Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation

Je Won Park, Sung Ryeol Park, Keshav Kumar Nepal, Ah Reum Han, Yeon Hee Ban, Young Ji Yoo, Eun Ji Kim, Eui Min Kim, Dooil Kim, Jae Kyung Sohng, Yeo Joon Yoon

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Kanamycin is one of the most widely used antibiotics, yet its biosynthetic pathway remains unclear. Current proposals suggest that the kanamycin biosynthetic products are linearly related via single enzymatic transformations. To explore this system, we have reconstructed the entire biosynthetic pathway through the heterologous expression of combinations of putative biosynthetic genes from Streptomyces kanamyceticus in the non-aminoglycoside-producing Streptomyces venezuelae. Unexpectedly, we discovered that the biosynthetic pathway contains an early branch point, governed by the substrate promiscuity of a glycosyltransferase, that leads to the formation of two parallel pathways in which early intermediates are further modified. Glycosyltransferase exchange can alter flux through these two parallel pathways, and the addition of other biosynthetic enzymes can be used to synthesize known and new highly active antibiotics. These results complete our understanding of kanamycin biosynthesis and demonstrate the potential of pathway engineering for direct in vivo production of clinically useful antibiotics and more robust aminoglycosides.

Original languageEnglish
Pages (from-to)843-852
Number of pages10
JournalNature Chemical Biology
Volume7
Issue number11
DOIs
Publication statusPublished - 2011 Nov
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Park, J. W., Park, S. R., Nepal, K. K., Han, A. R., Ban, Y. H., Yoo, Y. J., Kim, E. J., Kim, E. M., Kim, D., Sohng, J. K., & Yoon, Y. J. (2011). Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation. Nature Chemical Biology, 7(11), 843-852. https://doi.org/10.1038/nchembio.671