Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in Aspergillus fumigatus

MBio
Fang Yun LimNancy P Keller

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) h...Continue Reading

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Citations

Apr 30, 2019·Natural Product Reports·Hai-Ning LyuWen-Bing Yin
Apr 26, 2019·International Journal of Molecular Sciences·Nicholas RaffaNancy P Keller
Dec 17, 2020·International Journal of Molecular Sciences·Christelle El Hajj AssafSophie Lorber
Jan 7, 2021·Natural Product Reports·Jiawang LiuYoucai Hu
Feb 18, 2021·Proceedings of the National Academy of Sciences of the United States of America·Nicholas RaffaNancy P Keller
Jun 30, 2019·Inorganic Chemistry·Elizabeth W Hunsaker, Katherine J Franz
Aug 17, 2021·Beilstein Journal of Organic Chemistry·Jana M BoysenFalk Hillmann
May 24, 2019·ACS Chemical Biology·Claudio GrecoNancy P Keller
Jul 2, 2021·Chemical Reviews·Alberto MassarottiGian Cesare Tron
Oct 13, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Matthias MisslingerHubertus Haas

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Methods Mentioned

BETA
PCR
Restriction digest
nuclear magnetic resonance
NMR

Software Mentioned

hmmsearch
HMMER3
BLAST
IQ
RAxML
TREE
SeqBuilder
MAFFT
antiSMASH
ALLseq

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