A 2-deoxy analogue of KDO as the first inhibitor of the enzyme CMP-KDO synthetase

Claesson, Alf; Luthman, Kristina; Gustafsson, Kent; Bondesson, G

doi:10.1016/0006-291x(87)90360-3

Cited by 45 publications

(12 citation statements)

References 17 publications

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“…The importance of CMP-Kdo synthetase as a target has been recognized by a number of groups and has resulted in the successful design of a series of potent in vitro inhibitors of the enzyme based on the structure of 2␤-deoxy-Kdo ( Fig. 2) (10). However, none of the 2␤-deoxy-Kdo derivatives were capable of crossing the inner membrane and reaching the KdsB enzyme in the cytoplasm and consequently showed no in vivo activity (11,12).…”

Section: Lipopolysaccharide (Lps)mentioning

confidence: 99%

“…An overlay of the four individual monomers reveals that they all adopt an "open" conformation with little difference in backbone conformation, except for the Asp 163 -Phe 178 loop at the dimer interface, which has a conformation that is dependent on the crystal packing environment. Significantly higher B-factors are observed for sections of the CTPbinding domain, including the phosphate-binding PP-loop Arg 10 -Lys 19 , the C-terminal ␣-helix Gln 227 -Ala 245 , and the Arg 69 -Ser 74 loop region. A 2.6 Å structure for the ligand-free E. coli lipopolysaccharide-specific KdsB in a different space group has been deposited in the PDB data base (code 1VH1) by a structural genomics consortium.…”

mentioning

confidence: 97%

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Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

Heyes

Levy

Lafite

et al. 2009

Journal of Biological Chemistry

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Section: Lipopolysaccharide (Lps)mentioning

confidence: 99%

mentioning

confidence: 97%

Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

Heyes

Levy

Lafite

et al. 2009

Journal of Biological Chemistry

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“…Several inhibitors of CMP-KDO synthase have been described (147)(148)(149)(150)(151). These have promise as antibacterial agents.…”

Section: Biosynthesis and Activation Of Kdomentioning

confidence: 99%

Biochemistry Of Endotoxins

Raetz¹

1990

Annual Review of Biochemistry

166

192

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“…Because 3‐deoxy‐ d manno ‐oct‐2‐ulosonic acid (Kdo) is indispensable for the viability of gram‐negative bacteria, inhibitors of Kdo biosynthesis have been regarded as a potent new class of drugs [21]. Analogues have been synthesized [22–24] that inhibited the activation of Kdo by CMP‐Kdo synthetase prior to incorporation into LPS, and therefore led to the cessation of LPS biosynthesis. These compounds were reported to be bacteriostatic in vitro .…”

mentioning

confidence: 99%

Isolation and structural analysis of phosphorylated oligosaccharides obtained from Escherichia coli J‐5 lipopolysaccharide

Müller‐Loennies

Holst²,

Lindner

et al. 1999

European Journal of Biochemistry

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The chemical structure of the phosphorylated lipopolysaccharide (LPS) of Escherichia coli J-5 was investigated because it is of biomedical interest in the context of septic shock, a syndrome often encountered in nosocomial infections with gram-negative pathogens. The successive de-O-acylation and de-N-acylation of J-5 LPS yielded phosphorylated oligosaccharides which represent the complete carbohydrate backbone. Five compounds were separated by high-performance anion-exchange chromatography and analysed by one-dimensional and twodimensional homonuclear and heteronuclear 1 H-NMR, 13 C-NMR and 31 P-NMR spectroscopy. The main product was a nonasaccharide of the structurewherein all sugars are present as d-pyranoses. Hep and Kdo represent l-glycero-d-manno-heptose and 3-deoxy-d-manno-oct-2-ulosonic acid, respectively. In addition, two octasaccharides and two heptasaccharides were isolated that were partial structures of the nonasaccharide. In one octasaccharide the terminal a-d-GlcpN was missing and an additional phosphate group linked to O4 of the branched heptose was present, whereas in the other octasaccharide the sidechain Kdo was missing. In both heptasaccharides the side-chain a-d-GlcpN-(137)-l-a-d-Hepp-disaccharide was absent; they differed in their phosphate substitution. Whereas both heptasaccharides contained two phosphates in the lipid-A backbone (b-1,6-linked GlcpN-disaccharide at the reducing end) and one phosphate group at O4 of the first heptose, only one of them was additionally substituted with phosphate at O4 of the second heptose.Keywords: antibodies; biosynthesis; E. coli J-5; lipopolysaccharide; MALDI-TOF MS; phosphorylation; RcP + -chemotype.Lipopolysaccharide (LPS, endotoxin) is the major component of the outer membrane of gram-negative bacteria and is responsible for many of the pathophysiological effects observed during infections with gram-negative pathogens that may lead to septic shock and death [1,2]. Enterobacterial LPS consists of three domains, i.e. lipid A, core region and O-specific chain [1,3], of which lipid A is structurally the most conserved among different pathogenic bacteria [4] and represents the toxic principle of LPS [5]. Despite decades of intensive research and a great demand for alternatives, conventional antibiotic treatment still remains the main weapon of clinicians in the treatment of such infections. As the toxic effects exerted by LPS are independent of the viability of bacteria and considering the increasing resistance of pathogenic bacteria to antibiotics, the search for alternative strategies is of major importance. One of the most promising approaches for the immunotherapy of septic shock is passive immunization with antibodies that are directed against the conserved regions of LPS, i.e. lipid A and the core region. Such antibodies are expected to be cross-reactive with different gramnegative pathogens and might therefore be cross-protective. The induction of such antibodies could be achieved by immunization with lipid A presented in an appropriate form or mut...

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A 2-deoxy analogue of KDO as the first inhibitor of the enzyme CMP-KDO synthetase

Cited by 45 publications

References 17 publications

Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

Structure-based Mechanism of CMP-2-keto-3-deoxymanno-octulonic Acid Synthetase

Biochemistry Of Endotoxins

Isolation and structural analysis of phosphorylated oligosaccharides obtained from Escherichia coli J‐5 lipopolysaccharide

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