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Structure type: oligomer
Compound class: lipid A
Contained glycoepitopes: IEDB_135394,IEDB_137340,IEDB_141181,IEDB_141807,IEDB_151531,IEDB_176772,IEDB_534864

• Article ID: 565
  Kawasaki K, Ernst RK, Miller SI "3-O-Deacylation of lipid A by PagL, a PhoP/PhoQ-regulated deacylase of Salmonella typhimurium, modulates signaling through Toll-like receptor 4" - Journal of Biological Chemistry 279(19) (2004) 20044-20048
  

  Toll-like receptor 4 (TLR4)-mediated responses, which are induced by the lipid A portion of lipopolysaccharide, are important for host defense against Salmonellae infection. A variety of different data indicate that the acylation state of lipid A can alter TLR4-mediated responses. The S. typhimurium virulence gene product PhoP/PhoQ signals the presence of host microenvironments to regulate the expression of a lipid A 3-O-deacylase, PagL, and a lipid A palmitoyltransferase, PagP. We now demonstrate that 3-O-deacylation and palmitoylation of lipid A decreases its ability to induce TLR4-mediated signaling. Deacylated lipid A, deacylated and palmitoylated lipid A, palmitoylated lipid A, and unmodified lipid A species were purified from Escherichia coli heterologously expressing PagL and/or PagP. The purified lipid A preparations showed spectra of a single lipid A species on mass spectrometry and gave a single band on thin layer chromatography. The activity of purified lipid A species was examined using human and mouse cell lines that express recombinant human TLR4. Compared with unmodified lipid A, the modified lipid A species are 30-100-fold less active in the ability to induce NF-kappaB-dependent reporter activation. These results suggest that the lipid A modifications reduce TLR4-signaling as part of Salmonellae adaptation to host environments.

  Lipopolysaccharide, Escherichia coli, lipid A, mass spectrometrySalmonella typhimurium

  NCBI PubMed ID: 15014080
  Publication DOI: 10.1074/jbc.M401275200
  Journal NLM ID: 2985121R
  Publisher: Baltimore, MD: American Society for Biochemistry and Molecular Biology
  Correspondence: millersi@u.washington.edu
  Institutions: Department of Microbiology, University of Washington, Seattle, WA 98195, USA
  Methods: TLC, MALDI-TOF MS, biological assays, genetic methods, biochemical methods
  
   
  
  Salmonella typhimurium
  CSDB ID 31328 (all data & tools)
• Article ID: 1444
  Johnson DA, Sowell CG, Keegan DS, Livesay MT "Chemical synthesis of the major constituents of Salmonella minnesota monophosphoryl lipid A" - Journal of Carbohydrate Chemistry 17(9) (1998) 1421-1426
  

  Structural investigations have shown that lipid A constitutes the active principle of lipopoly saccharide (LPS, endotoxin), a complex amphipathic molecule located on the cell surface of Gram-negative bacteria.1 Lipid A elicits not only the typical endotoxic reactions such as fever and lethal shock but also adjuvant, antitumor and other beneficial effects.1 As a result, there has been a great deal of interest in the synthesis of lipid A derivatives possessing low toxicity.

  synthesis, lipid A, Salmonella, chemical synthesis, Salmonella minnesota, monophosphoryl lipid A

  Publication DOI: 10.1080/07328309808002363
  Journal NLM ID: 8218151
  Publisher: Marcel Dekker
  Institutions: Ribi ImmunoChem Research, Inc., Pharmaceutical Discovery Division 553 Old Corvallis Rd., Hamilton, MT 59840 USA
  Methods: 13C NMR, 1H NMR, FAB-MS, TLC, chemical synthesis, chemical methods, HPLC
  
   
  
  Salmonella minnesota R595
  CSDB ID 810 (all data & tools)
• Article ID: 1445
  Johnson DA, Keegan DS, Sowell CG, Livesay MT, Johnson CL, Taubner LM, Harris A, Myers KR, Thompson JD, Gustafson GL, Rhodes MJ, Ulrich JT, Ward JR, Yorgensen YM, Cantrell JL, Brookshire VG "3-O-Desacyl monophosphoryl lipid a derivatives: Synthesis and immunostimulant activities" - Journal of Medicinal Chemistry 42(22) (1999) 4640-4649
  

  The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.

