Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of 3-deoxy-manno-octulosonate cytidylytransferase (CMP-KDO transferase; EC 2.7.7.38) by 8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid (NH2dKDO) halts the growth of Gram-negative bacteria by depriving the cells of the 3-deoxy-D-manno-2-octulosonate required for the biosynthesis of the core region of the lipopolysaccharide components of the outer membrane. Low levels of this inhibitor increase the vulnerability of Escherichia coli to hydrophobic antibiotics, detergents, the complement-mediated antibacterial activity of serum, phagocytosis, and enhance the rate at which bacteria are cleared from the mouse bloodstream.
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PMID:Inhibitors of lipopolysaccharide biosynthesis impair the virulence potential of Escherichia coli. 133 47

In this study we compared the interleukin 1 (IL 1)-inducing capacity and the reactivity in the Limulus amoebocyte assay (LAL) of purified lipopolysaccharides (LPSs) from various bacterial strains. LPSs differed greatly in their capacities (on a weight basis) to induce IL 1 release from serum-free cultured human monocytes. LPS species that induced high levels of IL 1 release from human monocytes exhibited a high thiobarbiturate-reactive 2-keto-3-deoxy-octonic acid (KDO) content. No relationship was found between the IL 1-inducing activity and the LAL reactivity of purified LPSs. Filtration experiments in which membranes of decreasing size-exclusion limits were used demonstrated that molecular species of LPS with an apparent Mr below 3,000 may induce IL 1, whereas only species with an apparent Mr above 8,000 are recognized in the LAL assay. The latter observation suggests that the reaction with LAL requires an aggregated form of LPS. These results indicate that biologically active LPS species can cross dialysis membranes in vivo although no LAL reactive material is detected in the blood compartment. The Limulus assay is an insufficient criterion for the absence of LPS in biological fluids.
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PMID:Dissociation between the interleukin 1-inducing capacity and Limulus reactivity of lipopolysaccharides from gram-negative bacteria. 212 2

Although 8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid (2) is a potent inhibitor of 3-deoxy-D-manno-octulosonate cytidylyltransferase (CMP-KDO synthetase), it is unable to reach its cytoplasmic target and is therefore inactive as an antibacterial agent. However, esterification of 2 with 8-(hydroxymethyl)-1-naphthyl methyl disulfide (8) generates a prodrug (12), which gains entry into bacterial cells. Intracellular reduction of the disulfide leads to a rapid, intramolecular, displacement of the acid 2, which then inhibits the growth of Gram-negative bacteria by interfering with the biosynthesis of lipopolysaccharide.
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PMID:A novel prodrug of an impermeant inhibitor of 3-deoxy-D-manno-2-octulosonate cytidylyltransferase has antibacterial activity. 253 25

The minimal active immunogenic doses (intraperitoneal administration) of crude K-antigen extracts of Serratia marcescens for NMRI mice were 80 ng. Following ultracentrifugation (300,000 x g, 16 h), supernatant fluids of three K-antigen extracts were free of contaminating DNA, RNA, and 2-keto-3-deoxy-D-manno-octonic acid (KDO), and the contents of Limulus amoebocyte lysate-reactive lipopolysaccharide (LPS) had been reduced from 100- to 1000-fold. The minimal active immunogenic doses of two ultracentrifuged K-antigen extracts were 2 and 10 micrograms, respectively. A mucoid strain of S. marcescens (SM 20-M; serotype O6/O14:H12) yielded nonmucoid (= SM 29-NM) variants that had lost most of the O6/O14 O-antigen (LPS) and all of the SM 29-M K-antigen extract reactivity (ELISA test) and which were ca. 5-fold less mouse-virulent. Crude K-antigen extracts from S. marcescens strain SM 29-M and variant SM 29-NM failed to protect NMRI mice against strain SM 29-M.
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PMID:Active immunization of NMRI mice against Serratia marcescens. II. K-antigen extracts. 332 27

On the basis of the knowledge that the amino acid 3 (8-amino-2,6-anhydro-3,8-dideoxy-D-glycero-D-talo-octonic acid) is a potent inhibitor of 3-deoxy-manno-octulosonate cytidylyltransferase, attempts were made to design derivatives that would act as antibacterials against Gram-negative bacteria by inhibiting lipopolysaccharide biosynthesis. Compound 3 and the derivatives 15 and 16 containing an additional amino acid were not lethal to bacteria. However, compounds 17-22, which contain a N-terminally linked dipeptide, exhibited good antibacterial activity in vitro on testing against strains of the Gram-negative bacteria Escherichia coli and Salmonella typhimurium. They have no activity against Gram-positive bacteria such as Staphylococcus aureus.
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PMID:Design and synthesis of peptide derivatives of a 3-deoxy-D-manno-2-octulosonic acid (KDO) analogue as novel antibacterial agents acting upon lipopolysaccharide biosynthesis. 368 1

Lipopolysaccharide was prepared from the extracellular lipoglycopeptide produced by the lysine-requiring mutant Escherichia coli A.T.C.C. 12408 grown under lysine-limiting conditions. The lipid moiety, containing glucosamine phosphate and four fatty acids (lauric acid, myristic acid, beta-hydroxymyristic acid and palmitic acid) corresponded in composition to lipid A of known bacterial lipopolysaccharides. The components of the polysaccharide moiety were d-glucose, d-galactose, l-glycero-d-manno-heptose, 3-deoxy-2-oxo-octonic acid, ethanolamine and phosphate. These are the constituents of the polysaccharide of the cell-wall antigens from rough strains of E. coli. Lipopolysaccharides were also prepared from whole cells of E. coli 12408 grown with excess or limited amounts of lysine; they were identical in carbohydrate composition with the extracellular lipopolysaccharide. The biological properties of this material also resembled those of known lipopolysaccharides; it was antigenic, pyrogenic, toxic and had adjuvant activity.
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PMID:Chemical and biological properties of an extracellular lipopolysaccharide from Escherichia coli grown under lysine-limiting conditions. 533 57

