Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BvgAS two-component system is the master regulator of virulence gene expression in the mammalian pathogens Bordetella pertussis, Bordetella parapertussis and Bordetella bronchiseptica. This paper reports the partial cloning and characterization of the bvgAS loci of the 'new' Bordetella species Bordetella holmesii, Bordetella trematum and Bordetella hinzii, which are increasingly recognized as opportunistic pathogens in humans. It is demonstrated that the cytoplasmic signalling domains of the BvgS histidine kinases of B. pertussis and B. holmesii are functionally interchangeable, while signal perception by the two sensor proteins seems to be different. Furthermore, it is shown that, despite the high similarity of the BvgA proteins of B. pertussis and B. holmesii, promoter recognition by the response regulator proteins differs substantially in these organisms.
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PMID:Functional characterization of the BvgAS two-component system of Bordetella holmesii. 1552 58

The proliferation of human lymphoblastoma cell line (H9) was differently stimulated by Peptide Histidine Methionine (PHM) and Vasoactive Intestinal Peptide (VIP). PHM induced a cyclic AMP (cAMP) accumulation, abolished by Adenylate Cyclase (AC) inhibitors leading to a loss of proliferative effect. VIP mitogenic activity was Pertussis toxin (PTX) sensitive and AC inhibitors insensitive. Pharmacological experiments performed on H9 membranes with or without a GTP analogue indicated expression of both GTP-insensitive and -sensitive PHM/VIP high-affinity binding sites (HA). H9 cells expressed only the VPAC1 receptor. VIP(10-28), known as a VPAC1 antagonist, bond to all GTP-insensitive PHM sites and inhibited evenly the PHM and VIP mitogenic actions. These data strongly suggested different mechanisms initiated by VIP and PHM and highlighted the key role of GTP-insensitive binding sites in the control of cell proliferation.
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PMID:Human H9 cells proliferation is differently controlled by vasoactive intestinal peptide or peptide histidine methionine: implication of a GTP-insensitive form of VPAC1 receptor. 1558 42

During sympathetic neurotransmitter release, there is evidence for differential modulation of cotransmitter release by endothelin (ET)-1. Using nerve growth factor (NGF)-differentiated PC12 cells, the effects of ET-1 on K(+)-stimulated release of ATP, dopamine (DA), and neuropeptide Y (NPY) were quantified using high-pressure liquid chromatography or radioimmunoassay. ET-1, in a concentration-dependent manner, inhibited the release of ATP, but not DA and NPY. Preincubation with the ET(A/B) antagonist, PD 142893 (N-acetyl-beta-phenyl-D-Phe-Leu-Asp-Ile-Ile-Trp), reversed the inhibitory effect of ET-1 on ATP release, which remained unaffected in the presence of the ET(A)-specific antagonist BQ123 [cyclo(D-Asp-Pro-D-Val-Leu-D-Trp)]. The ET(B) agonists, sarafotoxin 6c (Cys-Thr-Cys-Asn-Asp-Met-Thr-Asp-Glu-Glu-Cys-Leu-Asn-Phe-Cys-His-Gln-Asp-Val-Ile-Trp), BQ 3020 (N-acetyl-[Ala(11,15)]-endothelin 1 fragment 6-21Ac-Leu-Met-Asp-Lys-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-IIe-IIe-Trp), and IRL 1620 (N-succinyl-[Glu(9), Ala(11,15)]-endothelin 1 fragment 8-21Suc-Asp-Glu-Glu-Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp), decreased K(+)-stimulated release of ATP in a dose-dependent manner, and this effect was reversed by the ET(B) antagonists RES 701-1 [cyclic (Gly1-Asp9) (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp-Trp-Phe-Phe-Asn-Tyr-Tyr-Trp)] and BQ 788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-l-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucine sodium salt). Preincubation of PC12 cells with pertussis toxin reversed the ET-1-induced inhibition of the K(+)-evoked ATP release. Real-time intracellular calcium level recordings were performed on PC-12 cell suspensions, and ET-1 induced a dose-dependent decrease in the K(+)-evoked calcium levels. Nifedipine, the L-type voltage-dependent Ca(2+) channel antagonist, caused inhibition of the K(+)-stimulated ATP release, but the N-type Ca(2+) channel antagonist, omega-conotoxin GVIA, did not reverse the effect on ATP release. These data suggest that ET-1 modulates the release of ATP via the ET(B) receptor and its associated G(i/o) G-protein through attenuation of the influx of extracellular Ca(2+) through L-type channels.
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PMID:Endothelin (ET)-1-induced inhibition of ATP release from PC-12 cells is mediated by the ETB receptor: differential response to ET-1 on ATP, neuropeptide Y, and dopamine levels. 1568 74

