Complete reconstitution of the diverse pathways of gentamicin B biosynthesis

Yeon Hee Ban, Myoung Chong Song, Jae yeon Hwang, Hea lyung Shin, Hak Joong Kim, Seung Kon Hong, Na Joon Lee, Je Won Park, Sun Shin Cha, Hung wen Liu, Yeo Joon Yoon

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
JournalNature Chemical Biology
DOIs
Publication statusAccepted/In press - 2019 Jan 1

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Aminoglycosides
Amination
Substrate Specificity
Micromonospora
Glycosyltransferases
Deamination
Nonsense Codon
Biosynthetic Pathways
Enzymes
Drug Discovery
Transaminases
gentamicin B
Anti-Bacterial Agents
Gene Expression

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Ban, Y. H., Song, M. C., Hwang, J. Y., Shin, H. L., Kim, H. J., Hong, S. K., ... Yoon, Y. J. (Accepted/In press). Complete reconstitution of the diverse pathways of gentamicin B biosynthesis. Nature Chemical Biology. https://doi.org/10.1038/s41589-018-0203-4

Complete reconstitution of the diverse pathways of gentamicin B biosynthesis. / Ban, Yeon Hee; Song, Myoung Chong; Hwang, Jae yeon; Shin, Hea lyung; Kim, Hak Joong; Hong, Seung Kon; Lee, Na Joon; Park, Je Won; Cha, Sun Shin; Liu, Hung wen; Yoon, Yeo Joon.

In: Nature Chemical Biology, 01.01.2019.

Research output: Contribution to journalArticle

Ban, Yeon Hee ; Song, Myoung Chong ; Hwang, Jae yeon ; Shin, Hea lyung ; Kim, Hak Joong ; Hong, Seung Kon ; Lee, Na Joon ; Park, Je Won ; Cha, Sun Shin ; Liu, Hung wen ; Yoon, Yeo Joon. / Complete reconstitution of the diverse pathways of gentamicin B biosynthesis. In: Nature Chemical Biology. 2019.
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