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)

The structure of lipid A from the lipopolysaccharide of Rhizobium leguminosarum bv. phaseoli (wild type strain CE3) was investigated by alkylation analysis, nuclear magnetic resonance spectroscopy, and electrospray and fast atom bombardment mass spectrometry of the de-O-acylated lipid A. The lipid A carbohydrate backbone was shown to be a trisaccharide containing galacturonic acid, glucosamine, and the unique sugar 2-amino-2-deoxygluconic acid, previously unreported in lipopolysaccharides. Nuclear magnetic resonance spectroscopy and ethylation analyses revealed that the galacturonic acid is alpha-1,4-linked to the glucosamine, while the amino aldonic acid residue, which may exist as the 1,5-lactone, is attached as an aglycone to the glucosamine and, thus, occupies the reducing end of the molecule. The resulting backbone is hydrophilic and analogous to the commonly observed bisphosphorylated glucosamine disaccharide from enteric bacterial lipopolysaccharides in that both the nonreducing and reducing ends carry negatively charged substituents. The fatty acids of the R. leguminosarum lipid A are attached both as O- and N-acyl substituents to glucosamine and 2-aminogluconate. All fatty acids are hydroxylated consisting of 3-hydroxymyristate (3-OH-C14.0), 3-hydroxypentadecanoate (3-OH-C15.0), 3-hydroxypalmitate (3-OH-C16.0), 3-hydroxystearate (3-OH-C18.0), and 27-hydroxyoctacosanoate (27-OH-C28.0) in the approximate mole ratio 3:0.2:1:0.6:1. Unlike lipid As from enteric bacteria, the R. leguminosarum lipid A lacks 3-acyloxyacyl substituents; however, the long chain 27-hydroxy fatty acid carries ester-linked beta-hydroxybutyrate at the 27-hydroxy position. Fast atom bombardment mass spectrometry of the de-O-acylated lipid A demonstrated the presence of 2 molecular species that differ by 28 mass units due to fatty acid heterogeneity at the two amide linkages. One species carries amide-linked 3-OH-C14.0 and 3-OH-C16.0; the second species carries 3-OH-C14.0 and 3-OH-C18.0. Each molecular species also exists as the aldonolactone, yielding molecular ions at ((M+H)+)-18. The heterogeneity in the amide-linked fatty acids further distinguishes the Rhizobium lipid A from enteric lipid As.
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PMID:Structure of lipid A component of Rhizobium leguminosarum bv. phaseoli lipopolysaccharide. Unique nonphosphorylated lipid A containing 2-amino-2-deoxygluconate, galacturonate, and glucosamine. 818 46

Four long-chain fatty acids, 2-hydroxy-27-oxo-octacosanoic acid (n28:0(2-OH,27-oxo)), 2-hydroxy-29-oxo-triacontanoic acid (n30:0(2-OH,29-oxo)), 2-hydroxy-heptacosane-1,27-dioic acid (27:0(2-OH)-dioic) and 2-hydroxy-nonacosane-1,29-dioic acid (29:0(2-OH)-dioic) were identified by GLC-MS analysis in the phenol-chloroform-petroleum ether (PCP) extracts of Legionella jordanis, L. maceachernii and L. micdadei indicating that they are constituents of lipopolysaccharide. Moreover, five long-chain fatty acids (28:0(27-OH), 28:0(27-oxo), 30:0(29-oxo), 27:0-dioic and 29:0-dioic) previously identified in L. pneumophila (Moll, H. et al., FEMS Microbiol. Lett., 97 (1992), 1-6) were also found in these species. This is to our knowledge the first report on the existence of long chain 2-hydroxylated (omega-1)-oxo fatty acids and 2-hydroxylated 1,omega-dioic fatty acids.
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PMID:Long-chain alpha-hydroxy-(omega-1)-oxo fatty acids and alpha-hydroxy-1,omega-dioic fatty acids are cell wall constituents of Legionella (L. jordanis, L. maceachernii and L. micdadei). 845 96