Outer membrane vesicle (OMV) vaccines were made from Neisseria meningitidis strain 44/76 and its two short-chain lipopolysaccharide (LPS) mutants, Mu-1 and Mu-4. Only the 44/76 vaccine contained LPS with the host antigen lacto-N-neotetraose. The protein composition of the vaccines was similar. The LPS carbohydrate chain length proved to influence drastic changes in the LPS immunogenicity as well as the outer membrane proteins (OMPs) ability to elicit functional antibodies in mice. Only LPS in the Mu-1 and Mu-4 vaccines were immunogenic, and the 44/76 vaccine differed also by not inducing antibodies to the class 4 OMP. The Mu-1 vaccine, with a LPS carbohydrate chain comprising only two residues of 2-keto-3-deoxy-octonic acid, induced lower bactericidal activity and less antibodies to the class 1 OMP, compared to the two other vaccines. This indicates that LPS of a certain carbohydrate chain length is required for adequate exposure of the class 1 OMP epitopes essential for inducing bactericidal antibodies.
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PMID:Outer membrane vesicle vaccines made from short-chain lipopolysaccharide mutants of serogroup B Neisseria meningitidis: effect of the carbohydrate chain length on the immune response. 928 48

Chemical and biological studies were performed on lipopolysaccharide isolated from Selenomonas sputigena ATCC 33150T, a possible causative agent of periodontal diseases. The sugar components of the lipopolysaccharide of S. sputigena were mannose, galactose, glucose, L-glycero-D-mannoheptose (heptose), 2-keto-3-deoxy-octonic acid, glucosamine and galactosamine in a molar ratio of 0.3:1.0:1.0:1.0:0.2:3.0:3.2 (mol/mol heptose). Sephadex G-50 chromatography of the polysaccharide portion of the lipopolysaccharide obtained by partial hydrolysis yielded three fractions: the O-polysaccharide chain attached to the core oligosaccharide, the core oligosaccharide and monosaccharides. Compositional analysis of these fractions revealed that lipopolysaccharide of S. sputigena carries a short O-polysaccharide chain consisting of galactose and glucosamine and that the core oligosaccharide consisted of glucose, heptose, glucosamine and 2-keto-3-deoxyoctonic acid. It is of particular interest that galactosamine was detected as a component sugar of the lipid A moiety in addition to glucosamine, which is a usual component sugar of the lipid A of most gram-negative bacteria. Thus, the lipid A of S. sputigena might have a unique backbone that differs from that of the lipid A of other gram-negative bacteria. Lipid A of S. sputigena consisted mainly of fatty acids such as undecanoic, tridecanoic, tridecenoic, 3-hydroxytridecanoic and 3-hydroxytetradecanoic acid in a molar ratio of 0.4:1.0:0.3:4.0:0.5 (mol/mol tridecanoic acid). Lipopolysaccharide and lipid A from S. sputigena both exhibited biological activity in activating the clotting enzyme of Limulus amebocytes, the Schwartzman reaction, mitogenicity for murine lymphocytes and in inducing interleukin-1 alpha and interleukin-6 production in murine macrophages to the same extent as those observed for lipopolysaccharide of the Salmonella serovar typhimurium used as a positive control. The results suggested that the lipopolysaccharide of S. sputigena is a virulent factor in human periodontal diseases.
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PMID:Chemical and biological properties of lipopolysaccharide from Selenomonas sputigena ATCC 33150. 946 2

Sialylated oligosaccharides, present on mammalian outer-cell surfaces, play vital roles in cellular interactions and some bacteria are able to mimic these structures to evade their host's immune system. It would be of great benefit to the study of infectious and autoimmune diseases and cancers, to understand the pathway of sialylation in detail to enable the design and production of inhibitors and mimetics. Sialylation occurs in two stages, the first to activate sialic acid and the second to transfer it to the target molecule. The activation step is catalysed by the enzyme CMP-Neu5Ac synthetase (CNS). Here we used crystal structures of CNS and similar enzymes to predict residues of importance in the CNS from Neisseria meningitidis. Nine residues were mutated to alanine, and the steady-state enzyme kinetic parameters were measured using a continuous assay to detect one of the products of the reaction, pyrophosphate. Mutations that caused the greatest loss in activity included K142A, D211A, D209A and a series of mutations at residue Q104, highlighted from sequence-alignment studies of related enzymes, demonstrating significant roles for these residues in the catalytic mechanism of CNS. The mutations of D211A and D209A provide strong evidence for a previously proposed metal-binding site in the enzyme, and the results of our mutations at residue Q104 lead us to include this residue in the metal-binding site of an intermediate complex. This suggests that, like the sugar-activating lipopolysaccharide-synthesizing CMP-2-keto-3-deoxy-manno-octonic acid synthetase enzyme KdsB, CNS recruits two Mg(2+) ions during the catalytic cycle.
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PMID:Identification and characterization of important residues in the catalytic mechanism of CMP-Neu5Ac synthetase from Neisseria meningitidis. 2049 13