Thioholgamides: Thioamide-Containing Cytotoxic RiPP Natural Products

Kjaerulff, Louise; Sikandar, Asfandyar; Zaburannyi, Nestor; Adam, Sebastian; Herrmann, Jennifer; Koehnke, Jesko; Müller, Rolf

doi:10.1021/acschembio.7b00676

Cited by 71 publications

(68 citation statements)

References 25 publications

(62 reference statements)

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“…1) 15,16 . Recent survey of the published genome sequences revealed a number of new biosynthetic gene clusters (BGCs) that share nearly head-to-tail homology with the prototypal TVA BGC (tva) characterized in Streptomyces olivoviridis 17 , and subsequent product mining in selected microorganisms led to a rapid enrichment of the TVA family [18][19][20][21][22] , in which several members appear to be promising for cancer treatment. All these BGCs do not encode any homologs of LanC, LanM, LanKC or LanL proteins that possess cyclase activity, consistent with the absence of (Me)Lan in the structures of TVAs.…”

Section: Resultsmentioning

confidence: 99%

LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus

Liu

Qiu

et al. 2020

Preprint

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Aminovinyl-cysteine residues arise from processing the C-terminal L-Cys and an internal L-Ser/L-Thr or L-Cys of a peptide. Formation of these nonproteinogenic amino acids, which occur in a macrocyclic ring of diverse ribosomally synthesized lanthipeptides and non-lanthipeptides, remains poorly understood. Here, we report that LanD-like flavoproteins in the biosynthesis of distinct non-lanthipeptides share an unexpected dual activity for aminovinylcysteine formation. Each flavoprotein catalyzes oxidative decarboxylation of the C-terminal L-Cys and couples the resulting enethiol nucleophile with the internal residue to afford a thioether linkage for peptide cyclization. The cyclization step, which largely depends on proximity effect by positioning the enethiol intermediate with a bent conformation at the active site, can be substrate-dependent, proceeding inefficiently through nucleophilic substitution for an unmodified peptide or efficiently through Michael addition for a dehydrated/dethiolated peptide. Uncovering this unusual flavin-dependent paradigm for thioether residue formation advances the understanding in the biosynthesis of aminovinyl-cysteine-containing RiPPs and renews interest in flavoproteins, particularly those involved in non-redox transformations. LanD-like flavoproteins activity, which is flexible in peptide substrate and amenable for evolution by engineering, can be combined with different post-translational modifications for structural diversity, thereby holding promise for peptide macrocyclization/functionalization in drug development by chemoenzymatic or synthetic biology approaches.

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Section: Resultsmentioning

confidence: 99%

LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus

Liu

Qiu

et al. 2020

Preprint

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“…YcaO proteins can also act as standalone proteins, as in bottromycin biosynthesis, [17][18][19] and many YcaO proteins are encoded in genomes without E1-like or Ocin-ThiF-like partner proteins, 9,15 including in the BGCs of thioviridamide-like molecules. 6,[20][21][22][23][24] Thioviridamide and related compounds are cytotoxic RiPPs that contain multiple thioamide groups ( Figure 1), but no azole or macroamidine rings. Thioamides are rare in nature [25][26][27][28][29][30][31] and it has been hypothesized that YcaO proteins could be responsible for this rare amide bond modification in thioviridamide biosynthesis, potentially in cooperation with TfuA domain proteins 15 (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool

Santos‐Aberturas

Chandra

Frattaruolo

et al. 2018

Preprint

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The rational discovery of new specialized metabolites by genome mining represents a very promising strategy in the quest for new bioactive molecules. Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a major class of natural product that derive from genetically encoded precursor peptides. However, RiPP gene clusters are particularly refractory to reliable bioinformatic predictions due to the absence of a common biosynthetic feature across all pathways. Here, we describe RiPPER, a new tool for the family-independent identification of RiPP precursor peptides and apply this methodology to search for novel thioamidated RiPPs in Actinobacteria. Until now, thioamidation was believed to be a rare post-translational modification, which is catalyzed by a pair of proteins (YcaO and TfuA) in Archaea. In Actinobacteria, the thioviridamide-like molecules are a family of cytotoxic RiPPs that feature multiple thioamides, and it has been proposed that a YcaO-TfuA pair of proteins also catalyzes their formation. Potential biosynthetic gene clusters encoding YcaO and TfuA protein pairs are common in Actinobacteria but the chemical diversity generated by these pathways is almost completely unexplored. A RiPPER analysis reveals a highly diverse landscape of precursor peptides encoded in previously undescribed gene clusters that are predicted to make thioamidated RiPPs. To illustrate this strategy, we describe the first rational discovery of a new family of thioamidated natural products, the thiovarsolins from Streptomyces varsoviensis.

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“…The complete biosynthetic gene cluster (BGC) of thioviridamide ( tva ) contains 12 genes, tvaA — tvaL . Among them, a structural gene, tvaA , encodes a precursor peptide with a C ‐terminal core peptide sequence of “SVMAAAASIALHC” . JBIR‐140 ( 2 ) is the first thioviridamide analogue produced by heterologous expression of the whole tva BGC in S. avermitilis SUKA17.…”

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confidence: 99%

“…acid backbone as a direct result of the core peptide variation to “SVMAAAATVAFHC”. Meanwhile, structural changes also take place in the tail, including four thioamide bonds and an N ‐terminal pyruvyl unit . Thioholgamide B ( 4 ) is highly homologous to thioholgamide A and exhibits an additional oxidation to methionine sulfur .…”

mentioning

confidence: 99%

“…Meanwhile, structural changes also take place in the tail, including four thioamide bonds and an N ‐terminal pyruvyl unit . Thioholgamide B ( 4 ) is highly homologous to thioholgamide A and exhibits an additional oxidation to methionine sulfur . Thiostreptamide S4 ( 5 ), whose backbone is determined by the core peptide “SVMAAIATVAYHC”, features four thioamide bonds and an N ‐terminal pyruvyl unit in the same manner as thioholgamides.…”

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confidence: 99%

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Discovery of New Thioviridamide‐Like Compounds with Antitumor Activities

Liu

Tang

et al. 2019

Chin. J. Chem.

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of main observation and conclusion Thioviridamide is a structurally unique compound with potent antitumor activity. The biosynthesis of thioviridamide follows a typical pathway as ribosomally synthesized and post-translationally modified peptides, making the genome mining-based discovery of thioviridamide-like compounds rational. Taking advantage of the linkage between the precursor peptide and the metabolite skeleton, we identified a new biosynthetic gene cluster in Streptomyces sp. NRRL S-87 that could encode thioviridamide analogues. Overexpression of the whole gene cluster led to the isolation and structure elucidation of TVA-YJ-4 and TVA-YJ-5, two novel thioviridamide-like compounds featuring N-terminal capping groups. Chemical screening of the fermentation extracts also detected TVA-YJ-6, another new thioviridamide-like compound with representative methionine sulfoxide. Detailed analysis further revealed that these structural modifications were introduced during the compound extraction process instead of through genuine enzymatic reactions. TVA-YJ-4 and TVA-YJ-5 display slightly reduced cytotoxic activities against a panel of tumor cell lines in comparison with their parental natural product, TVA-YJ-2. Our work will expand the membership of this rare class of compounds and promote related biosynthetic studies.www.cjc.wiley-vch.de

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Thioholgamides: Thioamide-Containing Cytotoxic RiPP Natural Products

Cited by 71 publications

References 25 publications

LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus

LanD-like Flavoprotein-Catalyzed Aminovinyl-Cysteine Formation through Oxidative Decarboxylation and Cyclization of a Peptide at the C-Terminus

Uncovering the unexplored diversity of thioamidated ribosomal peptides in Actinobacteria using the RiPPER genome mining tool

Discovery of New Thioviridamide‐Like Compounds with Antitumor Activities

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