Yersinia enterocolitica causes human gastroenteritis, and many isolates have been classified as either "American" or "non-American" strains based on their geographic prevalence and virulence properties. In this study we describe identification of a transcriptional regulator that controls expression of the Y. enterocolitica ytxAB genes. The ytxAB genes have the potential to encode an ADP-ribosylating toxin with similarity to pertussis toxin. However, a ytxAB null mutation did not affect virulence in mice. Nevertheless, the ytxAB genes are conserved in many Y. enterocolitica strains. Interestingly, American and non-American strains have different ytxAB alleles encoding proteins that are only 50 to 60% identical. To obtain further insight into the ytxAB locus, we investigated whether it is regulated as part of a known or novel regulon. Transposon mutagenesis identified a LysR-like regulator, which we designated YtxR. Expression of ytxR from a nonnative promoter increased Phi(ytxA-lacZ) operon fusion expression up to 35-fold. YtxR also activated expression of its own promoter. DNase I footprinting showed that a His(6)-YtxR fusion protein directly interacted with the ytxA and ytxR control regions at similar distances upstream of their probable transcription initiation sites, identified by primer extension. Deletion analysis demonstrated that removal of the regions protected by His(6)-YtxR in vitro eliminated YtxR-dependent induction in vivo. The ytxAB locus is not present in most Yersinia species. In contrast, ytxR is conserved in multiple Yersinia species, as well as in the closely related organisms Photorhabdus luminescens and Photorhabdus asymbiotica. These observations suggest that YtxR may play a conserved role involving regulation of other genes besides ytxAB.
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PMID:YtxR, a conserved LysR-like regulator that induces expression of genes encoding a putative ADP-ribosyltransferase toxin homologue in Yersinia enterocolitica. 1699 67

The BvgAS system controls the expression of most virulence factors in Bordetella pertussis. Recently, we identified an orthologous system in the related human pathogen Bordetella holmesii. However, while we found that the orthologous histidine kinases BvgS could be functionally exchanged between the two species, the B. holmesii response regulator BvgA(BH) could not substitute for its B. pertussis counterpart in vivo and, accordingly, was not able to bind to B. pertussis virulence promoters in vitro. Here we show that a hybrid response regulator consisting of the B. pertussis derived DNA-binding output domain of BvgA(BP) combined with the B. holmesii receiver domain binds to BvgA(BP) regulated virulence promoters of B. pertussis in vitro and is functional in B. pertussis in vivo. This shows that the inability of BvgA(BH) to complement BvgA(BP) in B. pertussis is due to the small number of sequence variations present in its output domain. However, by mutation analysis we show that four amino acid exchanges present in the helix-turn-helix motif of BvgA(BH) as compared to BvgA(BP) are not the only reason for its inability to substitute for BvgA(BP) but additional mutations present in the output domain must play a role.
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PMID:Molecular characterization of the BvgA response regulator of Bordetella holmesii. 1740 Apr 38

Neutrophils are a class of leukocytes involved in innate immunity by monitoring and scavenging invading microorganisms and toxic substances. The actions of neutrophils in damaged tissues are still not well understood, particularly in the early stage of inflammation, and as-yet-unknown neutrophil-activating substances are proposed to induce their acute transmigration and activation. Here, we isolated and identified from porcine hearts a neutrophil-activating peptide. Structural analyses indicated that the primary structure of this peptide is formyl-Met-Thr-Asn-Ile-Arg-Lys-Ser-His-Pro-Leu-Met-Lys-Ile-Ile-Asn, which is identical to that of the N-terminal pentadecapeptide of porcine mitochondrial cytochrome b; we therefore named the newly isolated peptide "mitocryptide-2" (MCT-2), since we have recently purified and identified mitocryptide-1, a different class of a neutrophil-activating peptide. Synthetic MCT-2 and its human homolog hMCT-2 induced beta-hexosaminidase release in and chemotaxis of HL-60 cells differentiated into neutrophilic/granulocytic cells. The induction of beta-hexosaminidase release, chemotaxis, and the increase in the intracellular free Ca(2+) concentration by hMCT-2 were completely suppressed by pertussis toxin, indicating the involvement of G(i)- or G(o)-type G proteins in the signaling pathways. Moreover, MCT-2 and hMCT-2 also stimulated beta-hexosaminidase secretion in human neutrophils isolated from peripheral blood in a concentration-dependent manner. Additionally, these peptides partially competed with [(3)H]formyl-Met-Leu-Phe binding to HL-60 cells differentiated into neutrophilic/granulocytic cells, presenting the possibility that the receptor for MCT-2 and hMCT-2 is one of the formyl peptide receptors. These results demonstrate that MCT-2 and its human homolog hMCT-2 are cryptides that activate neutrophils, thus suggesting the presence of regulatory mechanisms involving such mitocryptides in innate immunity.
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PMID:Mitocryptide-2: purification, identification, and characterization of a novel cryptide that activates neutrophils. 1934 87

