期刊
JOURNAL OF ANTIBIOTICS
卷 67, 期 1, 页码 89-97出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ja.2013.125
关键词
assembly line; orphan antibiotics; polyketide synthase
资金
- National Institutes of Health [R01 GM087936, P01 HG000205]
- Stanford Institute for Immunity, Transplantation, and Infection
- National Institute of General Medical Sciences Postdoctoral Fellowship [GM103165-01A1]
- Burroughs Wellcome Fund
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [P01HG000205] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM103165, R01GM087934] Funding Source: NIH RePORTER
The increasing availability of DNA sequence data offers an opportunity for identifying new assembly-line polyketide synthases (PKSs) that produce biologically active natural products. We developed an automated method to extract and consolidate all multimodular PKS sequences (including hybrid PKS/non-ribosomal peptide synthetases) in the National Center for Biotechnology Information (NCBI) database, generating a non-redundant catalog of 885 distinct assembly-line PKSs, the majority of which were orphans associated with no known polyketide product. Two in silico experiments highlight the value of this search method and resulting catalog. First, we identified an orphan that could be engineered to produce an analog of albocycline, an interesting antibiotic whose gene cluster has not yet been sequenced. Second, we identified and analyzed a hitherto overlooked family of metazoan multimodular PKSs, including one from Caenorhabditis elegans. We also developed a comparative analysis method that identified sequence relationships among known and orphan PKSs. As expected, PKS sequences clustered according to structural similarities between their polyketide products. The utility of this method was illustrated by highlighting an interesting orphan from the genus Burkholderia that has no close relatives. Our search method and catalog provide a community resource for the discovery of new families of assembly-line PKSs and their antibiotic products.
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