Complete reconstitution of the diverse pathways of gentamicin B biosynthesis
- 등재 SCIE, SCOPUS
- OA유형 Green Accepted
- 발행기관 Nature Publishing Group
- 발행년도 2019
- URI http://www.dcollection.net/handler/ewha/000000160769
- 본문언어 영어
- Published As http://dx.doi.org/10.1038/s41589-018-0203-4
- PubMed https://pubmed.ncbi.nlm.nih.gov/30643280
- 저작권 이화여자대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Gentamicin B (GB), a valuable starting material for the preparation of the semisynthetic aminoglycoside antibiotic isepamicin, is produced in trace amounts by the wild-type Micromonospora echinospora. Though the biosynthetic pathway to GB has remained obscure for decades, we have now identified three hidden pathways to GB production via seven hitherto unknown intermediates in M. echinospora. The narrow substrate specificity of a key glycosyltransferase and the C6′-amination enzymes, in combination with the weak and unsynchronized gene expression of the 2′-deamination enzymes, limits GB production in M. echinospora. The crystal structure of the aminotransferase involved in C6′-amination explains its substrate specificity. Some of the new intermediates displayed similar premature termination codon readthrough activity but with reduced toxicity compared to the natural aminoglycoside G418. This work not only led to the discovery of unknown biosynthetic routes to GB, but also demonstrated the potential to mine new aminoglycosides from nature for drug discovery. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
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