Metabologenomics: Correlation of Microbial Gene Clusters with Metabolites Drives Discovery of a Nonribosomal Peptide with an Unusual Amino Acid Monomer
| Autor: | Nicole A. Haverland, Neil L. Kelleher, James R. Doroghazi, Kou San Ju, Anthony W. Goering, Jessica C. Albright, Yongbo Zhang, Ryan A. McClure, William W. Metcalf, Regan J. Thomson |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Natural product 010405 organic chemistry General Chemical Engineering General Chemistry Bacterial genome size Biology 01 natural sciences Genome 0104 chemical sciences 3. Good health Amino acid lcsh:Chemistry 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology Monomer Metabolomics lcsh:QD1-999 chemistry Biochemistry Nonribosomal peptide Gene Research Article |
| Zdroj: | ACS Central Science, Vol 2, Iss 2, Pp 99-108 (2016) ACS Central Science |
| ISSN: | 2374-7951 2374-7943 |
| Popis: | For more than half a century the pharmaceutical industry has sifted through natural products produced by microbes, uncovering new scaffolds and fashioning them into a broad range of vital drugs. We sought a strategy to reinvigorate the discovery of natural products with distinctive structures using bacterial genome sequencing combined with metabolomics. By correlating genetic content from 178 actinomycete genomes with mass spectrometry-enabled analyses of their exported metabolomes, we paired new secondary metabolites with their biosynthetic gene clusters. We report the use of this new approach to isolate and characterize tambromycin, a new chlorinated natural product, composed of several nonstandard amino acid monomeric units, including a unique pyrrolidine-containing amino acid we name tambroline. Tambromycin shows antiproliferative activity against cancerous human B- and T-cell lines. The discovery of tambromycin via large-scale correlation of gene clusters with metabolites (a.k.a. metabologenomics) illuminates a path for structure-based discovery of natural products at a sharply increased rate. By correlating metabolite profiles for hundreds of soil bacteria with their interpreted genomes, the gene cluster encoding a new peptide natural product was identified—which included genes that produce a new amino acid (tambroline). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|