The cellular envelope is the first layer of defense protecting the cell from the hostilities of the surrounding environment. In order to thrive in their ever-changing environmental conditions, bacteria have developed mechanisms to adapt the biochemical properties of their membranes in response to environmental cues. Aminoacyl-phosphatidylglycerol synthases (aaPGSs) are integral membrane proteins responsible for the biosynthesis of aminoacyl-phosphatidylglycerol (aa-PG) in the cytoplasmic membrane of various bacteria. These enzymes divert several aminoacyl-tRNAs (aa-tRNAs) from their normal use in protein biosynthesis and utilize the amino acids of these charged tRNAs for the modification of the polar head of the phosphatidylglycerol (PG) constituting the cytoplasmic membrane. Addition of amino acids to the glycerol moiety of PG decreases the net negative charge of the membrane, thereby lowering the cellular permeability to cationic molecules and altering the physiological properties of the bacterial envelope. In Staphylococcus aureus, lysylated PG confers resistance to cationic antibacterial agents such as the pore forming peptides produced by the innate immune response during host infection (e.g., defensins produced by human neutrophils), and provides resistance to several other cationic antimicrobials (i.e., aminoglycosides, betalactamines and glycopeptides). aa-PGs not only provide bacteria with resistance to cationic antimicrobial agents and host defenses during infection, but also to other environmental stressors such as those encountered during extreme osmotic or acidic conditions.
Understanding the mechanisms of cell membrane permeation by antibiotics and the strategies utilized by bacteria to resist these antibiotics is crucial for the design of antimicrobial agents that target not only aaPGSs and their regulatory mechanisms, but also individual components of the remodeled membrane. The focus of our research is to define the structure-function relationship of aaPGS family members from a variety of microorganisms and to determine the extent of the different amino acids utilized by these enzymes for lipid modification. These studies will provide insight into the biological significance of aa-PGs and the role of these modified lipids in bacterial pathogenicity and environmental adaptation.
Recent publications:
  1. Yakobov N, Mahmoudi N, Grob G, Yokokawa D, Saga Y, Kushiro T, Worrell D, Roy H, Schaller H, Senger B, Huck L, Riera Gascon G, Becker HD, Fischer F. RNA-dependent synthesis of ergosteryl-3beta-O-glycine in Ascomycota expands the diversity of steryl-amino acids. J Biol Chem. 2022;298(3):101657; PMCID: PMC8913301.
  2. Grube CD, Gill CP, Roy H. Development of a continuous assay for high throughput screening to identify inhibitors of the purine salvage pathway in Plasmodium falciparum. SLAS Discov. 2022;27(2):114-20.
  3. Yokokawa D, Tatematsu S, Takagi R, Saga Y, Roy H, Fischer F, Becker HD, Kushiro T. Synthesis of aminoacylated ergosterols: A new lipid component of fungi. Steroids. 2021;169:108823.
  4. Yakobov N, Fischer F, Mahmoudi N, Saga Y, Grube CD, Roy H, Senger B, Grob G, Tatematsu S, Yokokawa D, Mouyna I, Latge JP, Nakajima H, Kushiro T, Becker HD. RNA-dependent sterol aspartylation in fungi. Proc Natl Acad Sci U S A. 2020;117(26):14948-57.
  5. Grube CD, Roy H. A continuous assay for monitoring the synthetic and proofreading activities of multiple aminoacyl-tRNA synthetases for high-throughput drug discovery. RNA Biol. 2018;15(4-5):659-66; PMCID: PMC6103669.
  6. Francklyn C, Roy H, Alexander R. 11th IUBMB Focused Meeting on the Aminoacyl-tRNA Synthetases: Sailing a New Sea of Complex Functions in Human Biology and Disease. Biomolecules. 2018;8(2):14.
  7. Fields RN, Roy H. Deciphering the tRNA-dependent lipid aminoacylation systems in bacteria: Novel components and structural advances. RNA Biol. 2017:1-12.
  8. Grube CD, Roy H. A quantitative spectrophotometric assay to monitor the tRNA-dependent pathway for lipid aminoacylation in vitro. J Biomol Screen. 2016;21(7):722-8; PMCID: PMC5938733.
  9. Smith AM, Harrison JS, Grube CD, Sheppe AE, Sahara N, Ishii R, Nureki O, Roy H. tRNA-dependent alanylation of diacylglycerol and phosphatidylglycerol in Corynebacterium glutamicum. Mol Microbiol. 2015;98(4):681-93; PMCID: 4639916.
  10. Dare K, Shepherd J, Roy H, Seveau S, Ibba M. LysPGS formation in Listeria monocytogenes has broad roles in maintaining membrane integrity beyond antimicrobial peptide resistance. Virulence. 2014;5(4):534-46; PMCID: PMC4063814.
  11. Smith AM, Harrison JS, Sprague KM, Roy H. A conserved hydrolase responsible for the cleavage of aminoacylphosphatidylglycerol in the membrane of Enterococcus faecium. J Biol Chem. 2013;288(31):22768-76; PMCID: PMC3829361.
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