Chloramphenicol Biosynthesis: The Structure of CmlS, a Flavin-Dependent Halogenase Showing a Covalent Flavin–Aspartate Bond

Podzelinska, Kateryna; Latimer, Ryan; Bhattacharya, Anupam; Vining, L. C.; Zechel, David L.; Jia, Zongchao

doi:10.1016/j.jmb.2010.01.020

Cited by 106 publications

(112 citation statements)

References 58 publications

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“…Because there are no predicted P450 enzymes in the ooc gene cluster, the main candidates for the halogenase are the flavin-dependent monooxygenases OocK and OocM. In agreement with this, the mechanism of action of flavin-containing halogenases is just a slight modification of that of monooxygenases (82), and crystallization of some of these halogenases has revealed a flavin monooxygenase domain in most of them (83). The chlorination could be a post-PKS biosynthesis step (Fig.…”

Section: (Mt-t-t-ks-t-ks-kr-t-ks-t-te-ks-t-c) -Mt-t-t (Modulementioning

confidence: 70%

Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules

Matilla

Stöckmann

Leeper

et al. 2012

Journal of Biological Chemistry

121

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Background: Oocydin A is an anticancer haterumalide with strong antimicrobial activity against agriculturally important plant pathogenic fungi and oomycetes. Results: The oocydin A gene cluster has been identified and characterized in four plant-associated enterobacteria. Conclusion:The ooc gene cluster is organized in three transcriptional units encoding enzymes that belong to a growing class of trans-acyltransferase polyketide synthases. Significance: Oocydin A has potential agricultural, pharmacological, and chemotherapeutic applications.

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Section: (Mt-t-t-ks-t-ks-kr-t-ks-t-te-ks-t-c) -Mt-t-t (Modulementioning

confidence: 70%

Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules

Matilla

Stöckmann

Leeper

et al. 2012

Journal of Biological Chemistry

121

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“…In contrast, our current study focuses on flavin-dependent halogenases, which employ FAD as a cofactor and use a halide anion and molecular oxygen to produce hypochlorous acid as a halogenating agent. Protein crystallography greatly helped in understanding the structural basis of regioselective formation of the carbon-halogen bond (50)(51)(52)(53). A. mellea halogenase genes encode the signature motif GW(A/V)W(F/L)I.…”

Section: Discussionmentioning

confidence: 99%

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

Wick

Heine

Lackner

et al. 2016

Appl Environ Microbiol

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The basidiomycetous tree pathogen Armillaria mellea (honey mushroom) produces a large variety of structurally related antibiotically active and phytotoxic natural products, referred to as the melleolides. During their biosynthesis, some members of the melleolide family of compounds undergo monochlorination of the aromatic moiety, whose biochemical and genetic basis was not known previously. This first study on basidiomycete halogenases presents the biochemical in vitro characterization of five flavin-dependent A. mellea enzymes (ArmH1 to ArmH5) that were heterologously produced in Escherichia coli. We demonstrate that all five enzymes transfer a single chlorine atom to the melleolide backbone. A 5-fold, secured biosynthetic step during natural product assembly is unprecedented. Typically, flavin-dependent halogenases are categorized into enzymes acting on free compounds as opposed to those requiring a carrier-protein-bound acceptor substrate. The enzymes characterized in this study clearly turned over free substrates. Phylogenetic clades of halogenases suggest that all fungal enzymes share an ancestor and reflect a clear divergence between ascomycetes and basidiomycetes.

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“…3 The ribbon diagram of tryptophan 7-halogenase (PrnA) from P. fluorescens (pdb 2aqj; Dong et al 2005) with the substrate tryptophan and its cofactor FAD shown as stick models. The figure was prepared by ccp4mg (McNicholas et al 2011) halogenase, which is responsible for the formation of the dichloroacetyl moiety of chloramphenicol has been reported (Podzelinska et al 2010). The structure reveals the enzyme to share the common flavin-binding domain, but also shows a novel 'winged helix' domain.…”

Section: Flavin-dependent Halogenasesmentioning

confidence: 99%

“…Glu44 is proposed to act as an acid catalyst in the neutralization of the nitranion; this process would occur in tandem to produce a dichloroacetoacetyl-CoA. The dichloroacetyl-CoA is released by hydrolysis of the terminal acetyl group (Podzelinska et al 2010). …”

Section: Flavin-dependent Halogenasesmentioning

confidence: 99%

Haloperoxidase Enzymes as ‘Redox Catalysts’ Important for Industrial Biocatalysis

Littlechild

Isupov

2014

Recent Advances in Redox Active Plant and Microbial Products

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Chloramphenicol Biosynthesis: The Structure of CmlS, a Flavin-Dependent Halogenase Showing a Covalent Flavin–Aspartate Bond

Cited by 106 publications

References 58 publications

Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules

Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules

A Fivefold Parallelized Biosynthetic Process Secures Chlorination of Armillaria mellea (Honey Mushroom) Toxins

Haloperoxidase Enzymes as ‘Redox Catalysts’ Important for Industrial Biocatalysis

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