Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
- Yale University, United States
- Yale Univeristy, United States
- 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.
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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.
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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Genome mining unearths a hybrid nonribosomal peptide synthetase-like-pteridine synthase biosynthetic gene cluster
eLife 6:e25229.
https://doi.org/10.7554/eLife.25229
