Muramyl dipeptide

Muramyl dipeptide
Names
IUPAC name
(4R)-4-[ [(2S)-2-[ [(2R)-2-[(2R,5S)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoic acid
Other names
Acetylmuramyl-Alanyl-Isoglutamine
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.053.343
MeSH Muramyl+dipeptide
UNII
  • InChI=1S/C19H32N4O11/c1-7(17(30)23-10(16(20)29)4-5-12(26)27)21-18(31)8(2)33-15-13(22-9(3)25)19(32)34-11(6-24)14(15)28/h7-8,10-11,13-15,19,24,28,32H,4-6H2,1-3H3,(H2,20,29)(H,21,31)(H,22,25)(H,23,30)(H,26,27)/t7-,8+,10+,11+,13+,14+,15+,19?/m0/s1 Y
    Key: BSOQXXWZTUDTEL-QAQREVAFSA-N Y
  • InChI=1/C19H32N4O11/c1-7(17(30)23-10(16(20)29)4-5-12(26)27)21-18(31)8(2)33-15-13(22-9(3)25)19(32)34-11(6-24)14(15)28/h7-8,10-11,13-15,19,24,28,32H,4-6H2,1-3H3,(H2,20,29)(H,21,31)(H,22,25)(H,23,30)(H,26,27)/t7-,8+,10+,11+,13+,14+,15+,19?/m0/s1
    Key: BSOQXXWZTUDTEL-QAQREVAFBN
  • O=C(N)[C@H](NC(=O)[C@@H](NC(=O)[C@H](O[C@H]1[C@H](O)[C@H](OC(O)[C@@H]1NC(=O)C)CO)C)C)CCC(=O)O
Properties
C19H32N4O11
Molar mass 492.47758
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Y verify (what is YN ?)
Infobox references

Muramyl dipeptide is a component of bacterial peptidoglycan, a recognition structure or activator for nucleotide-binding oligomerization domain 2 (NOD2) protein.[1] It is a constituent of both Gram-positive and Gram-negative bacteria composed of N-acetylmuramic acid linked by its lactic acid moiety to the N-terminus of an L-alanine D-isoglutamine dipeptide.[1] It can be recognized by the immune system as a pathogen-associated molecular pattern and activate the NALP3 inflammasome which, in turn, leads to cytokine activation, IL-1α and IL-1β especially.[2]

Human NOD2 protein of the nucleotide-binding leucine-rich repeat family, is a cytoplasmic receptor involved in host innate immune system defense. Mutations in the CARD15 gene encoding NOD2 protein have been observed in Crohn's disease patients,[3] decreasing the immune systems of these patients ability to recognize muramyl dipeptide. Analogues of muramyl dipeptide and their potential for immune response therapies in cancer and disease are being investigated.[4] Experiments published in 2008 showed that muramyl dipeptide is involved in a molecular pathway in mice that conferred protection from colitis.[5]

Mechanism of action

While muramyl dipeptide is recognized as the key ligand for the intracellular receptor NOD2, its cellular detection relies on a multi-step enzymatic pathway. Research has established that human cells cannot directly sense raw MDP; instead, the cytosolic enzyme N-acetylglucosamine kinase (NAGK) must first phosphorylate the N-acetylmuramic acid moiety at its C6 position, producing 6-O-phospho-MDP. Without this NAGK-mediated phosphorylation event, downstream NOD2 self-oligomerization and NF-κB inflammatory signaling are not triggered.[6]

Biomedical applications

Due to its robust immunogenic property as a pathogen-associated molecular pattern, MDP and its derivatives are heavily explored as molecular adjuvants for vaccine delivery and cancer treatments. However, free MDP has a high clearance rate and poor membrane penetration when administrated directly, Modern approaches leverage biomaterials engineering to overcome these limitations. For instance, MDP-presenting polymersomes have been designed to act as synthetic "artificial nanobacteria," which systematically enhance immune uptake by dendritic cells and macrophages, reversing the immunosuppressive properties of the tumor microenvironment in melanoma models.[7]

See also

References

  1. ^ a b Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. (February 2003). "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease". The Journal of Biological Chemistry. 278 (8): 5509–5512. doi:10.1074/jbc.C200673200. hdl:10379/9336. PMID 12514169.
  2. ^ Martinon F, Agostini L, Meylan E, Tschopp J (November 2004). "Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome". Current Biology. 14 (21): 1929–1934. doi:10.1016/j.cub.2004.10.027. PMID 15530394. S2CID 13728991.
  3. ^ Inohara N, Ogura Y, Fontalba A, Gutierrez O, Pons F, Crespo J, et al. (February 2003). "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease". The Journal of Biological Chemistry. 278 (8): 5509–5512. doi:10.1074/jbc.c200673200. hdl:10379/9336. PMID 12514169.
  4. ^ Li X, Yu J, Xu S, Wang N, Yang H, Yan Z, et al. (July 2008). "Chemical conjugation of muramyl dipeptide and paclitaxel to explore the combination of immunotherapy and chemotherapy for cancer". Glycoconjugate Journal. 25 (5): 415–425. doi:10.1007/s10719-007-9095-3. PMID 18161023. S2CID 19058605.
  5. ^ Watanabe T, Asano N, Murray PJ, Ozato K, Tailor P, Fuss IJ, et al. (February 2008). "Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis". The Journal of Clinical Investigation. 118 (2): 545–559. doi:10.1172/JCI33145. PMC 2176188. PMID 18188453.
  6. ^ Stafford, Che A.; Gassauer, Alicia-Marie; de Oliveira Mann, Carina C.; Tanzer, Maria C.; Fessler, Evelyn; Wefers, Benedikt; Nagl, Dennis; Kuut, Gunnar; Sulek, Karolina; Vasilopoulou, Catherine; Schwojer, Sophia J.; Wiest, Andreas; Pfautsch, Marie K.; Wurst, Wolfgang; Yabal, Monica (24 August 2022). "Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation". Nature. 609 (7927): 590–596. doi:10.1038/s41586-022-05125-x. ISSN 1476-4687.
  7. ^ Cui, Guanhong; Sun, Yinping; Wang, Shenqiang; Meng, Fenghua; Zhong, Zhiyuan (13 November 2024). "Muramyl Dipeptide-Presenting Polymersomes as Artificial Nanobacteria to Boost Systemic Antitumor Immunity". ACS Applied Materials & Interfaces. 16 (45): 61655–61663. doi:10.1021/acsami.4c13041. ISSN 1944-8244.
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