title: Correlation between chemical structure and biological activities of Porphyromonas gingivalis synthetic lipopeptide derivatives.
abstract: We recently separated a PG1828-encoded triacylated lipoprotein (Pg-LP), composed of two palmitoyl and one pentadecanoyl groups at the N-terminal of glycerocysteine from Porphyromonas gingivalis, a periodontopathic bacteria, and found that Pg-LP exhibited definite biological activities through Toll-like receptor (TLR) 2. In the present study, we synthesized 12 different Pg-LP N-terminal peptide moieties (PGTP) using four combinations of glyceryl (R and S) and cysteinyl (l and d) stereoisomers, and three different acyl group regioisomers, N-pentadecanoyl derivative (PGTP1), S-glycero 2-pentadecanoyl derivative (PGTP2) and S-glycero 3-pentadecanoyl derivative (PGTP3). All the PGTP compounds (RL, SL, SD, RD) tested showed TLR2-dependent cell activation. The activating capacities of the PGTP-R compounds were more potent than those of the PGTP-S compounds, whereas there were no differences between the PGTP-L and -D compounds. Furthermore, the production of interleukin (IL)-6 following stimulation with the PGTP1-RL, PGTP2-RL and PGTP3-RL compounds was impaired in peritoneal macrophages from TLR2 knock-out (KO), but not those from TLR1 KO or TLR6 KO mice. These results suggest that P. gingivalis triacylated lipopeptides are capable of activating host cells in a TLR2-dependent and TLR1-/TLR6-independent manner, and the fatty acid residue at the glycerol position in the PGTP molecule plays an important role in recognition by TLR2.
authors.affiliation: Department of Oral Microbiology, Asahi University School of Dentistry, Gifu, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Makimura
authors.forename: Y
authors.initials: Y
authors.lastname: Asai
authors.forename: Y
authors.initials: Y
authors.lastname: Taiji
authors.forename: A
authors.initials: A
authors.lastname: Sugiyama
authors.forename: R
authors.initials: R
authors.lastname: Tamai
authors.forename: T
authors.initials: T
authors.lastname: Ogawa
mesh_terms: D000328:Adult; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry* / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology; D008074:Lipoproteins / Q000737:chemistry* / Q000276:immunology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D016966:Porphyromonas gingivalis / Q000737:chemistry* / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; C493486:Tlr2 protein, mouse; C495369:Tlr6 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6