Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT Microbial secondary metabolites, including isocyanide moieties, have been extensively mined for their repertoire of bioactive properties. Although the first naturally occurring isocyanide (xanthocillin) was isolated from the fungus Penicillium notatum over half a century ago, the biosynthet...

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Autores principales:	Fang Yun Lim, Tae Hyung Won, Nicholas Raffa, Joshua A. Baccile, Jen Wisecaver, Antonis Rokas, Frank C. Schroeder, Nancy P. Keller
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Aspergillus fumigatus isocyanide synthase copper melanocin xanthocillin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b569dc18042d4c3798eb0e9cf656259d
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spelling	oai:doaj.org-article:b569dc18042d4c3798eb0e9cf656259d2021-11-15T16:00:25ZFungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mBio.00785-182150-7511https://doaj.org/article/b569dc18042d4c3798eb0e9cf656259d2018-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00785-18https://doaj.org/toc/2150-7511ABSTRACT Microbial secondary metabolites, including isocyanide moieties, have been extensively mined for their repertoire of bioactive properties. Although the first naturally occurring isocyanide (xanthocillin) was isolated from the fungus Penicillium notatum over half a century ago, the biosynthetic origins of fungal isocyanides remain unknown. Here we report the identification of a family of isocyanide synthases (ICSs) from the opportunistic human pathogen Aspergillus fumigatus. Comparative metabolomics of overexpression or knockout mutants of ICS candidate genes led to the discovery of a fungal biosynthetic gene cluster (BGC) that produces xanthocillin (xan). Detailed analysis of xanthocillin biosynthesis in A. fumigatus revealed several previously undescribed compounds produced by the xan BGC, including two novel members of the melanocin family of compounds. We found both the xan BGC and a second ICS-containing cluster, named the copper-responsive metabolite (crm) BGC, to be transcriptionally responsive to external copper levels and further demonstrated that production of metabolites from the xan BGC is increased during copper starvation. The crm BGC includes a novel type of fungus-specific ICS-nonribosomal peptide synthase (NRPS) hybrid enzyme, CrmA. This family of ICS-NRPS hybrid enzymes is highly enriched in fungal pathogens of humans, insects, and plants. Phylogenetic assessment of all ICSs spanning the tree of life shows not only high prevalence throughout the fungal kingdom but also distribution in species not previously known to harbor BGCs, indicating an untapped resource of fungal secondary metabolism. IMPORTANCE Fungal ICSs are an untapped resource in fungal natural product research. Their isocyanide products have been implicated in plant and insect pathogenesis due to their ability to coordinate transition metals and disable host metalloenzymes. The discovery of a novel isocyanide-producing family of hybrid ICS-NRPS enzymes enriched in medically and agriculturally important fungal pathogens may reveal mechanisms underlying pathogenicity and afford opportunities to discover additional families of isocyanides. Furthermore, the identification of noncanonical ICS BGCs will enable refinement of BGC prediction algorithms to expand on the secondary metabolic potential of fungal and bacterial species. The identification of genes related to ICS BGCs in fungal species not previously known for secondary metabolite-producing capabilities (e.g., Saccharomyces spp.) contributes to our understanding of the evolution of BGC in fungi.Fang Yun LimTae Hyung WonNicholas RaffaJoshua A. BaccileJen WisecaverAntonis RokasFrank C. SchroederNancy P. KellerAmerican Society for MicrobiologyarticleAspergillus fumigatusisocyanide synthasecoppermelanocinxanthocillinMicrobiologyQR1-502ENmBio, Vol 9, Iss 3 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus isocyanide synthase copper melanocin xanthocillin Microbiology QR1-502
spellingShingle	Aspergillus fumigatus isocyanide synthase copper melanocin xanthocillin Microbiology QR1-502 Fang Yun Lim Tae Hyung Won Nicholas Raffa Joshua A. Baccile Jen Wisecaver Antonis Rokas Frank C. Schroeder Nancy P. Keller Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT Microbial secondary metabolites, including isocyanide moieties, have been extensively mined for their repertoire of bioactive properties. Although the first naturally occurring isocyanide (xanthocillin) was isolated from the fungus Penicillium notatum over half a century ago, the biosynthetic origins of fungal isocyanides remain unknown. Here we report the identification of a family of isocyanide synthases (ICSs) from the opportunistic human pathogen Aspergillus fumigatus. Comparative metabolomics of overexpression or knockout mutants of ICS candidate genes led to the discovery of a fungal biosynthetic gene cluster (BGC) that produces xanthocillin (xan). Detailed analysis of xanthocillin biosynthesis in A. fumigatus revealed several previously undescribed compounds produced by the xan BGC, including two novel members of the melanocin family of compounds. We found both the xan BGC and a second ICS-containing cluster, named the copper-responsive metabolite (crm) BGC, to be transcriptionally responsive to external copper levels and further demonstrated that production of metabolites from the xan BGC is increased during copper starvation. The crm BGC includes a novel type of fungus-specific ICS-nonribosomal peptide synthase (NRPS) hybrid enzyme, CrmA. This family of ICS-NRPS hybrid enzymes is highly enriched in fungal pathogens of humans, insects, and plants. Phylogenetic assessment of all ICSs spanning the tree of life shows not only high prevalence throughout the fungal kingdom but also distribution in species not previously known to harbor BGCs, indicating an untapped resource of fungal secondary metabolism. IMPORTANCE Fungal ICSs are an untapped resource in fungal natural product research. Their isocyanide products have been implicated in plant and insect pathogenesis due to their ability to coordinate transition metals and disable host metalloenzymes. The discovery of a novel isocyanide-producing family of hybrid ICS-NRPS enzymes enriched in medically and agriculturally important fungal pathogens may reveal mechanisms underlying pathogenicity and afford opportunities to discover additional families of isocyanides. Furthermore, the identification of noncanonical ICS BGCs will enable refinement of BGC prediction algorithms to expand on the secondary metabolic potential of fungal and bacterial species. The identification of genes related to ICS BGCs in fungal species not previously known for secondary metabolite-producing capabilities (e.g., Saccharomyces spp.) contributes to our understanding of the evolution of BGC in fungi.
format	article
author	Fang Yun Lim Tae Hyung Won Nicholas Raffa Joshua A. Baccile Jen Wisecaver Antonis Rokas Frank C. Schroeder Nancy P. Keller
author_facet	Fang Yun Lim Tae Hyung Won Nicholas Raffa Joshua A. Baccile Jen Wisecaver Antonis Rokas Frank C. Schroeder Nancy P. Keller
author_sort	Fang Yun Lim
title	Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	fungal isocyanide synthases and xanthocillin biosynthesis in <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/b569dc18042d4c3798eb0e9cf656259d
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Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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