CMP‐Pseudaminic Acid is a Natural Potent Inhibitor of PseB, the First Enzyme of the Pseudaminic Acid Pathway in <i>Campylobacter jejuni</i> and <i>Helicobacter pylori</i>

McNally, David J.; Schoenhofen, Ian C.; Houliston, R. Scott; Khieu, Nam Huan; Whitfield, Dennis M.; Logan, Susan M.; Jarrell, Harold C.; Brisson, Jean‐Robert

doi:10.1002/cmdc.200700170

Cited by 20 publications

(21 citation statements)

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“…Further studies revealed that CMP-Pse acid was a potent inhibitor of the first enzyme (PseB) in the pathway with a K i (app) of 18.7 μM, allowing for negative feedback inhibition of the biosynthesis of the final CMP-Pse product. 89 A metabolomics approach, utilizing gene knockouts and detection of nucleotide intermediates by capillary electrophoresis–electrospray mass spectrometry, confirmed the direct involvement of the Pse proteins in pseudaminic acid biosynthesis. 101 Recently, pseudaminic acid has been chemically synthesized from GlcNAc, which will allow for more extensive studies for improving our understanding of the relationship between this sugar and bacterial O-linked glycosylation and pathogenicity.…”

Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 83%

“…88 Upon accumulation of the 4-keto sugar, PseB can also catalyze an additional C5 epimerization to generate UDP-2-acetamido-4-keto-2,4,6-trideoxy-α- d -glucose, the UDP-4-keto sugar utilized in the diNAcBac pathway. 89 This side reaction allows for cross talk between the two pathways and potentially establishes another level of control in the production of these sugars for the assembly of bacterial glycoconjugates, with respect to their involvement in pathogenicity. Electron microscopy and X-ray structural analysis of PseB from H. pylori revealed a hexameric assembly in the form of a compact doughnut-like structure (Figure 8).…”

Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 99%

“…Further mutagenesis studies with the PseB homolog in C. jejuni were confirmatory in nature, and Y135F and K127A mutations resulted in severe attenuation of enzyme activity. 89 The proposed PseB reaction mechanism can be dissected into three distinct steps starting with oxidation at the C4 position of UDP-GlcNAc through a catalytic base (Y141) and reduction of NADP + . This is followed by abstraction of the C5 proton (most likely by K133 acting as a general base), which results in the elimination of water and formation of an enone intermediate.…”

Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 99%

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The Renaissance of Bacillosamine and Its Derivatives: Pathway Characterization and Implications in Pathogenicity

Morrison

Imperiali

2014

Biochemistry

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Prokaryote-specific sugars, including N,N´-diacetylbacillosamine (diNAcBac) and pseudaminic acid, have experienced a renaissance in the past decade due to their discovery in glycans related to microbial pathogenicity. DiNAcBac is found at the reducing end of oligosaccharides of N- and O-linked bacterial protein glycosylation pathways of Gram-negative pathogens including Campylobacter jejuni and Neisseria gonorrhoeae. Further derivatization of diNAcBac results in the nonulosonic acid known as legionaminic acid, which was first characterized in the O-antigen of the lipopolysaccharide (LPS) in Legionella pneumophila. Pseudaminic acid, an isomer of legionaminic acid, is also important in pathogenic bacteria such as Helicobacter pylori due to its occurrence in O-linked glycosylation of flagellin proteins, which plays an important role in flagellar assembly and motility. Here, we present recent advances in the characterization of the biosynthetic pathways leading to these highly modified sugars and investigation of the roles that each plays in bacterial fitness and pathogenicity.

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Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 83%

Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 99%

Section: Derivatives Of Nn′-diacetylbacillosaminementioning

confidence: 99%

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The Renaissance of Bacillosamine and Its Derivatives: Pathway Characterization and Implications in Pathogenicity

Morrison

Imperiali

2014

Biochemistry

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“…All NulO genes showed much higher similarity to the C. jejuni / H. pylori Pse biosynthetic genes than to the Leg counterparts of C. jejuni (Table I). The presence of a homolog to PseB (Tanf_01185), in particular, was a strong indication towards Pse, as this enzyme is unique among other dehydratases in its ability to additionally perform a C-5 epimerization (McNally et al 2008). …”

