期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 6, 页码 1340-1345出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1711603115
关键词
aminoglycoside biosynthesis; methyltransferase; antibiotic; metabolic engineering
资金
- National Natural Science Foundation of China [31470186]
- 973 Program from the Ministry of Science and Technology of China [2012CB721005]
- Open Project from the State Key Laboratory of Microbial Metabolism, Shanghai Jiao Tong University [MMLKF15-12]
- Medical Research Council (MRC) [G1001687, MR/M019020/1]
- MRC postgraduate studentship [1343325]
- Medical Research Council [G1001687, 1343325, MR/M019020/1] Funding Source: researchfish
- MRC [G1001687, MR/M019020/1] Funding Source: UKRI
Gentamicin C complex from Micromonospora echinospora remains a globally important antibiotic, and there is revived interest in the semisynthesis of analogs that might show improved therapeutic properties. The complex consists of five components differing in their methylation pattern at one or more sites in the molecule. We show here, using specific gene deletion and chemical complementation, that the gentamicin pathway up to the branch point is defined by the selectivity of the methyltransferases GenN, GenD1, and GenK. Unexpectedly, they comprise a methylation network in which early intermediates are ectopically modified. Using whole-genome sequence, we have also discovered the terminal 6'-N-methyltransfer required to produce gentamicin C2b from C1a or gentamicin C1 from C2, an example of an essential biosynthetic enzyme being located not in the biosynthetic gene cluster but far removed on the chromosome. These findings fully account for the methylation pattern in gentamicins and open the way to production of individual gentamicins by fermentation, as starting materials for semisynthesis.
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