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Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme.

ABSTRACT: Tenuazonic acid (TeA) is a well-known mycotoxin produced by various plant pathogenic fungi. However, its biosynthetic gene has been unknown to date. Here we identify the TeA biosynthetic gene from Magnaporthe oryzae by finding two TeA-inducing conditions of a low-producing strain. We demonstrate that TeA is synthesized from isoleucine and acetoacetyl-coenzyme A by TeA synthetase 1 (TAS1). TAS1 is a unique non-ribosomal peptide synthetase and polyketide synthase (NRPS-PKS) hybrid enzyme that begins with an NRPS module. In contrast to other NRPS/PKS hybrid enzymes, the PKS portion of TAS1 has only a ketosynthase (KS) domain and this domain is indispensable for TAS1 activity. Phylogenetic analysis classifies this KS domain as an independent clade close to type I PKS KS domain. We demonstrate that the TAS1 KS domain conducts the final cyclization step for TeA release. These results indicate that TAS1 is a unique type of NRPS-PKS hybrid enzyme.

SUBMITTER: Yun CS

PROVIDER: S-EPMC4640141 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme.

Yun Choong-Soo CS Motoyama Takayuki T Osada Hiroyuki H

Nature communications 20151027

Tenuazonic acid (TeA) is a well-known mycotoxin produced by various plant pathogenic fungi. However, its biosynthetic gene has been unknown to date. Here we identify the TeA biosynthetic gene from Magnaporthe oryzae by finding two TeA-inducing conditions of a low-producing strain. We demonstrate that TeA is synthesized from isoleucine and acetoacetyl-coenzyme A by TeA synthetase 1 (TAS1). TAS1 is a unique non-ribosomal peptide synthetase and polyketide synthase (NRPS-PKS) hybrid enzyme that begi ...[more]

PMID: 26503170

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Project description:NRPS-PKS is web-based software for analysing large multi-enzymatic, multi-domain megasynthases that are involved in the biosynthesis of pharmaceutically important natural products such as cyclosporin, rifamycin and erythromycin. NRPS-PKS has been developed based on a comprehensive analysis of the sequence and structural features of several experimentally characterized biosynthetic gene clusters. The results of these analyses have been organized as four integrated searchable databases for elucidating domain organization and substrate specificity of nonribosomal peptide synthetases and three types of polyketide synthases. These databases work as the backend of NRPS-PKS and provide the knowledge base for predicting domain organization and substrate specificity of uncharacterized NRPS/PKS clusters. Benchmarking on a large set of biosynthetic gene clusters has demonstrated that, apart from correct identification of NRPS and PKS domains, NRPS-PKS can also predict specificities of adenylation and acyltransferase domains with reasonably high accuracy. These features of NRPS-PKS make it a valuable resource for identification of natural products biosynthesized by NRPS/PKS gene clusters found in newly sequenced genomes. The training and test sets of gene clusters included in NRPS-PKS correlate information on 307 open reading frames, 2223 functional protein domains, 68 starter/extender precursors and their specific recognition motifs, and also the chemical structure of 101 natural products from four different families. NRPS-PKS is a unique resource which provides a user-friendly interface for correlating chemical structures of natural products with the domains and modules in the corresponding nonribosomal peptide synthetases or polyketide synthases. It also provides guidelines for domain/module swapping as well as site-directed mutagenesis experiments to engineer biosynthesis of novel natural products. NRPS-PKS can be accessed at http://www.nii.res.in/nrps-pks.html.

Project description:BACKGROUND:Filamentous fungi produce a vast amount of bioactive secondary metabolites (SMs) synthesized by e.g. hybrid polyketide synthase-nonribosomal peptide synthetase enzymes (PKS-NRPS; NRPS-PKS). While their domain structure suggests a common ancestor with other SM proteins, their evolutionary origin and dynamics in fungi are still unclear. Recent rational engineering approaches highlighted the possibility to reassemble hybrids into chimeras - suggesting molecular recombination as diversifying mechanism. RESULTS:Phylogenetic analysis of hybrids in 37 species - spanning 9 sections of Aspergillus and Penicillium chrysogenum - let us describe their dynamics throughout the genus Aspergillus. The tree topology indicates that three groups of PKS-NRPS as well as one group of NRPS-PKS hybrids developed independently from each other. Comparison to other SM genes lead to the conclusion that hybrids in Aspergilli have several PKS ancestors; in contrast, hybrids are monophyletic when compared to available NRPS genes - with the exception of a small group of NRPSs. Our analysis also revealed that certain NRPS-likes are derived from NRPSs, suggesting that the NRPS/NRPS-like relationship is dynamic and proteins can diverge from one function to another. An extended phylogenetic analysis including bacterial and fungal taxa revealed multiple ancestors of hybrids. Homologous hybrids are present in all sections which suggests frequent horizontal gene transfer between genera and a finite number of hybrids in fungi. CONCLUSION:Phylogenetic distances between hybrids provide us with evidence for their evolution: Large inter-group distances indicate multiple independent events leading to the generation of hybrids, while short intra-group distances of hybrids from different taxonomic sections indicate frequent horizontal gene transfer. Our results are further supported by adding bacterial and fungal genera. Presence of related hybrid genes in all Ascomycetes suggests a frequent horizontal gene transfer between genera and a finite diversity of hybrids - also explaining their scarcity. The provided insights into relations of hybrids and other SM genes will serve in rational design of new hybrid enzymes.

Dataset Information

Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme.

Publications

Biosynthesis of the mycotoxin tenuazonic acid by a fungal NRPS-PKS hybrid enzyme.

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