  synthesis, lipid, lipid A, activity, monophosphoryl lipid A, immunostimulants

  NCBI PubMed ID: 10579826
  Journal NLM ID: 9716531
  Publisher: Washington, DC: American Chemical Society
  Correspondence: dajohn@corixa.com
  Institutions: Pharmaceutical Discovery Division, Ribi ImmunoChem Research, Inc., 553 Old Corvallis Road, Hamilton, Montana 59840, USA
  Methods: 13C NMR, 1H NMR, FAB-MS, TLC, ELISA, chemical synthesis, chemical methods, biological assays, serological methods, HPLC, UV
  
   
  
  Salmonella minnesota R595
  CSDB ID 811 (all data & tools)
• Article ID: 1464
  Janusch H, Brecker L, Lindner B, Alexander C, Gronow S, Heine H, Ulmer AJ, Rietschel ET, Zähringer U "Structural and biological characterization of highly purified hepta-acyl lipid A present in the lipopolysaccharide of the Salmonella enterica sv. Minnesota Re deep rough mutant strain R595" - Journal of Endotoxin Research 8(5) (2002) 343-356
  

  One major component of the Salmonella enterica sv. Minnesota Re deep rough mutant (strain R595) lipopolysaccharide is hepta-acyl lipid A (LAhepta). In a recent publication [Tanamoto K-l, Azurru S. Salmonella-type heptaacylated lipid A is inactive and acts as an antagonist of lipopolysaccharide action on human line cells. Journal of Immunology 2000; 164: 3149-3156] the corresponding synthetic hepta-acyl lipid A (compound 516) was reported to be agonistically inactive but to rather suppress pro-inflammatory activation by the endotoxic hexa-acyl lipid A (LAhexa, compound 506) and S-form LPS from Escherichia coli in the human macrophage-like cell lines THP-1 and U937. These results, however, were in contrast to previous findings with human mononuclear cells (hMNC) isolated from peripheral blood, in which compound 516 was found to be an agonist, expressing low, but significant, cytokine-inducing activity as compared to LAhexa. We have investigated the structure of natural LAhepta from the S. enterica sv. Minnesota Re deep rough mutant strain (R595) by TLC immunoblot, MALDI-TOF mass spectrometry and NMR spectroscopy. Using these techniques, the structural identity between Lahepta and the synthetic compound 516 was confirmed. In corroboration of previous findings with studies employing compound 516, purified LAhepta was found to induce the production of TNF-a, IL-1b and IL-6 in hMNC, thus displaying moderate agonistic activity. Furthermore, we showed that LAhepta agonistically activated nuclear translocation of NF-kB in THP-1 cells, thus clearly ruling out the possibility that LAhepta is an antagonist and that its biological activity is influenced by the type of human myeloid cells used for testing endotoxicity (hMNC versus THP-1 cells).

  Lipopolysaccharide, LPS, structure, strain, lipid A, Salmonella enterica, Re

  NCBI PubMed ID: 12537693
  Publication DOI: 10.1179/096805102125000678
  Journal NLM ID: 9433350
  Publisher: Maney Publishing
  Correspondence: uzaehr@fz-borstel.de
  Institutions: Research Center Borstel, Center of Medicine and Biosciences, Borstel, Germany
  Methods: 13C NMR, 1H NMR, NMR-2D, 31P NMR, MALDI-TOF MS, TLC immunoblot
  
   
  
  Salmonella enterica sv. Minnesota R595
  CSDB ID 2492 (all data & tools)
• Article ID: 1595
  Kawasaki K, Ernst RK, Miller SI "Purification and characterization of deacylated and/or palmitoylated lipid A species unique to Salmonella enterica serovar Typhimurium" - Journal of Endotoxin Research 11(1) (2005) 57-61
  

  The Salmonella enterica serovar Typhimurium virulence gene products PhoP/PhoQ sense host microenvironments to regulate the expression of a lipid A 3-O-deacylase, PagL, and a lipid A palmitoyltransferase, PagP. Therefore, deacylation and/or palmitoylation of lipid A could occur in Salmonellae adapted to host environments. The PhoP/PhoQ-regulated modification of lipid A alters host recognition and signaling, and may play an important role in host defense against Salmonellae infection. Here we report the purification and characterization of modified lipid A species. Deacylated lipid A, deacylated and palmitoylated lipid A, and palmitoylated lipid A species were generated in Escherichia coli cells heterologously expressing salmonellae PagL and/or PagP, and then purified by sequential thin-layer chromatography. The purified lipid A species showed m/z values that correspond to single lipid A species on mass spectrometry analysis. The modified lipid A species showed reduced ability to induce cellular signaling through Toll-like receptor 4, suggesting a specific function of the lipid A modifications in the pathogenesis of salmonellae infection.

