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Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides.

ABSTRACT: Microviridins are ribosomally synthesized tricyclic depsipeptides produced by different genera of cyanobacteria. The prevalence of the microviridin gene clusters and the natural diversity of microviridin precursor sequences are currently unknown. Screening of laboratory strains and field samples of the bloom-forming freshwater cyanobacterium Microcystis via PCR revealed global occurrence of the microviridin pathway and an unexpected natural variety. We could detect 15 new variants of the precursor gene mdnA encoding microviridin backbones that differ in up to 4 amino acid positions from known isoforms of the peptide. The survey not only provides insights into the versatility of the biosynthetic enzymes in a closely related group of cyanobacteria, but also facilitates the discovery and characterization of cryptic microviridin variants. This is demonstrated for microviridin L in Microcystis aeruginosa strain NIES843 and heterologously produced variants.

SUBMITTER: Ziemert N

PROVIDER: S-EPMC2876452 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides.

Ziemert Nadine N Ishida Keishi K Weiz Annika A Hertweck Christian C Dittmann Elke E

Applied and environmental microbiology 20100402 11

Microviridins are ribosomally synthesized tricyclic depsipeptides produced by different genera of cyanobacteria. The prevalence of the microviridin gene clusters and the natural diversity of microviridin precursor sequences are currently unknown. Screening of laboratory strains and field samples of the bloom-forming freshwater cyanobacterium Microcystis via PCR revealed global occurrence of the microviridin pathway and an unexpected natural variety. We could detect 15 new variants of the precurs ...[more]

PMID: 20363789

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Project description:Natural microbial communities produce a diverse array of secondary metabolites with ecologically and biotechnologically relevant activities. Some of them have been used clinically as drugs, and their production pathways have been identified in a few culturable microorganisms. However, since the vast majority of microorganisms in nature have not been cultured, identifying the synthetic pathways of these metabolites and tracking their hosts remain a challenge. The microbial biosynthetic potential of mangrove swamps remains largely unknown. Here, we examined the diversity and novelty of biosynthetic gene clusters in dominant microbial populations in mangrove wetlands by mining 809 newly reconstructed draft genomes and probing the activities and products of these clusters by using metatranscriptomic and metabolomic techniques. A total of 3,740 biosynthetic gene clusters were identified from these genomes, including 1,065 polyketide and nonribosomal peptide gene clusters, 86% of which showed no similarity to known clusters in the Minimum Information about a Biosynthetic Gene Cluster (MIBiG) repository. Of these gene clusters, 59% were harbored by new species or lineages of Desulfobacterota-related phyla and Chloroflexota, whose members are highly abundant in mangrove wetlands and for which few synthetic natural products have been reported. Metatranscriptomics revealed that most of the identified gene clusters were active in field and microcosm samples. Untargeted metabolomics was also used to identify metabolites from the sediment enrichments, and 98% of the mass spectra generated were unrecognizable, further supporting the novelty of these biosynthetic gene clusters. Our study taps into a corner of the microbial metabolite reservoir in mangrove swamps, providing clues for the discovery of new compounds with valuable activities. IMPORTANCE At present, the majority of known clinical drugs originated from cultivated species of a few bacterial lineages. It is vital for the development of new pharmaceuticals to explore the biosynthetic potential of naturally uncultivable microorganisms using new techniques. Based on the large numbers of genomes reconstructed from mangrove wetlands, we identified abundant and diverse biosynthetic gene clusters in previously unsuspected phylogenetic groups. These gene clusters exhibited a variety of organizational architectures, especially for nonribosomal peptide synthetase (NRPS) and polyketide synthase (PKS), implying the presence of new compounds with valuable activities in the mangrove swamp microbiome.

Project description:UnlabelledIn the discovery of secondary metabolites, analysis of sequence data is a promising exploration path that remains largely underutilized due to the lack of computational platforms that enable such a systematic approach on a large scale. In this work, we present IMG-ABC (https://img.jgi.doe.gov/abc), an atlas of biosynthetic gene clusters within the Integrated Microbial Genomes (IMG) system, which is aimed at harnessing the power of "big" genomic data for discovering small molecules. IMG-ABC relies on IMG's comprehensive integrated structural and functional genomic data for the analysis of biosynthetic gene clusters (BCs) and associated secondary metabolites (SMs). SMs and BCs serve as the two main classes of objects in IMG-ABC, each with a rich collection of attributes. A unique feature of IMG-ABC is the incorporation of both experimentally validated and computationally predicted BCs in genomes as well as metagenomes, thus identifying BCs in uncultured populations and rare taxa. We demonstrate the strength of IMG-ABC's focused integrated analysis tools in enabling the exploration of microbial secondary metabolism on a global scale, through the discovery of phenazine-producing clusters for the first time in Alphaproteobacteria. IMG-ABC strives to fill the long-existent void of resources for computational exploration of the secondary metabolism universe; its underlying scalable framework enables traversal of uncovered phylogenetic and chemical structure space, serving as a doorway to a new era in the discovery of novel molecules.ImportanceIMG-ABC is the largest publicly available database of predicted and experimental biosynthetic gene clusters and the secondary metabolites they produce. The system also includes powerful search and analysis tools that are integrated with IMG's extensive genomic/metagenomic data and analysis tool kits. As new research on biosynthetic gene clusters and secondary metabolites is published and more genomes are sequenced, IMG-ABC will continue to expand, with the goal of becoming an essential component of any bioinformatic exploration of the secondary metabolism world.

Dataset Information

Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides.

Publications

Exploiting the natural diversity of microviridin gene clusters for discovery of novel tricyclic depsipeptides.

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