title: Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products.
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.
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States; Department of Bioengineering, Stanford University, Stanford, CA, United States.
authors.forename: Yong Fuga
authors.initials: YF
authors.lastname: Li
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Kathleen J S
authors.initials: KJS
authors.lastname: Tsai
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States.
authors.forename: Colin J B
authors.initials: CJB
authors.lastname: Harvey
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States.
authors.forename: James Jian
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, United States.
authors.forename: Beatrice E
authors.initials: BE
authors.lastname: Ary
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Berlew
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Brenna L
authors.initials: BL
authors.lastname: Boehman
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: David M
authors.initials: DM
authors.lastname: Findley
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, United States.
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Friant
authors.affiliation: Department of Biology, Haverford College, Haverford, PA, United States.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Gardner
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Gould
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, United States.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Ha
authors.affiliation: Department of Biology, Haverford College, Haverford, PA, United States.
authors.forename: Brenna K
authors.initials: BK
authors.lastname: Lilley
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Emily L
authors.initials: EL
authors.lastname: McKinstry
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Saadia
authors.initials: S
authors.lastname: Nawal
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Parry
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Kristina W
authors.initials: KW
authors.lastname: Rothchild
authors.affiliation: Department of Chemistry, Bryn Mawr College, Bryn Mawr, PA, United States.
authors.forename: Samantha D
authors.initials: SD
authors.lastname: Silbert
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Tentilucci
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Alana M
authors.initials: AM
authors.lastname: Thurston
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Rebecca B
authors.initials: RB
authors.lastname: Wai
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States.
authors.forename: Raeka S
authors.initials: RS
authors.lastname: Aiyar
authors.affiliation: Bioinformatics Group, Wageningen University, The Netherlands.
authors.forename: Marnix H
authors.initials: MH
authors.lastname: Medema
authors.affiliation: Stanford Genome Technology Center, Stanford University, Palo Alto, CA, United States. Electronic address: maureenh@stanford.edu.
authors.forename: Maureen E
authors.initials: ME
authors.lastname: Hillenmeyer
authors.affiliation: Department of Chemistry, Haverford College, Haverford, PA, United States. Electronic address: lcharkou@haverford.edu.
authors.forename: Louise K
authors.initials: LK
authors.lastname: Charkoudian
mesh_terms: D000470:Alkaloids; D000595:Amino Acid Sequence; D001688:Biological Products; D053898:Biosynthetic Pathways / Q000235:genetics*; D019295:Computational Biology; D066289:Data Curation; D005658:Fungi / Q000235:genetics; D005800:Genes, Fungal; D016681:Genome, Fungal; D005810:Multigene Family; D010802:Phylogeny; D061065:Polyketides; D013729:Terpenes
chemical_list: D000470:Alkaloids; D001688:Biological Products; D061065:Polyketides; D013729:Terpenes
keywords: Biosynthetic gene cluster; Fungal metabolites; Genome mining; Manual curation; Natural product