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Article

Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis

by
Joachim J. Hug
1,2,†,
Nicolas A. Frank
1,2,†,
Christine Walt
1,2,
Petra Šenica
1,2,
Fabian Panter
1,2,3 and
Rolf Müller
1,2,3,*
1
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University, Campus E8 1, 66123 Saarbrücken, Germany
2
German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany
3
Helmholtz International Labs, Campus E8 1, 66123 Saarbrücken, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2021, 26(24), 7483; https://doi.org/10.3390/molecules26247483
Submission received: 23 November 2021 / Revised: 1 December 2021 / Accepted: 6 December 2021 / Published: 10 December 2021
(This article belongs to the Special Issue Microbial Natural Products in The Era of Genome- And Metabolome-Mining)
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Abstract

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a structurally diverse group of natural products. They feature a wide range of intriguing post-translational modifications, as exemplified by the biarylitides. These are a family of cyclic tripeptides found in Planomonospora, carrying a biaryl linkage between two aromatic amino acids. Recent genomic analyses revealed that the minimal biosynthetic prerequisite of biarylitide biosynthesis consists of only one ribosomally synthesized pentapeptide precursor as the substrate and a modifying cytochrome-P450-dependent enzyme. In silico analyses revealed that minimal biarylitide RiPP clusters are widespread among natural product producers across phylogenetic borders, including myxobacteria. We report here the genome-guided discovery of the first myxobacterial biarylitide MeYLH, termed Myxarylin, from Pyxidicoccus fallax An d48. Myxarylin was found to be an N-methylated tripeptide that surprisingly exhibits a C–N biaryl crosslink. In contrast to Myxarylin, previously isolated biarylitides are N-acetylated tripeptides that feature a C–C biaryl crosslink. Furthermore, the formation of Myxarylin was confirmed by the heterologous expression of the identified biosynthetic genes in Myxococcus xanthus DK1622. These findings expand the structural and biosynthetic scope of biarylitide-type RiPPs and emphasize the distinct biochemistry found in the myxobacterial realm.
Keywords: myxobacteria; secondary metabolites; biarylitide; natural product discovery; RiPPs; genome mining; Myxarylin myxobacteria; secondary metabolites; biarylitide; natural product discovery; RiPPs; genome mining; Myxarylin
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MDPI and ACS Style

Hug, J.J.; Frank, N.A.; Walt, C.; Šenica, P.; Panter, F.; Müller, R. Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis. Molecules 2021, 26, 7483. https://doi.org/10.3390/molecules26247483

AMA Style

Hug JJ, Frank NA, Walt C, Šenica P, Panter F, Müller R. Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis. Molecules. 2021; 26(24):7483. https://doi.org/10.3390/molecules26247483

Chicago/Turabian Style

Hug, Joachim J., Nicolas A. Frank, Christine Walt, Petra Šenica, Fabian Panter, and Rolf Müller. 2021. "Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis" Molecules 26, no. 24: 7483. https://doi.org/10.3390/molecules26247483

APA Style

Hug, J. J., Frank, N. A., Walt, C., Šenica, P., Panter, F., & Müller, R. (2021). Genome-Guided Discovery of the First Myxobacterial Biarylitide Myxarylin Reveals Distinct C–N Biaryl Crosslinking in RiPP Biosynthesis. Molecules, 26(24), 7483. https://doi.org/10.3390/molecules26247483

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