Two N-acyltransferases and Diversity of Lipid A Acylation in Francisella
Open AccessLipopolysaccharide (LPS) is the major constituent on the outer membrane of Gram negative bacteria. LPS is made up of a polysaccharide outer domain (O antigen), attached to a core oligosaccharide anchored in the membrane by lipid A. Lipid A is also the component of LPS responsible for endotoxin activity. Gram-negative bacteria have multiple mechanisms for modifying their lipid A structures to promote survival and pathogenesis. Francisella maintains two copies of LpxD, the third enzyme in the Raetz pathway, in order to remodel its overall lipid A content. LpxD adds N-linked acyl chains to the 2- and 2'- position of lipid A. At host temperatures (37°C), LpxD1 adds 18C acyl chains, while at environmental temperatures (18C°) LpxD2 adds C16 acyl chains. In this work, both LpxDs from Francisella have been purified for crystallography studies to determine the structure of each enzyme. Additionally, amino acid residues proposed to be involved in the specificity of the acyl chains incorporated on lipid A have been identified and evaluated through site directed mutagenesis. Residues N289 and A287 in LpxD1 were mutated to methionines and at 37°C produced structures suggesting the incorporation of shorter acyl chains.
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