The biosynthesis and function of membrane lipids have been the subject of intense research in the last ten years because of their important role in signal transduction Our laboratory has devised general autoradiographic screens for detecting bacterial or animal cell mutants defective in specific enzymes of lipid synthesis. We have discovered 20 genes in E. coli that are required for membrane lipid assembly. We are also studying mutants of animal cells that lack specific phospholipids secondary to defects in peroxisome formation. Our most intriguing discovery has been the recognition of a new family of glucosamine-based lipids in E. coli.
Endotoxins also play an important role in the pathogenesis of gram-negative infections.
We are especially interested in the mechanism and extraordinary potency of endotoxins as activators of cytokine synthesis in macrophages. We have elucidated the key enzymatic steps of endotoxin biosynthesis and are now exploring the molecular biology of the endotoxin system in bacteria with sequenced genomes. The endotoxin pathway is a target for the development of new antibiotics. Students participate in all aspects of the research projects. Current student projects include work on the active site of LpxA, the regulation of LpxC, the response of the lipid A pathway to cold shock, the expression cloning of novel genes involved in the later stages of the pathway, and the synthesis and reactivity of new lipid A affinity reagents.