Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation

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Title
Discovery of parallel pathways of kanamycin biosynthesis allows antibiotic manipulation
Author(s)
J W Park; S R Park; K K Nepal; A R Han; Y H Ban; Y J Yoo; E J Kim; E M Kim; Doo-Il Kim; J K Sohng; Y J Yoon
Bibliographic Citation
Nature Chemical Biology, vol. 7, no. 11, pp. 843-852
Publication Year
2011
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.
ISSN
1552-4450
Publisher
Springer-Nature Pub Group
DOI
http://dx.doi.org/10.1038/nchembio.671
Type
Article
Appears in Collections:
1. Journal Articles > Journal Articles
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