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A proteomics approach to discovering natural products and their biosynthetic pathways.

ABSTRACT: Many natural products with antibiotic, anticancer and antifungal properties are synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Although genome sequencing has revealed the diversity of these enzymes, identifying new products and their biosynthetic pathways remains challenging. By taking advantage of the size of these enzymes (often >2,000 amino acids) and unique marker ions derived from their common phosphopantetheinyl cofactor, we adapted mass spectrometry-based proteomics to selectively detect NRPS and PKS gene clusters in microbial proteomes without requiring genome sequence information. We detected known NRPS systems in members of the genera Bacillus and Streptomyces, and screened 22 environmental isolates to uncover production of unknown natural products from the hybrid NRPS-PKS zwittermicin A biosynthetic gene cluster. We also discovered an NRPS cluster that generates a seven-residue lipopeptide. This 'protein-first' strategy complements bioassay- and sequence-based approaches by finding expressed gene clusters that produce new natural products.

SUBMITTER: Bumpus SB

PROVIDER: S-EPMC2782881 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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A proteomics approach to discovering natural products and their biosynthetic pathways.

Bumpus Stefanie B SB Evans Bradley S BS Thomas Paul M PM Ntai Ioanna I Kelleher Neil L NL

Nature biotechnology 20090920 10

Many natural products with antibiotic, anticancer and antifungal properties are synthesized by nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). Although genome sequencing has revealed the diversity of these enzymes, identifying new products and their biosynthetic pathways remains challenging. By taking advantage of the size of these enzymes (often >2,000 amino acids) and unique marker ions derived from their common phosphopantetheinyl cofactor, we adapted mass spectromet ...[more]

PMID: 19767731

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Project description:Microbes host a huge variety of biosynthetic gene clusters that produce an immeasurable array of secondary metabolites with many different biological activities such as antimicrobial, anticarcinogenic and antiviral. Despite the complex task of isolating and characterizing novel natural products, microbial genomic strategies can be useful for carrying out these types of studies. However, although genomic-based research on secondary metabolism is on the increase, there is still a lack of reports focusing specifically on the genus Pseudomonas. In this work, we aimed (i) to unveil the main biosynthetic systems related to secondary metabolism in Pseudomonas type strains, (ii) to study the evolutionary processes that drive the diversification of their coding regions and (iii) to select Pseudomonas strains showing promising results in the search for useful natural products. We performed a comparative genomic study on 194 Pseudomonas species, paying special attention to the evolution and distribution of different classes of biosynthetic gene clusters and the coding features of antimicrobial peptides. Using EvoMining, a bioinformatic approach for studying evolutionary processes related to secondary metabolism, we sought to decipher the protein expansion of enzymes related to the lipid metabolism, which may have evolved toward the biosynthesis of novel secondary metabolites in Pseudomonas. The types of metabolites encoded in Pseudomonas type strains were predominantly non-ribosomal peptide synthetases, bacteriocins, N-acetylglutaminylglutamine amides and ß-lactones. Also, the evolution of genes related to secondary metabolites was found to coincide with Pseudomonas species diversification. Interestingly, only a few Pseudomonas species encode polyketide synthases, which are related to the lipid metabolism broadly distributed among bacteria. Thus, our EvoMining-based search may help to discover new types of secondary metabolite gene clusters in which lipid-related enzymes are involved. This work provides information about uncharacterized metabolites produced by Pseudomonas type strains, whose gene clusters have evolved in a species-specific way. Our results provide novel insight into the secondary metabolism of Pseudomonas and will serve as a basis for the prioritization of the isolated strains. This article contains data hosted by Microreact.

Dataset Information

A proteomics approach to discovering natural products and their biosynthetic pathways.

Publications

A proteomics approach to discovering natural products and their biosynthetic pathways.

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