The lipopolysaccharide of Rhizobium leguminosarum differs from that of other Gram-negative organisms. R. leguminosarum lipid A lacks phosphate groups, but it contains a galacturonic acid residue at the 4'-position and an aminogluconate moiety in place of the usual glucosamine 1-phosphate unit. R. leguminosarum lipid A is esterified with a peculiar long chain fatty acid, 27-hydroxyoctacosanoate, not found in enteric Gram-negative bacteria, and the inner core of R. leguminosarum contains mannose and galactose in place of heptose. Despite these differences, the biosynthesis of R. leguminosarum lipid A is initiated by the same seven enzyme pathway as in Escherichia coli (Raetz, C. R. H. (1993) J. Bacteriol. 175, 5745-5753) to form the phosphorylated precursor, (Kdo)2-lipid IVA, which is then processed differently. We now describe several novel Rhizobium-specific enzymes that recognize and modify (Kdo)2-lipid IVA. The 1- and 4'-phosphatases were detected using (Kdo)2-[1-32P]-lipid IVA and (Kdo)2-[4'-32P]-lipid IVA, respectively, as shown by release of 32Pi. In the presence of GDP-mannose and/or UDP-galactose, membranes of R. leguminosarum first transferred mannose and then galactose to (Kdo)2-[4'-32P]-lipid IVA. In addition, at least two hydrophobic metabolites were generated from (Kdo)2-[4'-32P]-lipid IVA in a manner that was dependent upon both membranes and a cytosolic factor from R. leguminosarum. These compounds are attributed to novel acylations of (Kdo)2-[4'-32P]-lipid IVA. E. coli membranes and cytosol did not catalyze any of the unique reactions detected in R. leguminosarum extracts. Our findings establish the conservation and versatility of (Kdo)2-lipid IVA as a lipid A precursor in bacteria.
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PMID:Lipopolysaccharide biosynthesis in Rhizobium leguminosarum. Novel enzymes that process precursors containing 3-deoxy-D-manno-octulosonic acid. 894 64

Dietary supplementation with fish oil, which contains high amounts of long chain omega 3 ((n-3)) polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), has recently been shown to have protective and ameliorative effects on diseases characterized by chronic inflammatory reactions. Interactions between vascular endothelium, mononuclear cells, and cytokines are crucial steps in the course of inflammatory processes such as chronic graft rejection. We therefore studied the effects of DHA and EPA on both the adhesion of peripheral blood lymphocytes (PBL) to human endothelial cells (EC) in culture and the expression of EC-adhesion molecules and their counterreceptors on PBL. The addition of DHA or EPA to the adhesion assay significantly decreased the adhesion of PBL to untreated EC and tumor necrosis factor-alpha (TNF alpha)-, interleukin (IL) 4-, and lipopolysaccharide-stimulated EC. When EC were pretreated with (n-3) PUFAs for 18 hr, washed, and then stimulated by TNF alpha, IL-4, or lipopolysaccharide, PBL adhesion was also significantly reduced compared with controls. We also showed that PBL preincubated with DHA or EPA, and then washed and chromium radiolabeled, still exhibited an adhesion inhibition to TNF alpha- and IL-4-treated EC as well as untreated EC. Cytofluorometry and immunoenzymatic analyses indicated that pretreatment of EC with (n-3) PUFAs before their activation significantly reduced the EC-induced expression of vascular cell adhesion molecule 1, whereas the level of expression of intercellular adhesion molecule 1 and E-selectin was not modified. Furthermore, we showed that incubation of PBL with DHA or EPA moderately reduced the level of cell surface expression of L-selectin and leukocyte function-associated antigen 1, but not of very late antigen 4. In all cases, the inhibitory effect of (n-3) PUFAs was specific and dose dependent. In addition, DHA seems to be a more potent inhibitor than EPA, but the two compounds in association had an additive effect. Regardless of the mode of action, this inhibitory effect may explain the protective and ameliorative effects of (n-3) PUFAs on diseases involving chronic inflammatory reaction.
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PMID:Docosahexaenoic and eicosapentaenoic acids inhibit in vitro human lymphocyte-endothelial cell adhesion. 897 Jun 22

Dictyostelium discoideum (Amoebidae) secretes cell-lysing enzymes: esterases, amidases, and glycosylases, many of which degrade soil bacteria to provide a source of nutrients. Two of these enzymes, fatty-acyl amidases FAA I and FAA II, act sequentially on the N-linked long chain acyl groups of lipid A, the lipid anchor of Gram-negative bacterial lipopolysaccharide. FAA I selectively hydrolyzes the 3-hydroxymyristoyl group N-linked to the proximal glucosamine residue of de-O-acylated lipid A. Substrate specificity for FAA II is less selective, but does require prior de-N-acylation of the proximal sugar, i.e. bis-N-acylated lipid A is not a substrate. We have synthesized a 14C-labeled substrate analog for FAA II and used this in a novel assay to monitor its purification. Inhibitory studies indicate that FAA II is not a serine protease, but may have a catalytic mechanism similar to metalloprotein de-N-acetylases such as LpxC. Interestingly, rhizobial Nod factor signal oligosaccharides that induce root nodules on leguminous plants have many of the structural requirements for substrate recognition by FAA II. In vitro evidence indicates that Rhizobium fredii Nod factors are selectively de-N-acylated by purified FAA II, suggesting that the enzyme may reduce the N2-fixing efficiency of Rhizobium-legume symbioses. In contrast, N-methylated Nod factors from transgenic R. fredii carrying the rhizobial nodS gene were resistant to FAA II, suggesting a mechanism by which Nod factors may be protected from enzymatic de-N-acylation. Since FAA II and Nod factors are both secreted, and Nod factors that lack the N-acyl group are unable to induce nodules, dictyostelial FAA II may decrease the efficiency of symbiotic nitrogen fixation in the environment by reducing the available biologically active nodule inducer signal.
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PMID:Dictyostelium discoideum fatty-acyl amidase II has deacylase activity on Rhizobium nodulation factors. 946 98