  deacylated lipid A, palmitoylated lipid A, Salmonella enterica serovar Typhimurium

  NCBI PubMed ID: 15826380
  Publication DOI: 10.1179/096805105225006696
  Journal NLM ID: 9433350
  Publisher: Maney Publishing
  Correspondence: kawa@nih.go.jp
  Institutions: Departments of Microbiology, Medicine, and Genome Sciences, University of Washington, Seattle, Washington, USA
  Methods: PCR, de-O-acylation, chemical methods, MALDI-TOF MS, biological assays, genetic methods, enzyme assay
  
   
  
  Salmonella enterica sv. Typhimurium
  CSDB ID 31285 (all data & tools)
• Article ID: 3882
  Kusumoto S, Hashimoto M, Kawahara K "Structure and Synthesis of Lipid A" - Book: Lipid A in Cancer Therapy (series: Advances in Experimental Medicine and Biology) (2010) Vol. 667, 5-23
  

  Lipid A is the lipophilic partial structure of bacterial lipopolysaccharide (LPS), which is a characteristic and essential component of the cell surface architecture of Gram negative bacteria. LPS constitutes the outer leaflet of the lipid bilayer of outer membrane which covers the outermost surface of bacterial cells. Structurally, LPS is composed of covalently bound three distinct parts, i. e., O-antigenic polysaccharide, core oligosaccharide and glycolipid called lipid A (Fig. 1). Westphal and Luderitz found that the linkage between the core oligosaccharide and glycolipid is selectively cleaved by mild acid hydrolysis of LPS. They also observed that the liberated glycolipid, which they named lipid A, is responsible for the endotoxic activity of LPS. (1) Figure 1. Schematic structure of lipopolysaccharide (LPS).

  Lipopolysaccharide, synthesis, structure, O-antigenic polysaccharide, lipid A, glycolipid

  NCBI PubMed ID: 20665196
  Publisher: New York: Springer.
  Correspondence: skus@sunbor.or.jp
  Editors: Jeannin J-F
  Institutions: Suntory Institute for Bioorganic Research, Wakayamadai 1-1-1, Shimamoto-cho, Mishima-gun, Osaka, 618-8503, Japan
  
   
  
  Salmonella minnesota
  CSDB ID 31184 (all data & tools)
• Article ID: 5085
  Ma H, Cummins DD, Edelstein NB, Gomez J, Khan A, Llewellyn MD, Picudella T, Willsey SR, Nangia S "Modeling Diversity in Structures of Bacterial Outer Membrane Lipids" - Journal of Chemical Theory and Computation 13(2) (2017) 811-824
  

  Lipopolysaccharides (LPSs) are vital components of the outer membrane of Gram-negative bacteria, and they act as extremely strong stimulators of innate immunity in diverse eukaryotic species. The primary immunostimulatory center of the LPS molecule is lipid A, a disaccharide-bound lipophilic domain. Considering the broad diversity in bacterial species, there are variations in the lipid A structures and their immunogenic potencies. In this work, we model the lipid A structures of eight commensal or human pathogenic bacterial species: Helicobacter pylori, Porphyromonas gingivalis, Bacteroides fragilis, Bordetella pertussis, Chlamydia trachomatis, Campylobacter jejuni, Neisseria meningitidis, and Salmonella minnesota. The membrane properties of these bacterial species were characterized and compared using molecular simulations. The structure-property relationships that emerge from this lipid A molecular library highlight the roles of acyl chain lengths, number of chains, phosphorylation state, membrane composition, and counterion charge in regulating the phase transition temperature of the membrane, diffusion coefficient of the lipids, and membrane thickness. The molecular and structural insights provided reveal the diversity in bacterial outer membrane lipids and their contribution to human disease and immunity.

  Lipopolysaccharide, lipid A, outer membrane

  NCBI PubMed ID: 28080049
  Publication DOI: 10.1021/acs.jctc.6b00856
  Journal NLM ID: 101232704
  Publisher: Washington, DC: American Chemical Society
  Correspondence: snangia@syr.edu
  Institutions: Department of Biomedical and Chemical Engineering, Syracuse University , Syracuse, New York 13244, United States
  Methods: MD simulations, molecular mechanics
  
   
  
  Salmonella minnesota
  CSDB ID 12409 (all data & tools)
• Article ID: 5421
  Di Lorenzo F, De Castro C, Silipo A, Molinaro A "Lipopolysaccharide structures of Gram-negative populations in the gut microbiota and effects on host interactions" - FEMS Microbiology Reviews 43(3) (2019) 257-272
  

