Biosynthesis of Himastatin: Assembly Line and Characterization of Three Cytochrome P450 Enzymes Involved in the Post‐tailoring Oxidative Steps

Ma, Junying; Wang, Zhongwen; Huang, Hongbo; Luo, Min; Zuo, Dianguang; Wang, Bo; Sun, Aijun; C, Yi; Zhang, Changsheng; Ju, Jianhua

doi:10.1002/anie.201102305

Cited by 96 publications

(86 citation statements)

References 42 publications

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“…The coupling of aromatic rings can create structural diversity (e.g., himastatin 95 and julichromes 96 ), give flexible backbones rigid conformations [e.g., glycopeptide antibiotics (GPA) 97–99 and staurosporine 100,101 ], and polymerize monomers to yield natural sunscreens (e.g., melanins 102,103 ). The signature structural feature in the GPA family, the most well known being vancomycin, is the heptapeptide backbone with multiple biaryl (C–C) or biaryl ether (C–O–C) bridges.…”

Section: Functionmentioning

confidence: 99%

Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function

et al. 2017

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Cytochrome P450 enzymes (P450s) are some of the most exquisite and versatile biocatalysts found in nature. In addition to their well-known roles in steroid biosynthesis and drug metabolism in humans, P450s are key players in natural product biosynthetic pathways. Natural products, the most chemically and structurally diverse small molecules known, require an extensive collection of P450s to accept and functionalize their unique scaffolds. In this review, we survey the current catalytic landscape of P450s within the Streptomyces genus, one of the most prolific producers of natural products, and comprehensively summarize the functionally characterized P450s from Streptomyces. A sequence similarity network of >8500 P450s revealed insights into the sequence–function relationships of these oxygen-dependent metalloenzymes. Although only ~2.4% and <0.4% of streptomycete P450s have been functionally and structurally characterized, respectively, the study of streptomycete P450s involved in the biosynthesis of natural products has revealed their diverse roles in nature, expanded their catalytic repertoire, created structural and mechanistic paradigms, and exposed their potential for biomedical and biotechnological applications. Continued study of these remarkable enzymes will undoubtedly expose their true complement of chemical and biological capabilities.

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Section: Functionmentioning

confidence: 99%

Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function

et al. 2017

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“…The archetypal P450-catalysed reaction -the selective hydroxylation of unactivated C-H bonds -has also been identied in the modication of NRPS-produced peptides that occurs aer cleavage of the peptide chain from the NRPS machinery (see also himastatin, vide infra). 270,271 An example of this chemistry is found in the biosynthesis of the a,b-epoxyketone proteasome inhibitor TMC-86A (a mixed NRPS/PKS pathway), in which the P450 enzyme TmcI performs the hydroxylation of the methyl group adjacent to the epoxy moiety in this compound. 239 The biosynthesis of the related compound eponemycin also contains a homologous P450 that is believed to perform the analogous reaction; such a P450 is absent in the epoxomicin gene cluster that lacks this hydroxyl group.…”

Section: 269mentioning

confidence: 99%

“…23C), three P450s (HmtN, HmtS and HmtT) play vital and yet highly different roles in the biogenesis of himastatin, a symmetrical dimeric cyclohexadepsipeptide antibiotic. 270,271 The rst P450 to act in this pathway is HmtT, which generates hexahydropyrroloindole from the Trp-6 residue in the cyclic hexadepsipeptide precursor, a reaction that has similarities to that of LtxB (vide supra) in lyngbyatoxin biosynthesis 283,284 and has been suggested to occur via epoxidation of the indole ring of the tryptophan moiety.…”

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confidence: 99%

“…270,271 Finally, HmtS then performs the symmetrical biaryl coupling of two cyclic hexadepsipeptide precursors via their hexahydropyrroloindole moieties, 270 a reaction with parallels to these found in aviolin and GPA biosynthesis. 175,243 The examples of the diversity of reactions displayed not only within himastatin biosynthesis but within all NRPS-biosynthetic pathways discussed here shown how important P450s are in the production of diverse secondary metabolites, and also gives an indication of the diversity of roles that should be considered when assigning potential roles to P450 enzymes in newly identied examples of such biosynthetic gene clusters.…”

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confidence: 99%

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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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“…The coupling of 3 and 16, in a not yet understood manner, would lead to the heterodimer difluostatin A (2). C−C coupled symmetric natural product homodimers are often encountered in nature, 19 such as actinorhodin (C10− C10′), 20 himastatin (C5−C5′), 21 julichrome Q (C7−C7′), 22 and lomaiviticin A (C2−C2′). 9b,c However, difluostatin A (2) represents a rare example of an asymmetric heterodimer with a C1−C5′ coupling.…”

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confidence: 99%

Heterologous Expression of Fluostatin Gene Cluster Leads to a Bioactive Heterodimer

et al. 2015

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The biosynthesis gene cluster (fls) for atypical angucycline fluostatins was identified from the marine derived Micromonospora rosaria SCSIO N160 and was confirmed by gene knockouts and the biochemical characterization of a bifunctional oxygenase FlsO2. The absolute configuration of the key biosynthetic intermediate prejadomycin was determined for the first time by Cu Kα X-ray analysis. Heterologous expression of the intact fls-gene cluster in Streptomyces coelicolor YF11 in the presence of 3% sea salts led to the isolation of two new compounds: fluostatin L (1) and difluostatin A (2). Difluostatin A (2), an unusual heterodimer, exhibited antibacterial activities.

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Biosynthesis of Himastatin: Assembly Line and Characterization of Three Cytochrome P450 Enzymes Involved in the Post‐tailoring Oxidative Steps

Cited by 96 publications

References 42 publications

Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function

Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function

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

Heterologous Expression of Fluostatin Gene Cluster Leads to a Bioactive Heterodimer

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