The long-term goal of the research is to understand the biochemical and genetic mechanisms that regulate membrane lipid biosynthesis in Escherichia coli. Fatty acid and phospholipid synthesis is a vital facet of bacterial physiology that is tightly regulated at several levels. The enzymes have been identified, their genes have been located and cloned, and their placement within the biosynthetic pathway determined. The three major challenges in the field are: a) to precisely define the physiological role for each pathway enzyme and isozyme, and to understand how their activities are regulated; b) to determine how the overall pathway activity is regulated and coordinated with major branches of intermediary metabolism; and c) to determine how expression of individual genes are modulated to transcribe the correct proportion of pathway enzymes. Dr. Rock and his colleagues have developed several important leads in each of these areas that form the cornerstones of the proposal. First, they have identified two key enzymes in the fatty acid biosynthetic pathway that are modulated by acyl-acyl carrier protein (ACP). Second, they found the glycerol-phosphate acyltransferase (plsB) to be regulated by the intracellular concentration of guanosine-3`-diphosphate-5`-diphosphate, and is envisioned as a sensor that coordinates fatty acid and phospholipid production with macromolecular biosynthesis. Third, they have verified that the ratio of the fabA and fabB gene products is a key element governing the proportion of unsaturated fatty acids produced by the pathway and have preliminary data that the expression of these two genes is coordinately regulated. The research plan will build on these advances and is organized around three specific aims: 1) To verify the proposed role of acyl-ACP and its target enzymes in the regulation of fatty acid biosynthesis; 2) To substantiate the role of the glycerol-phosphate acyltransferase system in the regulation of fatty acid and phospholipid biosynthesis; 3) To define biochemical and transcriptional mechanisms that regulate unsaturated fatty acid biosynthesis. The investigation of lipid synthesis in E. coli is a paradigm for the study of lipid metabolism in more advanced organisms, and recent results show that the fatty acid synthetic pathway is an important target for antimicrobial chemotherapy.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Microbial Physiology and Genetics Subcommittee 2 (MBC)
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St. Jude Children's Research Hospital
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Yao, Jiangwei; Rock, Charles O (2018) Therapeutic Targets in Chlamydial Fatty Acid and Phospholipid Synthesis. Front Microbiol 9:2291
Honsa, Erin S; Cooper, Vaughn S; Mhaissen, Mohammed N et al. (2017) RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host. MBio 8:
Robertson, Rosanna M; Yao, Jiangwei; Gajewski, Stefan et al. (2017) A two-helix motif positions the lysophosphatidic acid acyltransferase active site for catalysis within the membrane bilayer. Nat Struct Mol Biol 24:666-671
Arensdorf, Angela M; Dillard, Miriam E; Menke, Jacob M et al. (2017) Sonic Hedgehog Activates Phospholipase A2 to Enhance Smoothened Ciliary Translocation. Cell Rep 19:2074-2087
Ericson, Megan E; Subramanian, Chitra; Frank, Matthew W et al. (2017) Role of Fatty Acid Kinase in Cellular Lipid Homeostasis and SaeRS-Dependent Virulence Factor Expression in Staphylococcus aureus. MBio 8:
Yao, Jiangwei; Rock, Charles O (2017) Bacterial fatty acid metabolism in modern antibiotic discovery. Biochim Biophys Acta Mol Cell Biol Lipids 1862:1300-1309
Yao, Jiangwei; Rock, Charles O (2017) Exogenous fatty acid metabolism in bacteria. Biochimie 141:30-39
Subramanian, Chitra; Yun, Mi-Kyung; Yao, Jiangwei et al. (2016) Allosteric Regulation of Mammalian Pantothenate Kinase. J Biol Chem 291:22302-22314
Yao, Jiangwei; Rock, Charles O (2016) Resistance Mechanisms and the Future of Bacterial Enoyl-Acyl Carrier Protein Reductase (FabI) Antibiotics. Cold Spring Harb Perspect Med 6:a027045
Broussard, Tyler C; Miller, Darcie J; Jackson, Pamela et al. (2016) Biochemical Roles for Conserved Residues in the Bacterial Fatty Acid-binding Protein Family. J Biol Chem 291:6292-303

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