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Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
Nature Communications, Volume: 13, Issue: 1
Swansea University Author: Claudio Greco
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The genomes of many filamentous fungi, such as Aspergillus spp., include diverse biosynthetic gene clusters of unknown function. We previously showed that low copper levels upregulate a gene cluster that includes crmA, encoding a putative isocyanide synthase. Here we show, using untargeted comparati...
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The genomes of many filamentous fungi, such as Aspergillus spp., include diverse biosynthetic gene clusters of unknown function. We previously showed that low copper levels upregulate a gene cluster that includes crmA, encoding a putative isocyanide synthase. Here we show, using untargeted comparative metabolomics, that CrmA generates a valine-derived isocyanide that contributes to two distinct biosynthetic pathways under copper-limiting conditions. Reaction of the isocyanide with an ergot alkaloid precursor results in carbon-carbon bond formation analogous to Strecker amino-acid synthesis, producing a group of alkaloids we term fumivalines. In addition, valine isocyanide contributes to biosynthesis of a family of acylated sugar alcohols, the fumicicolins, which are related to brassicicolin A, a known isocyanide from Alternaria brassicicola. CrmA homologs are found in a wide range of pathogenic and non-pathogenic fungi, some of which produce fumicicolin and fumivaline. Extracts from A. fumigatus wild type (but not crmA-deleted strains), grown under copper starvation, inhibit growth of diverse bacteria and fungi, and synthetic valine isocyanide shows antibacterial activity. CrmA thus contributes to two biosynthetic pathways downstream of trace-metal sensing.
Data availability:MS and MS2 data for all fungal metabolome samples analyzed in this study (A. fumigatus, P. commune, P. expansum, C. heterostrophus, co-culture of A. fumigatus and P. expansum, and deuterium labeling experiments) are available at the GNPS Web site (massive.ucsd.edu) under MassIVE ID number MSV000089206. The crmA sequence data used in this study are available in the NCBI database under accession code XP_754255 for A. fumigatus, XP_016596276 for P. expansum, and EMD96666 for C. heterostrophus. The sequence data used in this study are available in the NCBI database under accession code GCF_000002655.1 for A. fumigatus, GCA_008931945.1 for P. commune, GCA_000338975.1 for C. heterostrophus. The sequence data for A. brassicicola is available in the JGI Mycocosm database under accession code ATCC96836. Source data are provided with this paper.
Faculty of Science and Engineering
This work was supported in part by the National Institutes of Health R01 2R01GM112739-05A1 to N.P.K., the National Institute of General Medical Sciences T32 GM135066 to G.N., NIH 5R44AI140943-03 to J.W.B., as well as the Howard Hughes Medical Foundation (to F.C.S.).