TY - JOUR
T1 - Synthesis of characteristic Mycobacterium peptidoglycan (PGN) fragments utilizing with chemoenzymatic preparation of meso-diaminopimelic acid (DAP), and their modulation of innate immune responses
AU - Wang, Qianqian
AU - Matsuo, Yusuke
AU - Pradipta, Ambara R.
AU - Inohara, Naohiro
AU - Fujimoto, Yukari
AU - Fukase, Koichi
N1 - Funding Information:
This work was supported in part by Grants-in-Aid for Scientific Research (no. 20241053, 22310136, and 26282211) from the Japan Society for the Promotion of Science, by ERATO Murata Lipid Active Structure Project, by a funding program for Next Generation World-Leading Researchers (NEXT Program; LR025) from JSPS and CSTP, by Keio Gijuku Academic Development Funds, by Yamada Science Foundation, and by The Sumitomo Foundation.
Publisher Copyright:
© The Royal Society of Chemistry 2016.
PY - 2016
Y1 - 2016
N2 - Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of d-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro-MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human Nod1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the d-Glu and meso-DAP in the peptide stem strongly reduced hNod1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human Nod1 and Nod2 stimulatory capabilities.
AB - Peptidoglycan (PGN) is a major component of bacterial cell wall and is recognized as a potent immunostimulant. The PGN in the cell envelope of Mycobacterium Tuberculosis has been shown to possess several unique characteristics including the presence of N-glycolyl groups (in addition to N-acetyl groups) in the muramic acid residues, and amidation of the free carboxylic acid of d-Glu or of meso-DAP in the peptide chains. Using a newly developed, highly stereoselective, chemoenzymatic approach for the synthesis of meso-DAP in peptide stems, we successfully synthesized for the first time, a series of Mycobacterium PGN fragments that include both mono- and disaccharides of MurNGlyc or 1,6-anhydro-MurNGlyc, as well as peptide-amidated variants. The ability of these PGN fragments to stimulate the immune system through activation of human Nod1 and Nod2 was examined. The PGN fragments were found to modulate immune stimulation, specifically, amidation at the d-Glu and meso-DAP in the peptide stem strongly reduced hNod1 activation. This effect was dependent on modification position. Additionally, N-glycolyl (instead of acetyl) of muramic acid was associated with slightly reduced human Nod1 and Nod2 stimulatory capabilities.
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U2 - 10.1039/c5ob02145f
DO - 10.1039/c5ob02145f
M3 - Article
C2 - 26631868
AN - SCOPUS:84983115057
SN - 1477-0520
VL - 14
SP - 1013
EP - 1023
JO - Organic and Biomolecular Chemistry
JF - Organic and Biomolecular Chemistry
IS - 3
ER -
