Class IV Lasso Peptides Synergistically Induce Proliferation of Cancer Cells and Sensitize Them to Doxorubicin

Garzón, Jaime Felipe Guerrero; Madland, Eva; Zehl, Martin; Singh, Madhurendra; Rezaei, Shiva; Aachmann, Finn Lillelund; Courtade, Gastón; Urban, Ernst; Rückert, Christian; Busche, Tobias; Kalinowski, Jörn; Cao, Yan-Ru; Jiang, Yi; Jiang, Cheng‐Lin; Selivanova, Galina; Zotchev, Sergey B.

doi:10.1016/j.isci.2020.101785

Cited by 13 publications

(18 citation statements)

References 45 publications

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“…A combined thermal and carboxypeptidase Y stability assay, previously established for this purpose, − ,,,,, was performed to further corroborate the lasso fold (SI Figure S3).…”

Section: Resultsmentioning

confidence: 99%

“…Extended Thermostability and Carboxypeptidase Y Assays of Cochonodin I (−2 aa). A combined thermal and carboxypeptidase Y stability assay, previously established for this purpose, [1][2][3]5,8,9,22,34 was performed to further corroborate the lasso fold (SI Figure S3).…”

mentioning

confidence: 99%

“…The precursors themselves are subdivided into a leader region, needed for enzyme recognition, and a core region, into which the processing enzymes incorporate the post-translational modifications. Lasso peptides exhibit various bioactivities including antimicrobial, cytotoxic, or antiviral. ,− …”

mentioning

confidence: 99%

“…Schematic representation of the (A) lasso fold and (B) the four currently known lasso peptide classes. − ,, (C) Basic principles of lasso peptide biosynthesis.…”

mentioning

confidence: 99%

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A Bifunctional Leader Peptidase/ABC Transporter Protein Is Involved in the Maturation of the Lasso Peptide Cochonodin I from Streptococcus suis

et al. 2021

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Lasso peptides are members of the natural product superfamily of ribosomally synthesized and post-translationally modified peptides (RiPPs). Here, we describe the first lasso peptide originating from a biosynthetic gene cluster belonging to a unique lasso peptide subclade defined by the presence of a bifunctional protein harboring both a leader peptidase (B2) and an ABC transporter (D) domain. Bioinformatic analysis revealed that these clusters also encode homologues of the NisR/NisK regulatory system and the NisF/NisE/NisG immunity factors, which are usually associated with the clusters of antimicrobial class I lanthipeptides, such as nisin, another distinct RiPP subfamily. The cluster enabling the heterologous production of the lasso peptide cochonodin I in E. coli originated from Streptococcus suis LSS65, and the threaded structure of cochonodin I was evidenced through extensive MS/MS analysis and stability assays. It was shown that the ABC transporter domain from SsuB2/D is not essential for lasso peptide maturation. By extensive genome mining dedicated exclusively to other lasso peptide biosynthetic gene clusters featuring bifunctional B2/D proteins, it was furthermore revealed that many bacteria associated with human or animal microbiota hold the biosynthetic potential to produce cochonodin-like lasso peptides, implying that these natural products might play roles in human and animal health.

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“…A combined thermal and carboxypeptidase Y stability assay, previously established for this purpose, − ,,,,, was performed to further corroborate the lasso fold (SI Figure S3).…”

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…Schematic representation of the (A) lasso fold and (B) the four currently known lasso peptide classes. − ,, (C) Basic principles of lasso peptide biosynthesis.…”

mentioning

confidence: 99%

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A Bifunctional Leader Peptidase/ABC Transporter Protein Is Involved in the Maturation of the Lasso Peptide Cochonodin I from Streptococcus suis

et al. 2021

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“…The extra amino group might increase activity. Amycolatopsis YIM10 has a similar cluster that is incompletely sequenced [60].…”

Section: Primer: 3-amino-5-hydroxybenzoatementioning

confidence: 99%

New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining

2022

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Glycosylated polyene macrolides include effective antifungal agents, such as pimaricin, nystatin, candicidin, and amphotericin B. For the treatment of systemic mycoses, amphotericin B has been described as a gold-standard antibiotic because of its potent activity against a broad spectrum of fungal pathogens, which do not readily become resistant. However, amphotericin B has severe toxic side effects, and the development of safer alternatives remains an important objective. One approach towards obtaining such compounds is to discover new related natural products. Advances in next-generation sequencing have delivered a wealth of microbial genome sequences containing polyene biosynthetic gene clusters. These typically encode a modular polyketide synthase that catalyzes the assembly of the aglycone core, a cytochrome P450 that oxidizes a methyl branch to a carboxyl group, and additional enzymes for synthesis and attachment of a single mycosamine sugar residue. In some cases, further P450s catalyze epoxide formation or hydroxylation within the macrolactone. Bioinformatic analyses have identified over 250 of these clusters. Some are predicted to encode potentially valuable new polyenes that have not been uncovered by traditional screening methods. Recent experimental studies have characterized polyenes with new polyketide backbones, previously unknown late oxygenations, and additional sugar residues that increase water-solubility and reduce hemolytic activity. Here we review these studies and assess how this new knowledge can help to prioritize silent polyene clusters for further investigation. This approach should improve the chances of discovering better antifungal antibiotics.

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Combined thermal and carboxypeptidase Y stability assays for probing the threaded fold of lasso peptides

Hegemann

2022

Methods in Enzymology

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Class IV Lasso Peptides Synergistically Induce Proliferation of Cancer Cells and Sensitize Them to Doxorubicin

Cited by 13 publications

References 45 publications

A Bifunctional Leader Peptidase/ABC Transporter Protein Is Involved in the Maturation of the Lasso Peptide Cochonodin I from Streptococcus suis

A Bifunctional Leader Peptidase/ABC Transporter Protein Is Involved in the Maturation of the Lasso Peptide Cochonodin I from Streptococcus suis

New Glycosylated Polyene Macrolides: Refining the Ore from Genome Mining

Combined thermal and carboxypeptidase Y stability assays for probing the threaded fold of lasso peptides

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