Native roles of Baeyer–Villiger monooxygenases in the microbial metabolism of natural compounds

Tolmie, Carmien; Smit, Martha S.; Opperman, Diederik J.

doi:10.1039/c8np00054a

Cited by 53 publications

(48 citation statements)

References 178 publications

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“…BVMOs have received a high level of attention due to being attractive candidates for "green synthesis" on account of their relatively relaxed substrate profile, high chemoselectivity and preference for mild catalytic conditions. These characteristics facilitate sustainable synthesis platforms, and as a result, there has been an increasing number of reports regarding the engineering of BVMOs [46,47].…”

Section: Baeyer-villiger Monooxygenasesmentioning

confidence: 99%

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

Thodberg

Neilson

2020

Catalysts

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Flavin-dependent monooxygenases (FMOs) are ancient enzymes present in all kingdoms of life. FMOs typically catalyze the incorporation of an oxygen atom from molecular oxygen into small molecules. To date, the majority of functional characterization studies have been performed on mammalian, fungal and bacterial FMOs, showing that they play fundamental roles in drug and xenobiotic metabolism. By contrast, our understanding of FMOs across the plant kingdom is very limited, despite plants possessing far greater FMO diversity compared to both bacteria and other multicellular organisms. Here, we review the progress of plant FMO research, with a focus on FMO diversity and functionality. Significantly, of the FMOs characterized to date, they all perform oxygenation reactions that are crucial steps within hormone metabolism, pathogen resistance, signaling and chemical defense. This demonstrates the fundamental role FMOs have within plant metabolism, and presents significant opportunities for future research pursuits and downstream applications.

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Section: Baeyer-villiger Monooxygenasesmentioning

confidence: 99%

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

Thodberg

Neilson

2020

Catalysts

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“…The ClusterFinder algorithm also employs a more global view to detecting NP pathways and is concerned with identifying genomic regions that are enriched in Pfam domains that occur frequently in known NP BGCs, rather than signature biosynthetic genes 216 . Cryptic clusters can be identified in this way because biosynthetic pathways that produce entirely different products employ members of many of the same enzyme superfamilies 115,116,146,[217][218][219][220] . This approach was successfully applied in a systematic effort to identify and characterize BGCs encoded across 1,154 diverse bacterial genomes and led to the identification of a previously unrecognized family of arylpolyene-encoding BGCs that are distributed across a wide range of bacterial phyla 216 .…”

Section: Decrypting Biosynthetic 'Dark Matter'mentioning

confidence: 99%

The hidden enzymology of bacterial natural product biosynthesis

Scott

Piel

2019

Nat Rev Chem

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Bacterial natural products display astounding structural diversity, which, in turn, endows them with a remarkable range of biological activities that are of significant value to modern society. Such structural features are generated by biosynthetic enzymes that construct core scaffolds or perform peripheral modifications, and can thus define natural product families, introduce pharmacophores and permit metabolic diversification. Modern genomics approaches have greatly enhanced our ability to access and characterize natural product pathways via sequence-similaritybased bioinformatics discovery strategies. However, many biosynthetic enzymes catalyse exceptional, unprecedented transformations that continue to defy functional prediction and remain hidden from us in bacterial (meta)genomic sequence data. In this Review, we highlight exciting examples of unusual enzymology that have been uncovered recently in the context of natural product biosynthesis. These suggest that much of the natural product diversity, including entire substance classes, awaits discovery. New approaches to lift the veil on the cryptic chemistries of the natural product universe are also discussed. Bacterial natural products (NPs) are specialized metabolites that encompass an extraordinary breadth of different biological activities, many of which are of considerable value to society. NPs or NP-inspired compounds represent ~65% of all small-molecule approved drugs 1 used in medicine to treat infectious diseases, cancers or as immunosuppressants 2 , and they are also applied extensively in agriculture 3. While NPs have been an extremely productive source of new leads for the chemicals that are integral to modern life, rapid increases in resistance to antibiotics, cancer chemotherapies and pesticides pose significant threats to medicine and agriculture 4,5 .

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“…Besides, BhmJ or BhmK are functional in heterologous hosts, suggesting their great potential as useful catalysts for industrial or pharmaceutical applications. [53][54][55][56][57] In conclusion, our study revealed the coordinated action of BhmJ/BhmK/BhmG for BHMs production in CB02009-R-5 assisted by a rapid ribosome engineering approach. We also revealed distinct biosynthetic mechanisms for two unusual methyl groups in BHMs, including (1) BhmG-catalyzed C-methylation and (2) incorporation of a non-proteinogenic amino acid (2S,5S)-5-methylproline.…”

mentioning

confidence: 61%

Coordinated Action of NRPS, Baeyer-Villiger Monooxygenase, and Methyltransferase Ensures the Economical Biosynthesis of Bohemamines in Streptomyces sp. CB02009

Liu¹,

Li²,

Sun³

et al. 2020

Preprint

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Bohemamines (BHMs) are bacterial alkaloids containing a pyrrolizidine core with two unprecedented methyl groups. Herein we report the activation of BHMs biosynthesis in Streptomyces sp. CB02009 using a ribosome engineering approach. Identification and characterization of the bhm gene cluster reveals a coordinated action of nonribosomal peptide synthetase BhmJ, Baeyer-villiger monooxygenase BhmK and methyltransferase BhmG for BHMs biosynthesis. BhmG is responsible for the C-methylation on C-7, while the C-9 methyl group is from a non-proteinogenic amino acid (2S,5S)-5-methylproline, required for BHMs production in three model Streptomyces hosts. Our study shed light on the intricate interaction of BhmJ/BhmK/BhmG for the economical biosynthesis of BHMs in their native producer, and also unraveled that BhmJ and BhmK are competent biocatalysts in Streptomyce albus.

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Native roles of Baeyer–Villiger monooxygenases in the microbial metabolism of natural compounds

Cited by 53 publications

References 178 publications

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

The “Green” FMOs: Diversity, Functionality and Application of Plant Flavoproteins

The hidden enzymology of bacterial natural product biosynthesis

Coordinated Action of NRPS, Baeyer-Villiger Monooxygenase, and Methyltransferase Ensures the Economical Biosynthesis of Bohemamines in Streptomyces sp. CB02009

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