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Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes.

ABSTRACT: Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as an S-adenosylmethionine-dependent ?-N-methyltransferase that converts phomopsin A to an N,N-dimethylated congener (phomopsin E), and show that the methyltransferases involved in dikaritin biosynthesis have evolved differently and likely have broad substrate specificities. Genome mining studies identified eight previously unknown dikaritins in different strains, highlighting the untapped capacity of RiPP biosynthesis in fungi and setting the stage for investigating the biological activities and unknown biosynthetic transformations of this family of fungal natural products.

SUBMITTER: Ding W

PROVIDER: S-EPMC4822579 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes.

Ding Wei W Liu Wan-Qiu WQ Jia Youli Y Li Yongzhen Y van der Donk Wilfred A WA Zhang Qi Q

Proceedings of the National Academy of Sciences of the United States of America 20160315 13

Production of ribosomally synthesized and posttranslationally modified peptides (RiPPs) has rarely been reported in fungi, even though organisms of this kingdom have a long history as a prolific source of natural products. Here we report an investigation of the phomopsins, antimitotic mycotoxins. We show that phomopsin is a fungal RiPP and demonstrate the widespread presence of a pathway for the biosynthesis of a family of fungal cyclic RiPPs, which we term dikaritins. We characterize PhomM as a ...[more]

PMID: 26979951

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Project description:Ribosomally synthesized and Post-translationally modified Peptides (RiPPs) take advantage of the ribosomal translation machinery to generate linear peptides that are subsequently modified with heterocycles and/or macrocycles to impose three-dimensional structure and thwart degradation by proteases. Although RiPP precursors are limited to proteinogenic amino acids, post-translational modifications (PTMs) can alter the structure of individual amino acids and thereby improve the stability and biological activity of the molecule. These "tailoring modifications" often occur on amino acid side chains-for example, hydroxylation, methylation, halogenation, prenylation, and acylation-but can also take place within the backbone, as in epimerization, or can result in capping of the N- or C-terminus. At one extreme, these modifications can be essential to the activity of the RiPP, either as a compulsory step in reaching the final molecule or by imparting chemical functionality required for biological activity. At the other extreme, tailoring PTMs may have little effect on the activity in an in vitro setting-possibly because of test conditions that do not match the biological context in which the PTMs evolved. Establishing the molecular basis for the function of tailoring PTMs often requires a three-dimensional structure of the RiPP bound to its biological target. These structures have revealed roles for tailoring PTMs that include providing additional hydrogen bonds to targets, rigidifying the RiPP structure to reduce the entropic cost of binding, or altering the secondary structure of the peptide backbone. Bacterial RiPPs are particularly suited to structural characterization, as they are relatively easy to isolate from laboratory cultures or to produce in a heterologous host. The identification of new tailoring PTMs within bacteria is also facilitated by clustering of the genes encoding tailoring enzymes with those of the RiPP precursor and primary modification enzymes. In this Account, we describe the effects of tailoring PTMs on RiPP structure, their interactions with biological targets, and their influence on RiPP stability, with a focus on bacterial RiPP classes. We also discuss the enzymes that generate tailoring PTMs and highlight examples of and prospects for engineering of RiPPs.

Dataset Information

Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes.

Publications

Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes.

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