title: Synthesis of diaminopimelic acid containing peptidoglycan fragments and tracheal cytotoxin (TCT) and investigation of their biological functions.
abstract: Bacterial cell wall peptidoglycan (PGN) is a potent immunostimulator and immune adjuvant. The PGN of Gram-negative bacteria and some Gram-positive bacteria contain meso-diaminopimelic acid (meso-DAP), and we have recently shown that the intracellular protein Nod1 is a PGN receptor and recognizes DAP-containing peptides. In this study, we achieved the synthesis of DAP-containing PGN fragments, including the first chemical synthesis of tracheal cytotoxin (TCT), GlcNAc-(beta1-4)-(anhydro)MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala, and a repeating-unit of DAP-type PGN, GlcNAc-(beta1-4)-MurNAc-L-Ala-gamma-D-Glu-meso-DAP-D-Ala. For the synthesis of PGN fragments, we first established a new synthetic method for an orthogonally protected meso-DAP derivative, and then we constructed the glycopeptide structures. The ability of these fragments to stimulate human Nod1, as well as differences in Nod1 recognition of the variety of synthesized ligand structures were examined. The results showed that the substitution of the N terminus of iE-DAP is necessary for stronger Nod1 recognition, but the structure of the substituent seems not to be strictly recognized. The importance of the carboxyl group at the 2-position of DAP for human Nod1 stimulation was also shown.
authors.affiliation: Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kawasaki
authors.forename: Yukie
authors.initials: Y
authors.lastname: Karasudani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Yukari
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Koichi
authors.initials: K
authors.lastname: Fukase
mesh_terms: D002460:Cell Line; D003603:Cytotoxins / Q000737:chemistry*; D003960:Diaminopimelic Acid / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D053474:Nod1 Signaling Adaptor Protein / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D003603:Cytotoxins; D016328:NF-kappa B; C119067:NOD1 protein, human; D053474:Nod1 Signaling Adaptor Protein; D010457:Peptidoglycan; D003960:Diaminopimelic Acid