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J. Biol. Chem., Vol. 281, Issue 31, 21974-21987, August 4, 2006

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An Outer Membrane Enzyme Encoded by Salmonella typhimurium lpxR That Removes the 3'-Acyloxyacyl Moiety of Lipid A^*

C. Michael Reynolds, Anthony A. Ribeiro, Sara C. McGrath^¶, Robert J. Cotter^¶, Christian R. H. Raetz¹, and M. Stephen Trent^||2

From the Department of Biochemistry and Duke NMR Spectroscopy Center and Department of Radiology, Duke University Medical Center, Durham, North Carolina 27710, ^¶Middle Atlantic Mass Spectrometry Laboratory, Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ^||Department of Microbiology, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee 37614

The Salmonella and related bacteria modify the structure of the lipid A portion of their lipopolysaccharide in response to environmental stimuli. Some lipid A modifications are required for virulence and resistance to cationic antimicrobial peptides. We now demonstrate that membranes of Salmonella typhimurium contain a novel hydrolase that removes the 3'-acyloxyacyl residue of lipid A in the presence of 5 mM Ca²⁺. We have identified the gene encoding the S. typhimurium lipid A 3'-O-deacylase, designated lpxR, by screening an ordered S. typhimurium genomic DNA library, harbored in Escherichia coli K-12, for expression of Ca²⁺-dependent 3'-O-deacylase activity in membranes. LpxR is synthesized with an N-terminal type I signal peptide and is localized to the outer membrane. Mass spectrometry was used to confirm the position of lipid A deacylation in vitro and the release of the intact 3'-acyloxyacyl group. Heterologous expression of lpxR in the E. coli K-12 W3110, which lacks lpxR, resulted in production of significant amounts of 3'-O-deacylated lipid A in growing cultures. Orthologues of LpxR are present in the genomes of E. coli 0157:H7, Yersinia enterocolitica, Helicobacter pylori, and Vibrio cholerae. The function of LpxR is unknown, but it could play a role in pathogenesis because it might modulate the cytokine response of an infected animal.

Received for publication, April 12, 2006 , and in revised form, May 15, 2006.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) DQ272513 [GenBank] .

^* This research was funded by National Institutes of Health Grants AI-064184 (to M. S. T.), GM-51310 (to C. R. H. R.), and GM-64402 (to R. J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Department of Biochemistry, Duke University, Medical Center, P. O. Box 3711, Durham, NC 27710. Tel.: 919-684-5326; Fax: 919-684-8885; E-mail: raetz{at}biochem.duke.edu. ² To whom correspondence may be addressed. Tel.: 423-439-6293; Fax: 423-439-8044; E-mail: trentms{at}mail.etsu.edu.

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