Phospholipids are a diverse class of amphipathic molecules present in all biological membranes. Because of the difficulties encountered in working with membrane components, little is known about the enzymatic and genetic control of phospholipid metabolism, or about the role of individual phospholipid species in membrane function. A greater understanding of this aspect of membrane biochemistry would be desirable, since phospholipids play a role in many disease processes, including hyperlipoproteinemias, sphingolipidoses and diabetes. The isolation and characterization of mutants lacking specific lipid molecules are the major goals of this project. The identification of genes that code for the enzymes involved in the synthesis and assembly of membrane lipids has rceived very little attention. Even in a simple organism like E. coli there must be 100-200 of such genes. At best, one-third of these have been identified. In the coming grant period, there will be three major areas of emphasis. 1) The enzymatic synthesis of the lipid A component of lipopolysaccharide will be elucidated. The P.I.'s recent discovery of the novel lipids 2, 3-diacyl-glucosamine 1-phosphate and UDP-2, 3-diacylglucosamine in E. coli pgsB mutants forms the basis for this effort. 2) Mutants in the biogenesis of lipid A will be isolated as the enzymatic studies unfold. Colony autoradiography techniques previously developed for isolation of mutants in phospholipid synthesis will be used for this purpose. 3) The control of membrane lipid biogenesis - especially the partitioning of chloroform-soluble nucleotides into different pathways -will be examined with genetic and biochemical techniques. The elucidation of lipid A biosynthesis in the context of recent revisions of its covalent structure are of special medical significance, since lipid A is responsible for endotoxic shock associated with Gram-negative sepsis and it has many important effects on the immune system.
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