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Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11030-11035. doi: 10.1073/pnas.1806268115. Epub 2018 Oct 8.

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

Author information

Laboratory of Genetics, Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706.
Wisconsin Energy Institute, University of Wisconsin-Madison, Madison, WI 53706.
J. F. Crow Institute for the Study of Evolution, University of Wisconsin-Madison, Madison, WI 53706.
DOE Great Lakes Bioenergy Research Center, University of Wisconsin-Madison, Madison, WI 53706.
Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235.
Mycotoxin Prevention and Applied Microbiology Research Unit, National Center for Agricultural Utilization Research, Agricultural Research Service, US Department of Agriculture, Peoria, IL 61604.
Laboratory of Genetics, Genome Center of Wisconsin, University of Wisconsin-Madison, Madison, WI 53706;


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. Here, 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. 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.


budding yeasts; cyclodipeptide synthase; gene cluster; secondary metabolism; siderophore

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