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Fungal Genet Biol. 2016 Apr;89:18-28. doi: 10.1016/j.fgb.2016.01.012. Epub 2016 Jan 22.

Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products.

Author information

1
Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States; Department of Bioengineering, Stanford University, Stanford, CA, United States.
2
Department of Chemistry, Haverford College, Haverford, PA, United States.
3
Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States.
4
Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, United States.
5
Department of Biology, Haverford College, Haverford, PA, United States.
6
Bioinformatics Group, Wageningen University, The Netherlands.
7
Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States. Electronic address: maureenh@stanford.edu.
8
Department of Chemistry, Haverford College, Haverford, PA, United States. Electronic address: lcharkou@haverford.edu.

Abstract

Microorganisms produce a wide range of natural products (NPs) with clinically and agriculturally relevant biological activities. In bacteria and fungi, genes encoding successive steps in a biosynthetic pathway tend to be clustered on the chromosome as biosynthetic gene clusters (BGCs). Historically, "activity-guided" approaches to NP discovery have focused on bioactivity screening of NPs produced by culturable microbes. In contrast, recent "genome mining" approaches first identify candidate BGCs, express these biosynthetic genes using synthetic biology methods, and finally test for the production of NPs. Fungal genome mining efforts and the exploration of novel sequence and NP space are limited, however, by the lack of a comprehensive catalog of BGCs encoding experimentally-validated products. In this study, we generated a comprehensive reference set of fungal NPs whose biosynthetic gene clusters are described in the published literature. To generate this dataset, we first identified NCBI records that included both a peer-reviewed article and an associated nucleotide record. We filtered these records by text and homology criteria to identify putative NP-related articles and BGCs. Next, we manually curated the resulting articles, chemical structures, and protein sequences. The resulting catalog contains 197 unique NP compounds covering several major classes of fungal NPs, including polyketides, non-ribosomal peptides, terpenoids, and alkaloids. The distribution of articles published per compound shows a bias toward the study of certain popular compounds, such as the aflatoxins. Phylogenetic analysis of biosynthetic genes suggests that much chemical and enzymatic diversity remains to be discovered in fungi. Our catalog was incorporated into the recently launched Minimum Information about Biosynthetic Gene cluster (MIBiG) repository to create the largest known set of fungal BGCs and associated NPs, a resource that we anticipate will guide future genome mining and synthetic biology efforts toward discovering novel fungal enzymes and metabolites.

KEYWORDS:

Biosynthetic gene cluster; Fungal metabolites; Genome mining; Manual curation; Natural product

PMID:
26808821
PMCID:
PMC4789092
DOI:
10.1016/j.fgb.2016.01.012
[Indexed for MEDLINE]
Free PMC Article

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