Identification of the First Diketomorpholine Biosynthetic Pathway Using FAC-MS Technology
Filamentous fungi are prolific producers of secondary metabolites with drug-like properties, and their genome sequences have revealed an untapped wealth of potential therapeutic leads. To better access these secondary metabolites and characterize their biosynthetic gene clusters, we applied a new pl...
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Published in | ACS chemical biology Vol. 13; no. 5; pp. 1142 - 1147 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Chemical Society
18.05.2018
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Online Access | Get full text |
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Summary: | Filamentous fungi are prolific producers of secondary metabolites with drug-like properties, and their genome sequences have revealed an untapped wealth of potential therapeutic leads. To better access these secondary metabolites and characterize their biosynthetic gene clusters, we applied a new platform for screening and heterologous expression of intact gene clusters that uses fungal artificial chromosomes and metabolomic scoring (FAC-MS). We leverage FAC-MS technology to identify the biosynthetic machinery responsible for production of acu-dioxomorpholine, a metabolite produced by the fungus, Aspergilllus aculeatus. The acu-dioxomorpholine nonribosomal peptide synthetase features a new type of condensation domain (designated CR) proposed to use a noncanonical arginine active site for ester bond formation. Using stable isotope labeling and MS, we determine that a phenyllactate monomer deriving from phenylalanine is incorporated into the diketomorpholine scaffold. Acu-dioxomorpholine is highly related to orphan inhibitors of P-glycoprotein targets in multidrug-resistant cancers, and identification of the biosynthetic pathway for this compound class enables genome mining for additional derivatives. |
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Bibliography: | SourceType-Other Sources-1 ObjectType-Article-2 content type line 63 ObjectType-Correspondence-1 Paul M. Thomas: 0000-0003-2887-4765 ORCID Nancy P. Keller: 0000-0002-4386-9473 Neil L. Kelleher: 0000-0002-8815-3372 |
ISSN: | 1554-8929 1554-8937 |
DOI: | 10.1021/acschembio.8b00024 |