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Title: Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts

Abstract

Secondary metabolites are key in how organisms from all domains of life interact with their environment and each other. The iron-binding molecule pulcherrimin was described a century ago, but the genes responsible for its production in budding yeasts have remained uncharacterized. In this study, we used phylogenomic footprinting on 90 genomes across the budding yeast subphylum Saccharomycotina to identify the gene cluster associated with pulcherrimin production. Using targeted gene replacements in Kluyveromyces lactis, we characterized the four genes that make up the cluster, which likely encode two pulcherriminic acid biosynthesis enzymes, a pulcherrimin transporter, and a transcription factor involved in both biosynthesis and transport. The requirement of a functional putative transporter to utilize extracellular pulcherrimin-complexed iron demonstrates that pulcherriminic acid is a siderophore, a chelator that binds iron outside the cell for subsequent uptake. Surprisingly, we identified homologs of the putative transporter and transcription factor genes in multiple yeast genera that lacked the biosynthesis genes and could not make pulcherrimin, including the model yeast Saccharomyces cerevisiae. We deleted these previously uncharacterized genes and showed they are also required for pulcherrimin utilization in S. cerevisiae, raising the possibility that other genes of unknown function are linked to secondary metabolism. Lastly, phylogeneticmore » analyses of this gene cluster suggest that pulcherrimin biosynthesis and utilization were ancestral to budding yeasts, but the biosynthesis genes and, subsequently, the utilization genes, were lost in many lineages, mirroring other microbial public goods systems that lead to the rise of cheater organisms.« less

Authors:
 [1];  [1];  [1];  [2];  [2];  [1];  [3];  [1];  [3]; ORCiD logo [2]; ORCiD logo [1]
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  1. Univ. of Wisconsin, Madison, WI (United States)
  2. Vanderbilt Univ., Nashville, TN (United States)
  3. US Department of Agriculture, Peoria, IL (United States)
Publication Date:
Research Org.:
Great Lakes Bioenergy Research Center (GLBRC), Madison, WI (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER)
Contributing Org.:
University of Wisconsin Biotechnology Center
OSTI Identifier:
1506646
Grant/Contract Number:  
SC0018409; FC02-07ER64494
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 115; Journal Issue: 43; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; secondary metabolism; gene cluster; siderophore; budding yeasts; cyclodipeptide synthase

Citation Formats

Krause, David J., Kominek, Jacek, Opulente, Dana A., Shen, Xing-Xing, Zhou, Xiaofan, Langdon, Quinn K., DeVirgilio, Jeremy, Hulfachor, Amanda Beth, Kurtzman, Cletus P., Rokas, Antonis, and Hittinger, Chris Todd. Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts. United States: N. p., 2018. Web. doi:10.1073/pnas.1806268115.
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Krause, David J., Kominek, Jacek, Opulente, Dana A., Shen, Xing-Xing, Zhou, Xiaofan, Langdon, Quinn K., DeVirgilio, Jeremy, Hulfachor, Amanda Beth, Kurtzman, Cletus P., Rokas, Antonis, & Hittinger, Chris Todd. Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts. United States. https://doi.org/10.1073/pnas.1806268115
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Krause, David J., Kominek, Jacek, Opulente, Dana A., Shen, Xing-Xing, Zhou, Xiaofan, Langdon, Quinn K., DeVirgilio, Jeremy, Hulfachor, Amanda Beth, Kurtzman, Cletus P., Rokas, Antonis, and Hittinger, Chris Todd. Mon . "Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts". United States. https://doi.org/10.1073/pnas.1806268115. https://www.osti.gov/servlets/purl/1506646.
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@article{osti_1506646,
title = {Functional and evolutionary characterization of a secondary metabolite gene cluster in budding yeasts},
author = {Krause, David J. and Kominek, Jacek and Opulente, Dana A. and Shen, Xing-Xing and Zhou, Xiaofan and Langdon, Quinn K. and DeVirgilio, Jeremy and Hulfachor, Amanda Beth and Kurtzman, Cletus P. and Rokas, Antonis and Hittinger, Chris Todd},
abstractNote = {Secondary metabolites are key in how organisms from all domains of life interact with their environment and each other. The iron-binding molecule pulcherrimin was described a century ago, but the genes responsible for its production in budding yeasts have remained uncharacterized. In this study, we used phylogenomic footprinting on 90 genomes across the budding yeast subphylum Saccharomycotina to identify the gene cluster associated with pulcherrimin production. Using targeted gene replacements in Kluyveromyces lactis, we characterized the four genes that make up the cluster, which likely encode two pulcherriminic acid biosynthesis enzymes, a pulcherrimin transporter, and a transcription factor involved in both biosynthesis and transport. The requirement of a functional putative transporter to utilize extracellular pulcherrimin-complexed iron demonstrates that pulcherriminic acid is a siderophore, a chelator that binds iron outside the cell for subsequent uptake. Surprisingly, we identified homologs of the putative transporter and transcription factor genes in multiple yeast genera that lacked the biosynthesis genes and could not make pulcherrimin, including the model yeast Saccharomyces cerevisiae. We deleted these previously uncharacterized genes and showed they are also required for pulcherrimin utilization in S. cerevisiae, raising the possibility that other genes of unknown function are linked to secondary metabolism. Lastly, phylogenetic analyses of this gene cluster suggest that pulcherrimin biosynthesis and utilization were ancestral to budding yeasts, but the biosynthesis genes and, subsequently, the utilization genes, were lost in many lineages, mirroring other microbial public goods systems that lead to the rise of cheater organisms.},
doi = {10.1073/pnas.1806268115},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 43,
volume = 115,
place = {United States},
year = {Mon Oct 08 00:00:00 EDT 2018},
month = {Mon Oct 08 00:00:00 EDT 2018}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1073/pnas.1806268115
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Cited by: 55 works
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Figures / Tables:

Figure 1 Figure 1: The PUL gene cluster and its phylogenetic distribution. The genome-scale cladogram was constructed using alignments of 1,037 conserved BUSCO genes with newly sequenced genomes in bold. Collapsed clades with multiple ($N$) species are shown as triangles, and the complete tree, with bootstrap values, is shown in SI Appendix,more » Fig. S1. Red filled boxes indicate pulcherrimin production has been observed in that species, and filled boxes for PUL1-4 indicate presence or absence of the corresponding PUL gene. Gene arrow diagrams show the arrangement of the four PUL genes in representative species that produce pulcherrimin. The gene table contains putative annotations for the four genes prior to this study.« less
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    Works referencing / citing this record:

    Pulcherrimin formation controls growth arrest of the Bacillus subtilis biofilm
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