Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster

  1. Hyun Bong Park
  2. Corey E Perez
  3. Karl W Barber
  4. Jesse Rinehart
  5. Jason M Crawford  Is a corresponding author
  1. Yale University, United States
  2. Yale Univeristy, United States
  3. Yale, United States

Abstract

Nonribosomal peptides represent a large class of metabolites with pharmaceutical relevance. Pteridines, such as pterins, folates, and flavins, are heterocyclic metabolites that often serve as redox-active cofactors. The biosynthetic machineries for the construction of these distinct classes of small molecules operate independently in the cell. Here, we discovered an unprecedented nonribosomal peptide synthetase-like-pteridine synthase hybrid biosynthetic gene cluster in Photorhabdus luminescens using genome synteny analysis. P. luminescens is a Gammaproteobacterium that undergoes phenotypic variation and can serve both pathogenic and mutualistic roles. Through extensive gene deletion, pathway-targeted molecular networking, quantitative proteomic analysis, and NMR, we show that the genetic locus affects the regulation of quorum sensing and secondary metabolic enzymes and encodes new pteridine metabolites functionalized with cis-amide acyl-side chains, termed pepteridine A <b>1</b> and B <b>2</b>. The pepteridines are produced in the pathogenic phenotypic variant and represent the first reported metabolites to be synthesized by a hybrid NRPS-pteridine pathway.

Article and author information

Author details

  1. Hyun Bong Park

    Department of Chemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Corey E Perez

    Department of Chemistry, Yale University, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Karl W Barber

    Cellular and Molecular Physiology, Systems Biology, Yale Univeristy, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jesse Rinehart

    Cellular and Molecular Physiology, Systems Biology, Yale Univeristy, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jason M Crawford

    Chem, Microbial Path, Chem Bio, Yale, West Haven, United States
    For correspondence
    jason.crawford@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7583-1242

Funding

National Cancer Institute (1DP2-CA186575)

  • Hyun Bong Park
  • Corey E Perez
  • Jason M Crawford

National Institute of General Medical Sciences (R00-GM097096)

  • Hyun Bong Park
  • Corey E Perez
  • Jason M Crawford

Damon Runyon Cancer Research Foundation (DRR 39-16)

  • Hyun Bong Park
  • Corey E Perez
  • Jason M Crawford

National Science Foundation (DGE-1122492)

  • Karl W Barber

the Searle Scholars (13-SSP-210)

  • Hyun Bong Park
  • Corey E Perez
  • Jason M Crawford

National Institutes of Health Chemistry Biology Interface Training (5T32GM067543-12)

  • Corey E Perez

National Institute of General Medical Sciences (R01GM117230)

  • Jesse Rinehart

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Jon Clardy, Harvard Medical School, United States

Publication history

  1. Received: January 17, 2017
  2. Accepted: February 28, 2017
  3. Accepted Manuscript published: March 15, 2017 (version 1)
  4. Accepted Manuscript updated: March 15, 2017 (version 2)
  5. Version of Record published: April 7, 2017 (version 3)

Copyright

© 2017, Park et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hyun Bong Park
  2. Corey E Perez
  3. Karl W Barber
  4. Jesse Rinehart
  5. Jason M Crawford
(2017)
Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
eLife 6:e25229.
https://doi.org/10.7554/eLife.25229

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