期刊
ACS CHEMICAL BIOLOGY
卷 9, 期 10, 页码 2382-2392出版社
AMER CHEMICAL SOC
DOI: 10.1021/cb500438x
关键词
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资金
- National Institutes of Health [AI064184, AI76322, GM103655, GM106112]
- Welch Foundation [F-1155]
- Army Research Office [W911NF-12-1-0390]
- College of Natural Sciences at UT Austin
- Office of the Executive Vice President and Provost at UT Austin
- Institute for Cellular and Molecular Biology at UT Austin
- U.S. DOE [DE-AC02-06CH11357]
The current pandemic El Tor biotype of O1 Vibrio cholerae is resistant to polymyxins, whereas the previous pandemic strain of the classical biotype is polymyxin sensitive. The almEFG operon found in El Tor V. cholerae confers >100-fold resistance to polymyxins through the glycylation of lipopolysaccharide. Here, we present the mechanistic determination of initial steps in the AlmEFG pathway. We verify that AlmF is an aminoacyl carrier protein and identify AlmE as the enzyme required to activate AlmF as a functional carrier protein. A combination of structural information and activity assays was used to identify a pair of active site residues that are important for mediating AlmE glycine specificity. Overall, the structure of AlmE in complex with its glycyl-adenylate intermediate reveals that AlmE is related to Gram-positive D-alanine/D-alanyl carrier protein ligase, while the trio of proteins in the AlmEFG system forms a chemical pathway that resembles the division of labor in nonribosomal peptide synthetases.
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