title: Evolution of Chemical Diversity in Echinocandin Lipopeptide Antifungal Metabolites.
abstract: The echinocandins are a class of antifungal drugs that includes caspofungin, micafungin, and anidulafungin. Gene clusters encoding most of the structural complexity of the echinocandins provided a framework for hypotheses about the evolutionary history and chemical logic of echinocandin biosynthesis. Gene orthologs among echinocandin-producing fungi were identified. Pathway genes, including the nonribosomal peptide synthetases (NRPSs), were analyzed phylogenetically to address the hypothesis that these pathways represent descent from a common ancestor. The clusters share cooperative gene contents and linkages among the different strains. Individual pathway genes analyzed in the context of similar genes formed unique echinocandin-exclusive phylogenetic lineages. The echinocandin NRPSs, along with the NRPS from the inp gene cluster in Aspergillus nidulans and its orthologs, comprise a novel lineage among fungal NRPSs. NRPS adenylation domains from different species exhibited a one-to-one correspondence between modules and amino acid specificity that is consistent with models of tandem duplication and subfunctionalization. Pathway gene trees and Ascomycota phylogenies are congruent and consistent with the hypothesis that the echinocandin gene clusters have a common origin. The disjunct Eurotiomycete-Leotiomycete distribution appears to be consistent with a scenario of vertical descent accompanied by incomplete lineage sorting and loss of the clusters from most lineages of the Ascomycota. We present evidence for a single evolutionary origin of the echinocandin family of gene clusters and a progression of structural diversification in two fungal classes that diverged approximately 290 to 390 million years ago. Lineage-specific gene cluster evolution driven by selection of new chemotypes contributed to diversification of the molecular functionalities.
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Yue
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Kuan
authors.initials: K
authors.lastname: Li
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jingzu
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xingzhong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA zhiqiang.an@uth.tmc.edu gerald.f.bills@uth.tmc.edu.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: An
authors.affiliation: Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA zhiqiang.an@uth.tmc.edu gerald.f.bills@uth.tmc.edu.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Bills
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism*; D001203:Ascomycota / Q000502:physiology*; D001688:Biological Products / Q000378:metabolism*; D054714:Echinocandins / Q000378:metabolism*; D019143:Evolution, Molecular; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D016681:Genome, Fungal; D005810:Multigene Family; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D010802:Phylogeny
chemical_list: D000935:Antifungal Agents; D001688:Biological Products; D054714:Echinocandins; D005656:Fungal Proteins; D010453:Peptide Synthases; C104385:non-ribosomal peptide synthase