Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships

Kathryn E. Bushley, B. Gillian Turgeon

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169 Scopus citations


Background. Nonribosomal peptide synthetases (NRPSs) are multimodular enzymes, found in fungi and bacteria, which biosynthesize peptides without the aid of ribosomes. Although their metabolite products have been the subject of intense investigation due to their life-saving roles as medicinals and injurious roles as mycotoxins and virulence factors, little is known of the phylogenetic relationships of the corresponding NRPSs or whether they can be ranked into subgroups of common function. We identified genes (NPS) encoding NRPS and NRPS-like proteins in 38 fungal genomes and undertook phylogenomic analyses in order to identify fungal NRPS subfamilies, assess taxonomic distribution, evaluate levels of conservation across subfamilies, and address mechanisms of evolution of multimodular NRPSs. We also characterized relationships of fungal NRPSs, a representative sampling of bacterial NRPSs, and related adenylating enzymes, including -aminoadipate reductases (AARs) involved in lysine biosynthesis in fungi. Results. Phylogenomic analysis identified nine major subfamilies of fungal NRPSs which fell into two main groups: one corresponds to NPS genes encoding primarily mono/bi-modular enzymes which grouped with bacterial NRPSs and the other includes genes encoding primarily multimodular and exclusively fungal NRPSs. AARs shared a closer phylogenetic relationship to NRPSs than to other acyl-adenylating enzymes. Phylogenetic analyses and taxonomic distribution suggest that several mono/bi-modular subfamilies arose either prior to, or early in, the evolution of fungi, while two multimodular groups appear restricted to and expanded in fungi. The older mono/bi-modular subfamilies show conserved domain architectures suggestive of functional conservation, while multimodular NRPSs, particularly those unique to euascomycetes, show a diversity of architectures and of genetic mechanisms generating this diversity. Conclusions. This work is the first to characterize subfamilies of fungal NRPSs. Our analyses suggest that mono/bi-modular NRPSs have more ancient origins and more conserved domain architectures than most multimodular NRPSs. It also demonstrates that the -aminoadipate reductases involved in lysine biosynthesis in fungi are closely related to mono/bi-modular NRPSs. Several groups of mono/bi-modular NRPS metabolites are predicted to play more pivotal roles in cellular metabolism than products of multimodular NRPSs. In contrast, multimodular subfamilies of NRPSs are of more recent origin, are restricted to fungi, show less stable domain architectures, and biosynthesize metabolites which perform more niche-specific functions than mono/bi-modular NRPS products. The euascomycete-only NRPS subfamily, in particular, shows evidence for extensive gain and loss of domains suggestive of the contribution of domain duplication and loss in responding to niche-specific pressures.

Original languageEnglish (US)
Article number26
JournalBMC evolutionary biology
Issue number1
StatePublished - 2010

Bibliographical note

Funding Information:
BGT acknowledges, with gratitude, the US Department of Energy Joint Genome Institute (JGI) for their fungal genome program, in particular, for their support in generating the sequence of race O, strain C5, of Cochliobolus heterostrophus home.html. BGT and KEB are especially grateful to D. Schneider (USDA ARS) for helpful discussions and for providing computer resources for phylogenetic and other analyses. KEB would like to thank J. Doyle, S. Kroken, and A. Siepel for discussions of phylogenetic analyses, J. Stajich and M. Hahn for discussions of ultrametric tree construction and birth-death analyses, and the Cornell Computational Biology Service Unit facility and staff, A. Siepel, K. Nixon, and the CIPRES project for computer resources for phylogenetic and other computational analyses. BGT acknowledges the support of the Division of Molecular and Cellular Biosciences, National Science Foundation, the USDA Cooperative State Research Education and Extension Service, National Research Initiative and the BARD foundation.


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