shown to be ineffective, if possible at all (5). Thus, it is desirable to identify the natural redox partners, especially if genomic sequence information is available. However, even then the identification of the correct interaction partners remains challenging because the encoding genes are frequently located at genomic loci distant to the cytochrome P450 genes (6, 7 To fulfill the role as electron mediator, the ferredoxin component of any given cytochrome P450 system has to be reduced. This reduction is achieved by a ferredoxin reductase, which in turn takes up electrons from NAD(P)H. The ferredoxin reductase is often the least characterized constituent of the cytochrome P450 system because these flavoproteins may be unstable (i.e. easily lose their cofactor) and usually show a relatively low level of expression (10...

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Section: The [3fe-4s] or [4fe-4s] And The [3fe-4s] ϩ [4fe-4s] Or [4fementioning

confidence: 99%

Genome Mining in Sorangium cellulosum So ce56

Ewen

Hannemann

Khatri

et al. 2009

Journal of Biological Chemistry

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“…1) domains rather than the standard AT L -ACP L -KS 1 -AT 1 -ACP 1 assembly as observed in prototypical PKSs such as 6-deoxyerythronolide B synthase 1 (14). This noncanonical domain architecture is, however, found in several myxobacterial megasynthases such as those involved in stigmatellin, soraphen, and aurafuranone biosynthesis (15)(16)(17). Stable isotope feeding studies showed that salinosporamide A is biosynthesized from the building blocks acetate, the nonproteinogenic amino acid ␤-hydroxy-L-3-cyclohex-2Ј-enylalanine (CHA) and a sugar-derived chlorinated molecule that we hypothesized was a previously unknown PKS extender unit, namely chloroethylmalonyl-CoA (9).…”

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confidence: 97%

Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S -adenosyl- l -methionine

Eustáquio

McGlinchey

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

169

201

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Polyketides are among the major classes of bioactive natural products used to treat microbial infections, cancer, and other diseases. Here we describe a pathway to chloroethylmalonyl-CoA as a polyketide synthase building block in the biosynthesis of salinosporamide A, a marine microbial metabolite whose chlorine atom is crucial for potent proteasome inhibition and anticancer activity. S-adenosyl-L-methionine (SAM) is converted to 5-chloro-5-deoxyadenosine (5-ClDA) in a reaction catalyzed by a SAMdependent chlorinase as previously reported. By using a combination of gene deletions, biochemical analyses, and chemical complementation experiments with putative intermediates, we now provide evidence that 5-ClDA is converted to chloroethylmalonyl-CoA in a 7-step route via the penultimate intermediate 4-chlorocrotonyl-CoA. Because halogenation often increases the bioactivity of drugs, the availability of a halogenated polyketide building block may be useful in molecular engineering approaches toward polyketide scaffolds.actinomycete ͉ biological halogenation ͉ marine natural product ͉ proteasome inhibitor ͉ Salinispora tropica

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“…197 Lending support to the substrate for AufB being a PKSbound intermediate is the homology AufB has to P450s NikQ and NovI, both of which function against PCP-bound amino acids in NRPS-mediated biosynthesis (vide infra). As with the majority of such P450-mediated reactions that are proposed to occur against PKS-bound intermediates clarication of the role of AufB awaits further experimental analysis.…”

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confidence: 99%

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

et al. 2018

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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. 1.Introduction to P450s 2.Chemistry of P450 enzymes 3.Bacterial biosynthesis pathways involving P450s 3.1Terpene metabolism 3.1. Battersby (1925Battersby ( -2018 to the molecular understanding of biosynthesis over the course of their careers.

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From Genetic Diversity to Metabolic Unity: Studies on the Biosynthesis of Aurafurones and Aurafuron-like Structures in Myxobacteria and Streptomycetes

Cited by 60 publications

References 60 publications

Genome Mining in Sorangium cellulosum So ce56

Genome Mining in Sorangium cellulosum So ce56

Biosynthesis of the salinosporamide A polyketide synthase substrate chloroethylmalonyl-coenzyme A from S -adenosyl- l -methionine

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

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