| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Li, Steven Thibodeaux, Christopher J. Wang, Kwo-kwang A. Metzger, Emily Lee, Jaeheon Hirota, Ryuichi Fudala, John Cioni, Joel P. Metcalf, William W. Labeda, David P. Van Der Donk, Wilfred A. Gao, Jiangtao Zhang, Jun Kai Doroghazi, James R. Su, Joleen Ju, Kou-san Evans, Bradley S. |
| Description |
Author Affiliation: Ju KS ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Gao J ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Doroghazi JR ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Wang KK ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Thibodeaux CJ ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Li S ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Metzger E ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Fudala J ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Su J ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Zhang JK ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Lee J ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Cioni JP ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Evans BS ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Hirota R ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Labeda DP ( Bacterial Foodborne Pathogens and Mycology Research, US Department of Agriculture, Agricultural Research Service, National Center for Agricultural Utilization Research, Peoria, IL 61604); van der Donk WA ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); Metcalf WW ( Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana, IL 61801); |
| Abstract |
Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed 'genome mining' as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N(5)-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
39 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-09-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Actinobacteria Chemistry Genetics Biological Products Drug Discovery Genome, Bacterial Genomics Phosphorous Acids Gene Library Molecular Sequence Data Sequence Analysis, DNA Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