  The human gastrointestinal tract harbors a heterogeneous and complex microbial community, which plays a key role in human health. The gut microbiota controls the development of the immune system by setting systemic threshold for immune activation. Glycoconjugates, such as lipopolysaccharides, from gut bacteria have been shown to be able to elicit both systemic proinflammatory and immunomodulatory responses. This phenomenon is particularly intriguing considering that the immune system is charged with the task to distinguish the beneficial microbes from the pathogens, even if the commensal bacteria have molecular patterns resembling those of the pathogenic counterparts. Therefore, the importance of the chemical structure of these macromolecules in fine tuning this delicate equilibrium is beyond question. This review offers an overview of the current understanding of chemical peculiarities of the lipopolysaccharides isolated from the gut microbiota, and their relationships to their biological activity in terms of immune system maturation and development.

  innate immunity, Structural characterization, gut immunity, gut microbiota, TLR4/MD-2

  NCBI PubMed ID: 30649292
  Publication DOI: 10.1093/femsre/fuz002
  Journal NLM ID: 8902526
  Publisher: Oxford University Press
  Correspondence: flaviana.dilorenzo@unina.it
  Institutions: Department of Chemical Sciences, University of Naples Federico II, via Cinthia 4, 80126 Naples, Italy, Task Force on Microbiome Studies, University of Naples Federico II, Naples 80126, Italy, Department of Agricultural Sciences, University of Naples Federico II, via Università 100, 80055 Portici, Italy
  
   
  
  Salmonella typhimurium
  CSDB ID 681 (all data & tools)
• Article ID: 6319
  Strobl S, Hofbauer K, Heine H, Zamyatina A "Lipid A Mimetics Based on Unnatural Disaccharide Scaffold as Potent TLR4 Agonists for Prospective Immunotherapeutics and Adjuvants" - Chemistry: a European Journal 28(35) (2022) e202200547
  

  TLR4 is a key pattern recognition receptor that can sense pathogen- and danger- associated molecular patterns to activate the downstream signaling pathways which results in the upregulation of transcription factors and expression of interferons and cytokines to mediate protective pro-inflammatory responses involved in immune defense. Bacterial lipid A is the primary TLR4 ligand with very complex, species-specific, and barely predictable structure-activity relationships. Given that therapeutic targeting of TLR4 is an emerging tool for management of a variety of human diseases, the development of novel TLR4 activating biomolecules other than lipid A is of vast importance. We report on design, chemical synthesis and immunobiology of novel glycan-based lipid A-mimicking molecules that can activate human and murine TLR4-mediated signaling with picomolar affinity. Exploiting crystal structure - based design we have created novel disaccharide lipid A mimetics (DLAMs) where the inherently flexible β(1→6)-linked diglucosamine backbone of lipid A is exchanged with a conformationally restrained non-reducing βGlcN(1↔1')βGlcN scaffold. Excellent stereoselectivity in a challenging β,β-1,1' glycosylation was achieved by tuning the reactivities of donor and acceptor molecules using protective group manipulation strategy. Divergent streamlined synthesis of β,β-1,1'-linked diglucosamine-derived glycolipids entailing multiple long-chain (R)-3- acyloxyacyl residues and up two three phosphate groups was developed. Specific 3D-molecular shape and conformational rigidity of unnatural β,β-1,1'-linked diglucosamine combined with carefully optimized phosphorylation and acylation pattern ensured efficient induction of the TLR4-mediated signaling in a species-independent manner.

  Lipopolysaccharide, carbohydrates, lipid A, glycosylation, adjuvant, modulation of the innate immune responses

  NCBI PubMed ID: 35439332
  Publication DOI: 10.1002/chem.202200547
  Journal NLM ID: 9513783
  Publisher: Weinheim: VCH Verlagsgesellschaft/Verlag I
  Correspondence: A. Zamyatina
  Institutions: Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, Vienna, 1190, Austria, Research Group Innate Immunity, Research Center Borstel-Leibniz Lung Center, Airway Research Center North (ARCN), German Center for Lung Disease (DZL), Parkallee 22, Borstel, 23845, Germany
  Methods: 13C NMR, 1H NMR, TLC, 31P NMR, chemical synthesis, chemical methods, MALDI-TOF MS, HPLC, optical rotation measurement, SEC, HR-ESI-MS, immunobiology
  
   
  
  Salmonella minnesota
  CSDB ID 8831 (all data & tools)