Antiterminator‐Mediated Unveiling of Cryptic Polythioamides in an Anaerobic Bacterium

Behnken, Swantje; Lincke, Thorger; Kloß, Florian; Ishida, Keishi; Hertweck, Christian

doi:10.1002/anie.201108214

Cited by 48 publications

(21 citation statements)

References 22 publications

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“…For example, many non-pathogenic Clostridia encode an abundance of cryptic PKS gene clusters that exhibit evidence of horizontal gene transfer 36 , a subset of which are associated with a loaP homologue. In an earlier study, a novel C. cellulolyticum poly-thioamide (closthioamide) was produced upon overexpression of a NusG homologue 28 , which our phylogenetic analysis revealed to be within the LoaP subclass, providing further evidence for a regulatory relationship between loaP and PKS genes.…”

Section: Discussionmentioning

confidence: 52%

“…Although antitermination activity has yet to be observed for TaA, this discovery suggested proof in principle that transcription elongation factors may affect specialized metabolite pathways. In a separate study, general overexpression of a NusG homologue led to discovery of a new Clostridium cellulolyticum natural product 28 . Inspired by these findings, we hypothesized that more antitermination systems await discovery and that they will prove to be essential for the transcription of important pathways, including those encoding specialized metabolites.…”

Section: Discussionmentioning

confidence: 99%

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LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

et al. 2017

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A valuable resource available in the search for new natural products is the diverse microbial life that spans the planet. A large subset of these microorganisms synthesize complex specialized metabolites exhibiting biomedically important activities. A limiting step to the characterization of these compounds is an elucidation of the genetic regulatory mechanisms that oversee their production. Although proteins that control transcription initiation of specialized metabolite gene clusters have been identified, those affecting transcription elongation have not been broadly investigated. In this study, we analysed the phylogenetic distribution of the large, widespread NusG family of transcription elongation proteins and found that it includes a cohesive outgroup of paralogues (herein coined LoaP), which are often positioned adjacent or within gene clusters for specialized metabolites. We established Bacillus amyloliquefaciens LoaP as a paradigm for this protein subgroup and showed that it regulated the transcriptional readthrough of termination sites located within two different antibiotic biosynthesis operons. Both of these antibiotics have been implicated in plant-protective activities, demonstrating that LoaP controls an important regulon of specialized metabolite genes for this microorganism. These data therefore reveal transcription elongation as a point of regulatory control for specialized metabolite pathways and introduce a subgroup of NusG proteins for this purpose.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

et al. 2017

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“…From a conformational perspective, more interesting are the two endothioxopeptides thioviridamide, from the actinomycete Streptomyces olivoviridis , and closthioamide, an antibiotic from Clostridium cellulolyticum . Thioviridamide is partly similar to methanobactin, but only because it is formed by a cyclic moiety and a pendant linear chain.…”

Section: Resultsmentioning

confidence: 99%

“…The thionamide bonds are among the factors responsible for the antibacterial property of this endothioxopeptide since the all-amide synthetic analog is inactive. Seven closthioamide congeners (2)(3)(4)(5)(6)(7)(8) with varying numbers of thionamide linkages also occur in Nature [29] (Figure 2). A large set of closthioamide analogs were synthesized to reveal in detail the crucial motifs for its antibiotic activity.…”

Section: Naturally Occurring Endothioxopeptidesmentioning

confidence: 99%

Endothioxopeptides: A conformational overview

et al. 2016

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Although thionamides would have been first prepared two centuries ago and their chemical and spectroscopic properties extensively investigated, only much more recently (since about 1985) a well deserved but still insufficient attention has been paid to their endothioxopeptide subfamily which nonetheless currently represents a rapidly emerging area of great scientific interest in the broader field of foldameric compounds based on biologically relevant building blocks. After two brief sections offering information on the unfortunately still limited number of endothioxopeptides discovered from natural sources but also on the impressive advancements registered in the last few years in their synthetic methods, this review article outlines the results of a detailed literature survey on the ongoing great, but not systematic, progress related to the conformational consequences generated by incorporating one (or more) thionamide group(s) into a polypeptide chain. Finally, a short discussion of the growing, but still in its infancy, class of the endoselenoxopeptide congeners is also presented.

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“…In recent years,ag rowing number of thioamide-bearing natural products have been discovered. [11] In cases where it has been investigated, the thioamide functionality in these compounds has been shown to be an essential pharmacophore or chelating residue. [11d, 12] Whereas the chemical synthesis of thioamides with phosphorus sulfides (Lawessonsr eagent) and other reagents is already well established, [13] the biochemical basis of enzymatic amide thionation has remained obscure.O nly recently,p osttranslational thioamidations of the protein methyl-coenzyme Mr eductase [14] and the ribosomal peptide methanobactin [15] have been uncovered.…”

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confidence: 99%

Enzymatic Thioamide Formation in a Bacterial Antimetabolite Pathway

et al. 2018

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6-Thioguanine (6TG) is aDNA-targeting therapeutic used in the treatment of various cancers.W hile 6TG was rationally designed as ap roof of concept for antimetabolite therapy, it is also ar are thioamide-bearing bacterial natural product and critical virulence factor of Erwinia amylovorans, plant pathogens that cause fire blight. Through gene expression, biochemical assays,a nd mutational analyses,w ei dentified as pecialized bipartite enzyme system, consisting of an ATP-dependent sulfur transferase (YcfA) and as ulfur-mobilizing enzyme (YcfC), that is responsible for the peculiar oxygen-by-sulfur substitution found in the biosynthesis of 6TG.Mechanistic and phylogenetic studies revealed that YcfAmediated 6TG biosynthesis evolved from ancient tRNA modifications that support translational fidelity.The successful in vitro reconstitution of 6TG thioamidation showed that YcfA employs aspecialized sulfur shuttle that markedly differs from universal RNA-related systems.T his study sheds light on underexplored enzymatic C À Sb ond formation in natural product biosynthesis.

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Antiterminator‐Mediated Unveiling of Cryptic Polythioamides in an Anaerobic Bacterium

Cited by 48 publications

References 22 publications

LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

LoaP is a broadly conserved antiterminator protein that regulates antibiotic gene clusters in Bacillus amyloliquefaciens

Endothioxopeptides: A conformational overview

Enzymatic Thioamide Formation in a Bacterial Antimetabolite Pathway

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