Section: Resultsmentioning

confidence: 99%

Tannerella forsythiastrains display different cell-surface nonulosonic acids: biosynthetic pathway characterization and first insight into biological implications

et al. 2016

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Tannerella forsythia is an anaerobic, Gram-negative periodontal pathogen. A unique O-linked oligosaccharide decorates the bacterium’s cell surface proteins and was shown to modulate the host immune response. In our study, we investigated the biosynthesis of the nonulosonic acid (NulO) present at the terminal position of this glycan. A bioinformatic analysis of T. forsythia genomes revealed a gene locus for the synthesis of pseudaminic acid (Pse) in the type strain ATCC 43037 while strains FDC 92A2 and UB4 possess a locus for the synthesis of legionaminic acid (Leg) instead. In contrast to the NulO in ATCC 43037, which has been previously identified as a Pse derivative (5-N-acetimidoyl-7-N-glyceroyl-3,5,7,9-tetradeoxy-l-glycero-l-manno-NulO), glycan analysis of strain UB4 performed in this study indicated a 350-Da, possibly N-glycolyl Leg (3,5,7,9-tetradeoxy-d-glycero-d-galacto-NulO) derivative with unknown C5,7 N-acyl moieties. We have expressed, purified and characterized enzymes of both NulO pathways to confirm these genes’ functions. Using capillary electrophoresis (CE), CE–mass spectrometry and NMR spectroscopy, our studies revealed that Pse biosynthesis in ATCC 43037 essentially follows the UDP-sugar route described in Helicobacter pylori, while the pathway in strain FDC 92A2 corresponds to Leg biosynthesis in Campylobacter jejuni involving GDP-sugar intermediates. To demonstrate that the NulO biosynthesis enzymes are functional in vivo, we created knockout mutants resulting in glycans lacking the respective NulO. Compared to the wild-type strains, the mutants exhibited significantly reduced biofilm formation on mucin-coated surfaces, suggestive of their involvement in host-pathogen interactions or host survival. This study contributes to understanding possible biological roles of bacterial NulOs.

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“…and Helicobacter spp. and function as virulence factors [ 216 ]. Leptospiral flagella are located between the inner membrane (IM) and outer membrane (OM) and drive motility [ 217 ].…”

Section: Discussionmentioning

confidence: 99%

What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira

et al. 2016

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Leptospirosis, caused by spirochetes of the genus Leptospira, is a globally widespread, neglected and emerging zoonotic disease. While whole genome analysis of individual pathogenic, intermediately pathogenic and saprophytic Leptospira species has been reported, comprehensive cross-species genomic comparison of all known species of infectious and non-infectious Leptospira, with the goal of identifying genes related to pathogenesis and mammalian host adaptation, remains a key gap in the field. Infectious Leptospira, comprised of pathogenic and intermediately pathogenic Leptospira, evolutionarily diverged from non-infectious, saprophytic Leptospira, as demonstrated by the following computational biology analyses: 1) the definitive taxonomy and evolutionary relatedness among all known Leptospira species; 2) genomically-predicted metabolic reconstructions that indicate novel adaptation of infectious Leptospira to mammals, including sialic acid biosynthesis, pathogen-specific porphyrin metabolism and the first-time demonstration of cobalamin (B12) autotrophy as a bacterial virulence factor; 3) CRISPR/Cas systems demonstrated only to be present in pathogenic Leptospira, suggesting a potential mechanism for this clade’s refractoriness to gene targeting; 4) finding Leptospira pathogen-specific specialized protein secretion systems; 5) novel virulence-related genes/gene families such as the Virulence Modifying (VM) (PF07598 paralogs) proteins and pathogen-specific adhesins; 6) discovery of novel, pathogen-specific protein modification and secretion mechanisms including unique lipoprotein signal peptide motifs, Sec-independent twin arginine protein secretion motifs, and the absence of certain canonical signal recognition particle proteins from all Leptospira; and 7) and demonstration of infectious Leptospira-specific signal-responsive gene expression, motility and chemotaxis systems. By identifying large scale changes in infectious (pathogenic and intermediately pathogenic) vs. non-infectious Leptospira, this work provides new insights into the evolution of a genus of bacterial pathogens. This work will be a comprehensive roadmap for understanding leptospirosis pathogenesis. More generally, it provides new insights into mechanisms by which bacterial pathogens adapt to mammalian hosts.

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CMP‐Pseudaminic Acid is a Natural Potent Inhibitor of PseB, the First Enzyme of the Pseudaminic Acid Pathway in Campylobacter jejuni and Helicobacter pylori

Cited by 20 publications

References 43 publications

The Renaissance of Bacillosamine and Its Derivatives: Pathway Characterization and Implications in Pathogenicity

The Renaissance of Bacillosamine and Its Derivatives: Pathway Characterization and Implications in Pathogenicity

Tannerella forsythiastrains display different cell-surface nonulosonic acids: biosynthetic pathway characterization and first insight into biological implications

What Makes a Bacterial Species Pathogenic?:Comparative Genomic Analysis of the Genus Leptospira

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