A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity

Frattaruolo, Luca; Lacret, Rodney; Cappello, Anna Rita; Truman, Andrew W.

doi:10.1021/acschembio.7b00677

Cited by 88 publications

(108 citation statements)

References 33 publications

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“…Thioviridamide contains an AviCys moiety, the formation of which requires a dehydrated serine residue. The enzymes responsible for dehydration and subsequent cyclization have not been identified yet 65,75 . Since both gene clusters share a common modification for which the enzyme is unknown, we hypothesized that sprH3 and sprPT should be responsible for dehydration and cyclization, and thus are hallmarks for a new lanthipeptide subtype, which we designate type V.…”

Section: Resultsmentioning

confidence: 99%

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Kloosterman

Cimermančič

Elsayed

et al. 2020

Preprint

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12Most clinical drugs are based on microbial natural products, with compound classes including 13 polyketides (PKS), non-ribosomal peptides (NRPS), fluoroquinones and ribosomally synthesized and 14 post-translationally modified peptides (RiPPs). While variants of biosynthetic gene clusters (BGCs) for 15 known classes of natural products are easy to identify in genome sequences, BGCs for new 16 compound classes escape attention. In particular, evidence is accumulating that for RiPPs, subclasses 17 known thus far may only represent the tip of an iceberg. Here, we present decRiPPter (Data-driven 18Exploratory Class-independent RiPP TrackER), a RiPP genome mining algorithm aimed at the 19 discovery of novel RiPP classes. DecRiPPter combines a Support Vector Machine (SVM) that identifies 20candidate RiPP precursors with pan-genomic analyses to identify which of these are encoded within 21 operon-like structures that are part of the accessory genome of a genus. Subsequently, it prioritizes 22 such regions based on the presence of new enzymology and based on patterns of gene cluster and 23 precursor peptide conservation across species. We then applied decRiPPter to mine 1,295 24Streptomyces genomes, which led to the identification of 42 new candidate RiPP families that could 25 not be found by existing programs. One of these was studied further and elucidated as a novel 26 subfamily of lanthipeptides, designated Class V. Two previously unidentified modifying enzymes are 27proposed to create the hallmark lanthionine bridges. Taken together, our work highlights how novel 28 natural product families can be discovered by methods going beyond sequence similarity searches to 29 integrate multiple pathway discovery criteria. 30 31 Code and data availability 32The source code of DecRiPPter is freely available online at https://github.com/Alexamk/decRiPPter. 33Results of the data analysis are available online at 34

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Section: Resultsmentioning

confidence: 99%

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Kloosterman

Cimermančič

Elsayed

et al. 2020

Preprint

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“…[13] YcaO proteins have also been demonstrated to catalyse the formation of amidine rings in bottromycin [14] and klebsazolicin, [15] and can also function with a TfuA-domain protein to introduce thioamide bonds into RiPPs such as thiopeptin [16] and the thiovarsolins. [7,17] Over 9,000 YcaO-domain proteins have been bioinformatically identified in GenBank, but the function of the majority of these remain unknown. [18]…”

Section: Introductionmentioning

confidence: 99%

Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature

Russell

Vior

Hems

et al. 2020

Preprint

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Ribosomally synthesised and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural product with a range of bioactivities. Genome mining for RiPP biosynthetic gene clusters (BGCs) is often hampered by poor detection of the short precursor peptides that are ultimately modified into the final molecule. Here, we utilise a previously described genome mining tool, RiPPER, to identify novel RiPP precursor peptides near YcaOdomain proteins, enzymes that catalyse various RiPP post-translational modifications including heterocyclisation and thioamidation. Using this dataset, we identified a novel, diverse and highly conserved family of RiPP BGCs spanning over 230 species of Actinobacteria and Firmicutes. A representative BGC from Streptomyces albus J1074 was characterised, leading to the discovery of streptamidine, a novel-amidine containing RiPP. This highlights the breadth of unexplored natural products with structurally rare features, even in model organisms.

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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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A Genomics-Based Approach Identifies a Thioviridamide-Like Compound with Selective Anticancer Activity

Cited by 88 publications

References 33 publications

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Integration of machine learning and pan-genomics expands the biosynthetic landscape of RiPP natural products

Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature

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

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