X-adrenoleukodystrophy (X-ALD) is an inherited fatty acid metabolic disorder with secondary manifestation of neuroinflammatory disease process. We report that compounds (forskolin, 8-bromo cAMP, and rolipram) that increase cAMP and activate protein kinase A (PKA) were found to stimulate the peroxisomal beta-oxidation of lignoceric acid (C24:0) whereas compounds (H-89 and myristoylated PKI) that decrease cAMP and PKA activity inhibited the peroxisomal beta-oxidation of lignoceric acid in cultured skin fibroblasts from X-ALD patients. Consistent with the stimulation of beta-oxidation of lignoceric acid, activators of PKA normalized the level of very long chain fatty acids (VLCFA) in X-ALD cultured skin fibroblasts. This normalization of VLCFA in X-ALD cells with forskolin, 8-Br cAMP or with rolipram, an inhibitor of cAMP phosphodiesterase, was realized independent of expression of mRNA or protein of the ALD gene, suggesting that cAMP derivatives can correct the metabolic defect in X-ALD fibroblasts without involving the candidate gene for the disease. Because astrocytes and microglia in demyelinating lesions of X-ALD brain express proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), we examined the effect of cAMP derivatives or rolipram on lipopolysaccharide-stimulated rat primary astrocytes and microglia and found that cAMP derivatives and rolipram inhibited the induction of TNF-alpha and IL-1beta in both astrocytes and microglia. The ability of cAMP derivatives and rolipram to block the induction of TNF-alpha and IL-1beta in astrocytes and microglia and to normalize the fatty acid pathogen in skin fibroblasts of x-adrenoleukodystrophy (X-ALD) clearly identify cAMP analogs or rolipram as candidates for potential therapy for X-ALD patients.
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PMID:Therapy for X-adrenoleukodystrophy: normalization of very long chain fatty acids and inhibition of induction of cytokines by cAMP. 961 Jul 77

The structure/function of peroxisomal lipids in rat liver treated with a sublethal dose of endotoxin, a lipopolysaccharide (LPS), was investigated. Peroxisomes isolated from LPS-treated rat liver had remarkable alterations in lipid content compared with saline treated control liver peroxisomes. Cholesterol and phospholipids (PL) decreased significantly by 28.7% and 50.8%, respectively, leading to the change in the ratio of cholesterol/phospholipids (control 0.081 versus LPS 0.118, P < 0.001). A quantitative analysis from LPS-treated rat liver peroxisomes showed a general decrease in all classes of PL. No such alterations were observed in lipid content of other subcellular organelles. The peroxisomal fatty acid composition in LPS-treated animals was also altered. An analysis of fatty acid composition in PL and phosphatidylcholine from LPS-treated peroxisomes showed an increase in arachidonic acid (C20:4) and docosahexaenoic acid (C22:6). Very long chain (VLC) fatty acids (> C22:0) were also found increased in all classes of lipids in LPS-treated peroxisomes. Gadolinium chloride (GAD) mediated inactivation of Kupffer cells (KC) normalized cholesterol/PL ratio in LPS-treated peroxisomes. Collectively, the results indicate that the peroxisome metabolism of lipids and fatty acids is specifically altered in endotoxin-treated rat liver and at least part of the alterations may be mediated by factors released by KC.
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PMID:Endotoxin-induced alterations of lipid and fatty acid compositions in rat liver peroxisomes. 1106 Oct 31

