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Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family

View ORCID ProfileMark C. Walker, View ORCID ProfileDouglas A. Mitchell, View ORCID ProfileWilfred A. van der Donk
doi: https://doi.org/10.1101/2020.03.13.990614
Mark C. Walker
1Department of Chemistry and Chemical Biology, University of New Mexico, 346 Clark Hall, 300 Terrace St. NE, Albuquerque, NM 87131, United States
2Department of Chemistry, University of Illinois at Urbana-Champaign, Roger Adams Laboratory, 600 S. Mathews Ave., Urbana, Illinois 61801, United States
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  • For correspondence: markcwalker@unm.edu
Douglas A. Mitchell
2Department of Chemistry, University of Illinois at Urbana-Champaign, Roger Adams Laboratory, 600 S. Mathews Ave., Urbana, Illinois 61801, United States
3Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801, United States
4Department of Microbiology, University of Illinois at Urbana-Champaign, 601 S. Goodwin Ave., Urbana, IL, 61801
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Wilfred A. van der Donk
2Department of Chemistry, University of Illinois at Urbana-Champaign, Roger Adams Laboratory, 600 S. Mathews Ave., Urbana, Illinois 61801, United States
5Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, 600 S. Mathews Ave., Urbana, Illinois 61801, United States
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Abstract

Background Lanthipeptides belong to the ribosomally synthesized and post-translationally modified peptide group of natural products and have a variety of biological activities ranging from antibiotics to antinociceptives. These peptides are cyclized through thioether crosslinks and can bear other secondary post-translational modifications. While lanthipeptide biosynthetic gene clusters can be identified by the presence of characteristic enzymes involved in the post-translational modification of these peptides, locating the precursor peptides encoded within these clusters is challenging due to their short length and high sequence variability, which limits the high-throughput exploration of lanthipeptide precursor peptides. To address this challenge, we enhanced the predictive capabilities of Rapid ORF Description & Evaluation Online (RODEO) to identify all known classes of lanthipeptides.

Results Using RODEO, we mined over 100,000 bacterial and archaeal genomes in the RefSeq database. We identified nearly 8,500 lanthipeptide precursor peptides. These precursor peptides were identified in a broad range of bacterial phyla as well as the Euryarchaeota phylum of archaea. Bacteroidetes were found to encode a large number of these biosynthetic gene clusters, despite making up a relatively small portion of the genomes in this dataset. While a number of these precursor peptides are similar to those of previously characterized lanthipeptides, even more were not, including potential antibiotics. Additionally, examination of the biosynthetic gene clusters revealed enzymes that install secondary post-translational modifications are more widespread than initially thought.

Conclusion Lanthipeptide biosynthetic gene clusters are more widely distributed and the precursor peptides encoded within these clusters are more diverse than previously appreciated, demonstrating that the lanthipeptide sequence-function space remains largely underexplored.

Footnotes

  • http://ripp.rodeo/

  • List of Abbreviations

    BGC
    biosynthetic gene cluster,
    HMM
    hidden Markov model,
    LanA
    lanthipeptide precursor peptide;
    LanB
    class I lanthipeptide dehydratatse;
    LanC
    class I lanthipeptide cyclase
    LanKC
    class III lanthipeptide synthetase
    LanL
    class IV lanthipeptide synthetase
    LanM
    class II lanthipeptide synthetase;
    MEME
    Multiple Em for Motif Elicitation;
    ORF
    open reading frame.
    Pfam
    protein family;
    RODEO
    Rapid ORF Description & Evaluation Online;
    RiPP
    ribosomally synthesized and post-translationally modified peptide;
    SVM
    support vector machine.
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    Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family
    Mark C. Walker, Douglas A. Mitchell, Wilfred A. van der Donk
    bioRxiv 2020.03.13.990614; doi: https://doi.org/10.1101/2020.03.13.990614
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    Precursor peptide-targeted mining of more than one hundred thousand genomes expands the lanthipeptide natural product family
    Mark C. Walker, Douglas A. Mitchell, Wilfred A. van der Donk
    bioRxiv 2020.03.13.990614; doi: https://doi.org/10.1101/2020.03.13.990614

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