An Unexpected Split‐Merge Pathway in the Assembly of the Symmetric Nonribosomal Peptide Antibiotic Closthioamide

Dunbar, Kyle L.; Dell, Maria; Molloy, Evelyn M.; Büttner, Hannah; Kumpfmüller, Jana; Hertweck, Christian

doi:10.1002/ange.202011741

Cited by 6 publications

(2 citation statements)

References 48 publications

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“…Only two transglutaminases AdmF and CtaJ were reported to catalyze the formation of amide bonds in the biosynthesis of andrimid and closthioamide respectively to date. [ 28‐29 ] Nevertheless, Phyre 2 prediction placed KstB6 in the cysteine protease (Figure S10). Considering that there is no amide bond in KST, KstB6 might release the free acid 11 through hydrolyzing thioester linkage.…”

Section: Resultsmentioning

confidence: 99%

Deciphering the Origin and Formation of Aminopyrrole Moiety in Kosinostatin Biosynthesis

Zhou

Zhang

et al. 2021

Chin. J. Chem.

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Main observation and conclusion Kosinostatin (KST) contains an uncommon aminopyrrole moiety, whose biosynthesis has remained elusive. Herein, aminopyrrolinic acid, which was generated by an L‐ectoine synthase‐like enzyme KstB3 via cyclization of L‐glutamine, was identified to be the real substrate of adenylation enzyme KstB1. Subsequently, a FAD‐dependent dehydrogenase KstB4 along with a transglutaminase‐like enzyme KstB6 were also involved in formation of aminopyrrole. These results provided an unusual pathway for 2‐aminopyrrole formation in KST biosynthesis.

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Section: Resultsmentioning

confidence: 99%

Deciphering the Origin and Formation of Aminopyrrole Moiety in Kosinostatin Biosynthesis

Zhou

Zhang

et al. 2021

Chin. J. Chem.

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“…In particular, recently identified biosynthetic pathways that install thioamides in place of traditional oxoamides along the main-chain of peptides suggest an evolutionary benefit to the specific properties of thioamides. [1][2][3][4][5][6][7][8] Thioamides have become intriguing probes of hydrogen-bonding, 9-12 hydrophobicity, 13,14 and stereoelectronic effects [15][16][17][18][19][20] along the peptide backbone. Thioamides can also serve as quenchers of fluorescent dyes in experiments designed to study peptide conformation and proteolysis.…”

Section: Introductionmentioning

confidence: 99%

Thioimidate Solutions to Thioamide Problems during Peptide Synthesis

Byerly-Duke,

Donovan,

Sharma

et al. 2023

Preprint

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Thioamides have structural and chemical similarity to peptide bonds, and therefore offer valuable insights when probing peptide backbone interactions, including hydrogen bonding, stereoelectronic, and hydrophobicity effects. There is a perception that methods to install thioamides within peptides are sufficient, yet anecdotal reports indicate that many labs have sought to employ thioamides in a variety of studies but the results of many synthetic campaigns do not yield the intended products, leading researchers to abandon such projects and any information these structural probes would provide. We catalogue and provide evidence for the major pitfalls associated with current methods to synthesize thioamide-containing peptides during each stage of solid-phase peptide synthesis (SPPS), including (A) thioamide coupling, (B) peptide elongation, and (C) peptide cleavage from resin. We then demonstrate the utility of thioimidate protecting groups as a means to side-step each of these problematic synthetic difficulties. Our approach is generally applicable to all peptides and ultimately permits access to an important benchmark $\alpha$-helical peptide that had previously eluded synthesis and isolation. With the process of thionopeptide synthesis demystified, a broader range of researchers should find it easier to employ thioamides in the study of peptide-based biomolecules.

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Alternative Benzoxazole Assembly Discovered in Anaerobic Bacteria Provides Access to Privileged Heterocyclic Scaffold

et al. 2022

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Benzoxazole scaffolds feature prominently in diverse synthetic and natural product-derived pharmaceuticals. Our understanding of their bacterial biosynthesis is, however, limited to ortho-substituted heterocycles from actinomycetes. We report an overlooked biosynthetic pathway in anaerobic bacteria (typified in Clostridium cavendishii) that expands the benzoxazole chemical space to meta-substituted heterocycles and heralds a distribution beyond Actinobacteria. The first benzoxazoles from the anaerobic realm (closoxazole A and B) were elucidated by NMR and chemical synthesis. By genome editing in the native producer, heterologous expression in Escherichia coli, and systematic pathway dissection we show that closoxazole biosynthesis invokes an unprecedented precursor usage (3-amino-4-hydroxybenzoate) and manner of assembly. Synthetic utility was demonstrated by the precursor-directed biosynthesis of a tafamidis analogue. A bioinformatic survey reveals the pervasiveness of related gene clusters in diverse bacterial phyla.

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An Unexpected Split‐Merge Pathway in the Assembly of the Symmetric Nonribosomal Peptide Antibiotic Closthioamide

Cited by 6 publications

References 48 publications

Deciphering the Origin and Formation of Aminopyrrole Moiety in Kosinostatin Biosynthesis

Deciphering the Origin and Formation of Aminopyrrole Moiety in Kosinostatin Biosynthesis

Thioimidate Solutions to Thioamide Problems during Peptide Synthesis

Alternative Benzoxazole Assembly Discovered in Anaerobic Bacteria Provides Access to Privileged Heterocyclic Scaffold

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