Chemistry:Muramyl dipeptide
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| 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
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| Other names
Acetylmuramyl-Alanyl-Isoglutamine
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| Identifiers | |
3D model (JSmol)
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| ChemSpider | |
| MeSH | Muramyl+dipeptide |
PubChem CID
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| UNII | |
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| 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). | |
 verify (what is   ?)
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| 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
- Taxol
- Dipeptide
- Mifamurtide, a synthetic analogue for the treatment of osteosarcoma
References
- ↑ 1.0 1.1 "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease". The Journal of Biological Chemistry 278 (8): 5509–5512. February 2003. doi:10.1074/jbc.C200673200. PMID 12514169.
- ↑ "Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome". Current Biology 14 (21): 1929–1934. November 2004. doi:10.1016/j.cub.2004.10.027. PMID 15530394.
- ↑ "Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn's disease". The Journal of Biological Chemistry 278 (8): 5509–5512. February 2003. doi:10.1074/jbc.c200673200. PMID 12514169.
- ↑ "Chemical conjugation of muramyl dipeptide and paclitaxel to explore the combination of immunotherapy and chemotherapy for cancer". Glycoconjugate Journal 25 (5): 415–425. July 2008. doi:10.1007/s10719-007-9095-3. PMID 18161023.
- ↑ "Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis". The Journal of Clinical Investigation 118 (2): 545–559. February 2008. doi:10.1172/JCI33145. PMID 18188453.
- ↑ Stafford, Che A.; Gassauer, Alicia-Marie; de Oliveira Mann, Carina C.; Tanzer, Maria C.; Fessler, Evelyn; Wefers, Benedikt; Nagl, Dennis; Kuut, Gunnar et al. (24 August 2022). "Phosphorylation of muramyl peptides by NAGK is required for NOD2 activation" (in en). Nature 609 (7927): 590–596. doi:10.1038/s41586-022-05125-x. ISSN 1476-4687. https://www.nature.com/articles/s41586-022-05125-x.
- ↑ 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. https://doi.org/10.1021/acsami.4c13041.
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