The production of inflammatory mediators, relevant to (auto)immune diseases and chronic inflammatory conditions, can be modulated by dietary intake of n-3 and n-6 long chain polyunsaturated fatty acids (PUFAs). It was suggested that these effects are related to the formation of different series of eicosanoids, in particular prostaglandin-E (PGE). In this study we investigated whether prostaglandin subtypes metabolized from arachidonic acid (PGE2), dihomo-gamma-linolenic acid (PGE1) or eicosapentaenoic acid (PGE3) have different effects on T-cell proliferation and cytokine production in vitro. Freshly isolated human peripheral blood mononuclear cells (PBMC) were stimulated with concanavalin A (ConA) or lipopolysaccharide (LPS) in the presence or absence of exogenous PGE1, PGE2 or PGE3. We found that tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) and to a lesser extent interleukin (IL)-10 production was inhibited by all PGE-subtypes in ConA-stimulated PBMC concomitant with unaffected IL-2 levels. The modulated cytokine production of ConA stimulated cells was independent of T-cell proliferation. PGE2 and PGE1 moderately stimulated proliferation, while PGE3 inhibited the proliferative response to some extent. In LPS-stimulated PBMC, TNF-alpha production was inhibited by all PGE-subtypes, whereas IL-6 remained unaffected and IL-10 production was increased. Time course experiments on the effects of PGE-subtypes on cytokine production after ConA or LPS stimulation showed these effects to be time dependent, but indifferent of the prostaglandin subtype added. Overall, the modulatory effects of PGE on cytokine production were irrespective of the subtype. This may implicate that the immunomodulatory effects of PUFAs, with respect to cytokine production, are not caused by a shift in the subtype of PGE.
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PMID:The modulatory effects of prostaglandin-E on cytokine production by human peripheral blood mononuclear cells are independent of the prostaglandin subtype. 1222 74

A broad-host-range endosymbiont, Sinorhizobium sp. NGR234 is a component of several legume-symbiont model systems; however, there is little structural information on the cell surface glycoconjugates. NGR234 cells in free-living culture produce a major rough lipopolysaccharide (LPS, lacking O-chain) and a minor smooth LPS (containing O-chain), and the structure of the lipid A components was investigated by chemical analyses, mass spectrometry, and NMR spectroscopy of the underivatized lipids A. The lipid A from rough LPS is heterogeneous and consists of six major bisphosphorylated species that differ in acylation. Pentaacyl species (52%) are acylated at positions 2, 3, 2', and 3', and tetraacyl species (46%) lack an acyl group at C-3 of the proximal glucosamine. In contrast to Rhizobium etli and Rhizobium leguminosarum, the NGR234 lipid A contains a bisphosphorylated beta-(1' --> 6)-glucosamine disaccharide, typical of enterobacterial lipid A. However, NGR234 lipid A retains the unusual acylation pattern of R. etli lipid A, including the presence of a distal, amide-linked acyloxyacyl residue containing a long chain fatty acid (LCFA) (e.g. 29-hydroxytriacontanoate) attached as the secondary fatty acid. As in R. etli, a 4-carbon fatty acid, beta-hydroxybutyrate, is esterified to (omega - 1) of the LCFA forming an acyloxyacyl residue at that location. The NGR234 lipid A lacks all other ester-linked acyloxyacyl residues and shows extensive heterogeneity of the amide-linked fatty acids. The N-acyl heterogeneity, including unsaturation, is localized mainly to the proximal glucosamine. The lipid A from smooth LPS contains unique triacyl species (20%) that lack ester-linked fatty acids but retain bisphosphorylation and the LCFA-acyloxyacyl moiety. The unusual structural features shared with R. etli/R. leguminosarum lipid A may be essential for symbiosis.
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PMID:Structural characterization of the lipid A component of Sinorhizobium sp. NGR234 rough and smooth form lipopolysaccharide. Demonstration that the distal amide-linked acyloxyacyl residue containing the long chain fatty acid is conserved in rhizobium and Sinorhizobium sp. 1245 72

The structure of the lipid A from Rhizobium etli and Rhizobium leguminosarum lipopolysaccharides (LPSs) lacks phosphate and contains a galacturonosyl residue at its 4' position, an acylated 2-aminogluconate in place of the proximal glucosamine, and a very long chain omega-1 hydroxy fatty acid, 27-hydroxyoctacosanoic acid (27OHC28:0). The 27OHC28:0 moiety is common in lipid A's among members of the Rhizobiaceae and also among a number of the facultative intracellular pathogens that form chronic infections, e.g., Brucella abortus, Bartonella henselae, and Legionella pneumophila. In this paper, a mutant of R. leguminosarum was created by placing a kanamycin resistance cassette within acpXL, the gene which encodes the acyl carrier protein for 27OHC28:0. The result was an LPS containing a tetraacylated lipid A lacking 27OHC28:0. A small amount of the mutant lipid A may contain an added palmitic acid residue. The mutant is sensitive to changes in osmolarity and an increase in acidity, growth conditions that likely occur in the nodule microenvironment. In spite of the probably hostile microenvironment of the nodule, the acpXL mutant is still able to form nitrogen-fixing root nodules even though the appearance and development of nodules are delayed. Therefore, it is possible that the acpXL mutant has a host-inducible mechanism which enables it to adapt to these physiological changes.
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PMID:A Rhizobium leguminosarum AcpXL mutant produces lipopolysaccharide lacking 27-hydroxyoctacosanoic acid. 1261 48


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