Journal
NATURE CHEMICAL BIOLOGY
Volume 8, Issue 9, Pages 791-797Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1040
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Funding
- Japan Society for the Promotion of Science (JSPS) [22688007]
- Industrial Technology Research Grant Program from the New Energy and Industrial Technology Development Organization of Japan
- JSPS [23108520]
- Grants-in-Aid for Scientific Research [22688007] Funding Source: KAKEN
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The streptothricin (ST) antibiotics, produced by Streptomyces bacteria, contain L-beta-lysine ((3S)-3,6-diaminohexanoic acid) oligopeptides as pendant chains. Here we describe three unusual nonribosomal peptide synthetases (NRPSs) involved in ST biosynthesis: ORF 5 (a stand-alone adenylation (A) domain), ORF 18 (containing thiolation (T) and condensation (C) domains) and ORF 19 (a stand-alone A domain). We demonstrate that ST biosynthesis begins with adenylation of L-beta-lysine by ORF 5, followed by transfer to the T domain of ORF 18. In contrast, L-beta-lysine molecules adenylated by ORF 19 are used to elongate an L-beta-lysine peptide chain on ORF 18, a reaction unexpectedly catalyzed by ORF 19 itself. Finally, the C domain of ORF 18 catalyzes the condensation of L-beta-lysine oligopeptides covalently bound to ORF 18 with a freely diffusible intermediate to release the ST products. These results highlight an unusual activity for an A domain and unique mechanisms of crosstalk within NRPS machinery.
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