Identification of essential biosynthetic genes and a true biosynthetic product for thioviridamide

Izawa, Masako; Nagamine, Shota; Aoki, Haruna; Hayakawa, Yoichi

doi:10.2323/jgam.2017.05.002

Cited by 15 publications

(16 citation statements)

References 9 publications

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“…[3] Posttranslational modification enzymes are identified in the tva gene cluster (Figure S1A), including TvaH/TvaI as a pair of homologs to YcaO/TfuA proteins for the thioamidation of peptide backbone and TvaG as a putative methyltransferase for the double methylation of His(12) residue [4] . The N‐terminal 2‐hydroxy‐2‐methyl‐4‐oxopentanoyl group is the product of acetone addition to a pyruvate motif, which is derived from the hydrolysis of a dehydroalanine (Dha) residue during purification [2d, 5] . The C‐terminal 2‐aminovinyl‐cysteine (AviCys) motif is another structural feature of thioamitides and exists in a variety of RiPPs , including lanthipeptides (e.g., epidermin), lipolanthines (e.g., microvionin) and linaridins (e.g., cypemycin) (Figure 1 A).…”

Section: Introductionmentioning

confidence: 99%

The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2‐Aminovinyl‐Cysteine Motifs in Thioamitides**

et al. 2020

Angew Chem Int Ed

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The biosynthesis of thioamitide natural products remains largely unknown, especially for the characteristic Cterminal 2-aminovinyl-cysteine (AviCys) motifs.H erein, we report the discovery that homologues of class-III lanthipeptide synthetases (LanKC t s) encoded outside putative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides.L anKCt enzymes bind tightly to cysteine decarboxylases encoded inside thioamitide BGCs and the resulting enzyme complex completes the macrocyclization of AviCys rings.F urthermore,L anKC t enzymes are present in the genomes of many thioamitide-producing strains and participate in the generation of AviCys macrocycles.T ogether,o ur study reveals an unprecedented system that lanthipeptide synthetases outside thioamitide BGCs participate in their biosynthesis by specific association with cysteine decarboxylases encoded inside BGCs.

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Section: Introductionmentioning

confidence: 99%

The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2‐Aminovinyl‐Cysteine Motifs in Thioamitides**

et al. 2020

Angew Chem Int Ed

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“…[8][9][10] Posttranslational modification enzymes are identified in the tva gene cluster ( Fig. S1A), including TvaH/TvaI as a pair of homologs to YcaO/TfuA proteins for the thioamidation of peptide backbone and TvaG as a putative methyltransferase for the double methylation of His (12) residue. 11 The N-terminal 2-hydroxy-2methyl-4-oxopentanoyl group is the product of acetone addition to a pyruvate motif derived from the hydrolysis of a dehydroalanine (Dha) residue during purification.…”

Section: Introductionmentioning

confidence: 99%

“…11 The N-terminal 2-hydroxy-2methyl-4-oxopentanoyl group is the product of acetone addition to a pyruvate motif derived from the hydrolysis of a dehydroalanine (Dha) residue during purification. 6,12 The C-terminal 2-aminovinyl-cysteine (AviCys) motif is another structural feature of thioamitides and exists in a variety of RiPPs, including lanthipeptides (e.g., epidermin), [13][14][15] lipolanthines (e.g., microvionin) 16 and linaridins (e.g., cypemycin) 17 (Fig. 1A).…”

Section: Introductionmentioning

confidence: 99%

Lanthipeptide Synthetases Participate the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides

et al. 2020

Preprint

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Thioamitides are a group of ribosomally synthesized and post-translational modified peptides with potent antiproliferative and proapoptotic activities. Their biosynthesis remains largely unknown, especially for the characteristic C-terminal 2-aminovinyl-Cysteine (AviCys) motifs. Herein, we report the discovery that homologs of class III lanthipeptide synthetases (LanKCts)encoded outside putative thioamitide biosynthetic gene clusters (BGCs) fully dehydrate the precursor peptides. Remarkably, LanKCt enzymes bind tightly to cysteine decarboxylases encoded inside thioamitide BGCs, and the resulting complex complete the macrocyclization of AviCys rings. Furthermore, LanKCt enzymes are present in the genomes of many thioamitide-producing strains and are functional when in complex with cysteine decarboxylases to produce AviCys macrocycles. Thus, our study reveals the participation of lanthipeptide synthetases as a general strategy for dehydration and AviCys formation during thioamitides biosynthesis and thus paves the way for the bioengineering of this class of bioactive natural products.

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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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Identification of essential biosynthetic genes and a true biosynthetic product for thioviridamide

Cited by 15 publications

References 9 publications

The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2‐Aminovinyl‐Cysteine Motifs in Thioamitides**

The Utilization of Lanthipeptide Synthetases Is a General Strategy for the Biosynthesis of 2‐Aminovinyl‐Cysteine Motifs in Thioamitides**

Lanthipeptide Synthetases Participate the Biosynthesis of 2-Aminovinyl-Cysteine Motifs in Thioamitides

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

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