Enzymatic Thioamide Formation in a Bacterial Antimetabolite Pathway

Litomska, Agnieszka; Ishida, Keishi; Dunbar, Kyle L.; Boettger, M. A.; Coyne, Sébastien; Hertweck, Christian

doi:10.1002/ange.201804158

Cited by 10 publications

(10 citation statements)

References 37 publications

(19 reference statements)

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“…31 YcfA (WP_004156383.1) is homologous to proteins of the diverse AANH-like superfamily, which display a conserved ATP-binding αβα fold and includes enzymes responsible for sulfur incorporation on tRNA nucleobases. 56 YcfB (WP_004156386.1) is a homolog of NUDIX hydrolase while YcfD (WP_004156390.1) is a transporter, and thus, neither were implicated directly in thioamidation chemistry. YcfC (WP_004156388.1) is distantly related to pyridoxal phosphate (PLP)-dependent transferases.…”

Section: Thioamides In Nature: Biosynthesis Structure and Functionmentioning

confidence: 99%

Biosynthesis and Chemical Applications of Thioamides

et al. 2019

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Thioamidation as a posttranslational modification is exceptionally rare, with only a few reported natural products and exactly one known protein example (methyl-coenzyme M reductase from methane-metabolizing archaea). Recently, there has been significant progress in elucidating the biosynthesis and function of several thioamide-containing natural compounds. Separate developments in the chemical installation of thioamides into peptides and proteins have enabled cell biology and biophysical studies that advance the current understanding of natural thioamides. This review highlights the various strategies used by Nature to install thioamides in peptidic scaffolds and the potential functions of this rare but important modification. We also discuss synthetic methods used for the site-selective incorporation of thioamides into polypeptides with a brief discussion of the physicochemical implications. This account will serve as a foundation for further study of thioamides in natural products and their various applications.

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Section: Thioamides In Nature: Biosynthesis Structure and Functionmentioning

confidence: 99%

Biosynthesis and Chemical Applications of Thioamides

et al. 2019

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“…8Ac), thereby decrypting the previously unknown origins of the thioamide moieties present in other peptides (for example, thiopeptin and Sch 18640) 132 and consistent with the involvement of YcaO-TfuA-like protein pairs in the biosynthesis of thioviridamide (27)-like RiPPs [133][134][135][136][137] . Thioamide bonds are also present in a number of other non-RiPP NPs, such as closthioamide (28), a remarkable symmetrical peptide comprising six thioamide moieties 138,139 , and 6thioguanine (29), a guanosine nucleotide mimic with potent DNA-targeting and RNAtargeting cytotoxicity 140,141 . In these examples however, thioamide formation is catalysed by members of a novel family of alpha hydrolase (AANH)-like proteins and not YcaO proteins 139,141 .…”

Section: Ycao Proteinsmentioning

confidence: 99%

“…Thioamide bonds are also present in a number of other non-RiPP NPs, such as closthioamide (28), a remarkable symmetrical peptide comprising six thioamide moieties 138,139 , and 6thioguanine (29), a guanosine nucleotide mimic with potent DNA-targeting and RNAtargeting cytotoxicity 140,141 . In these examples however, thioamide formation is catalysed by members of a novel family of alpha hydrolase (AANH)-like proteins and not YcaO proteins 139,141 .…”

Section: Ycao Proteinsmentioning

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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“…Reactions were allowed to proceed for 5 h at 25°C before being quenched by the addition of 1 volume of methanol. Samples were analyzed by HPLC according to an established method (44). The HPLC profiles were compared with those of reference compounds (Jena Bioscience).…”

Section: Methodsmentioning

confidence: 99%

Reconstitution of polythioamide antibiotic backbone formation reveals unusual thiotemplated assembly strategy

Dunbar

Dell

Gude

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Closthioamide (CTA) is a rare example of a thioamide-containing nonribosomal peptide and is one of only a handful of secondary metabolites described from obligately anaerobic bacteria. Although the biosynthetic gene cluster responsible for CTA production and the thioamide synthetase that catalyzes sulfur incorporation were recently discovered, the logic for peptide backbone assembly has remained a mystery. Here, through the use of in vitro biochemical assays, we demonstrate that the amide backbone of CTA is assembled in an unusual thiotemplated pathway involving the cooperation of a transacylating member of the papain-like cysteine protease family and an iteratively acting ATP-grasp protein. Using the ATP-grasp protein as a bioinformatic handle, we identified hundreds of such thiotemplated yet nonribosomal peptide synthetase (NRPS)-independent biosynthetic gene clusters across diverse bacterial phyla. The data presented herein not only clarify the pathway for the biosynthesis of CTA, but also provide a foundation for the discovery of additional secondary metabolites produced by noncanonical biosynthetic pathways.

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Enzymatic Thioamide Formation in a Bacterial Antimetabolite Pathway

Cited by 10 publications

References 37 publications

Biosynthesis and Chemical Applications of Thioamides

Biosynthesis and Chemical Applications of Thioamides

The hidden enzymology of bacterial natural product biosynthesis

Reconstitution of polythioamide antibiotic backbone formation reveals unusual thiotemplated assembly strategy

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