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Journal of Lipid Research, Vol. 50, S103-S108, April 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Metabolism

Discovery of new biosynthetic pathways: the lipid A story

Christian R. H. Raetz¹, Ziqiang Guan, Brian O. Ingram, David A. Six, Feng Song, Xiaoyuan Wang and Jinshi Zhao

Department of Biochemistry, Duke University Medical Center, P.O. Box 3711, Durham, NC 27710

This research is supported by the National Institutes of Health (NIH) grants GM-51310 and GM-51796 to C.R.H.R. The mass spectrometry facility in the Department of Biochemistry at the Duke University Medical Center is supported by the LIPID MAPS Large Scale Collaborative Grant GM-069338 from the NIH.

Published, JLR Papers in Press, October 29, 2008.

¹ To whom correspondence should be addressed. email: raetz{at}biochem.duke.edu

ABSTRACT

The outer monolayer of the outer membrane of Gram-negative bacteria consists of the lipid A component of lipopolysaccharide (LPS), a glucosamine-based saccharolipid that is assembled on the inner surface of the inner membrane. The first six enzymes of the lipid A pathway are required for bacterial growth and are excellent targets for the development of new antibiotics. Following assembly, the ABC transporter MsbA flips nascent LPS to the periplasmic side of the inner membrane, whereupon additional transport proteins direct it to the outer surface of the outer membrane. Depending on the bacterium, various covalent modifications of the lipid A moiety may occur during the transit of LPS to the outer membrane. These extra-cytoplasmic modification enzymes are therefore useful as reporters for monitoring LPS trafficking. Because of its conserved structure in diverse Gram-negative pathogens, lipid A is recognized as foreign by the TLR4/MD2 receptor of the mammalian innate immune system, resulting in rapid macrophage activation and robust cytokine production.

Supplementary key words Francisella tularensis • endotoxin • vaccine adjuvant

Abbreviations: GalN, galactosamine; IM, inner membrane; LPS, lipopolysaccharide; OM, outer membrane

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