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Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi

Tae Hyung Won, Jin Woo Bok, Nischala Nadig, Nandhitha Venkatesh, Grant Nickles Orcid Logo, Claudio Greco Orcid Logo, Fang Yun Lim Orcid Logo, Jennifer B. González, B. Gillian Turgeon, Nancy P. Keller Orcid Logo, Frank C. Schroeder Orcid Logo

Nature Communications, Volume: 13, Issue: 1

Swansea University Author: Claudio Greco Orcid Logo

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DOI (Published version): 10.1038/s41467-022-32394-x

Abstract

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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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2022
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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. 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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. 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spelling 2022-10-20T13:59:19.2240901 v2 61510 2022-10-10 Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi cacac6459bd7cf4a241f63661006036f 0000-0003-3067-0999 Claudio Greco Claudio Greco true false 2022-10-10 SBI 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. Journal Article Nature Communications 13 1 Springer Science and Business Media LLC 2041-1723 16 8 2022 2022-08-16 10.1038/s41467-022-32394-x 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. COLLEGE NANME Biosciences COLLEGE CODE SBI Swansea University 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.). 2022-10-20T13:59:19.2240901 2022-10-10T17:22:30.4795513 Faculty of Science and Engineering School of Biosciences, Geography and Physics - Biosciences Tae Hyung Won 1 Jin Woo Bok 2 Nischala Nadig 3 Nandhitha Venkatesh 4 Grant Nickles 0000-0002-0234-8049 5 Claudio Greco 0000-0003-3067-0999 6 Fang Yun Lim 0000-0001-7406-2317 7 Jennifer B. González 8 B. Gillian Turgeon 9 Nancy P. Keller 0000-0002-4386-9473 10 Frank C. Schroeder 0000-0002-4420-0237 11 61510__25528__fb2d6109d16b49da85c3f01ca558d4be.pdf 61510_VoR.pdf 2022-10-20T13:56:37.2127019 Output 1873587 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
spellingShingle Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
Claudio Greco
title_short Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
title_full Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
title_fullStr Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
title_full_unstemmed Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
title_sort Copper starvation induces antimicrobial isocyanide integrated into two distinct biosynthetic pathways in fungi
author_id_str_mv cacac6459bd7cf4a241f63661006036f
author_id_fullname_str_mv cacac6459bd7cf4a241f63661006036f_***_Claudio Greco
author Claudio Greco
author2 Tae Hyung Won
Jin Woo Bok
Nischala Nadig
Nandhitha Venkatesh
Grant Nickles
Claudio Greco
Fang Yun Lim
Jennifer B. González
B. Gillian Turgeon
Nancy P. Keller
Frank C. Schroeder
format Journal article
container_title Nature Communications
container_volume 13
container_issue 1
publishDate 2022
institution Swansea University
issn 2041-1723
doi_str_mv 10.1038/s41467-022-32394-x
publisher Springer Science and Business Media LLC
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Biosciences, Geography and Physics - Biosciences{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Biosciences, Geography and Physics - Biosciences
document_store_str 1
active_str 0
description 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.
published_date 2022-08-16T04:20:22Z
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score 11.012678

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