Adenylate cyclase-hemolysin toxin (CyaA) produced from the human respiratory tract pathogen Bordetella pertussis requires fatty-acyl modification by CyaC-acyltransferase to become an active toxin. Previously, the recombinant CyaA pore-forming (CyaA-PF) fragment expressed in Escherichia coli was shown to be hemolytically active upon palmitoylation in vivo by cosynthesized CyaC. Here, the 21-kDa CyaC enzyme separately expressed in E. coli as an inclusion body was solubilized in 8 M urea and successfully refolded into an enzymatically active monomer. In addition to the capability of activating CyaA-PF in vitro, CyaC showed esterase activity against p-nitrophenyl acetate (pNPA) and p-nitrophenyl palmitate (pNPP), with preferential hydrolysis toward pNPP when compared with chymotrypsin. A homology-based CyaC structure suggested a conceivable role of a catalytic triad including Ser(30), His(33) and Tyr(66) in substrate catalysis. Alanine substitutions of these individual residues caused a drastic decrease in specific activities of all three mutant enzymes (S30A, H33A and Y66A) toward pNPP, signifying that CyaC-acyltransferase shares a similar mechanism of hydrolysis with a serine esterase in which Ser(30) is part of the catalytic triad.
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PMID:Esterase activity of Bordetella pertussis CyaC-acyltransferase against synthetic substrates: implications for catalytic mechanism in vivo. 2013 7

Pertussis toxoid, an acellular pertussis vaccine prepared by hydrogen peroxide treatment in the presence of Fe(3+), has not been well characterized. Because the toxoid has been a part of the DTaP vaccine for infants, it is of interest and significance to have a clear understanding of its structure. The five subunits of pertussis toxin (PT) have a combined molecular weight of approximately 95,000Da. The peroxide treatment in toxoid formation introduces additional complexity into the protein sequence. To maximize sequence coverage, a two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS) approach was used to analyze the tryptic digest of toxoid as a whole. An analytical-scale high-performance liquid chromatography (HPLC) instrument using a pentafluorophenyl (PFP) column was used as the first-dimensional LC for fraction collection. The fractions were then analyzed by nanoLC-MS/MS using a C18 column to acquire collision-activated dissociation (CAD) spectra of the tryptic peptides. It is shown that a PFP column has a different peptide retention specificity from a C18 column. A combination of a PFP column and a C18 column is a viable approach for dispersing peptides in a complex mixture. From the structures of 65 peptides that represented approximately 50% of its sequence, PT was found to have sustained heavy oxidative damages during toxoid preparation. Nearly all methionine, cysteine, and (likely) tryptophan residues were oxidized. Evidence of histidine and tyrosine oxidation was also observed. In addition, a large percentage of asparagine was found hydrolyzed to aspartic acid. These findings corrrelate well with the reduction of PT toxicity by peroxide treatment.
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PMID:Characterization of pertussis toxoid by two-dimensional liquid chromatography-tandem mass spectrometry. 2020 17

2,3-Diacetamido-2,3-dideoxy-d-mannuronic acid (ManNAc3NAcA) is an unusual dideoxy sugar first identified nearly 30 years ago in the lipopolysaccharide of Pseudomonas aeruginosa O:3a,d. It has since been observed in other organisms, including Bordetella pertussis, the causative agent of whooping cough. Five enzymes are required for the biosynthesis of UDP-ManNAc3NAcA starting from UDP-N-acetyl-d-glucosamine. Here we describe a structural study of WlbA, the NAD-dependent dehydrogenase that catalyzes the second step in the pathway, namely, the oxidation of the C-3' hydroxyl group on the UDP-linked sugar to a keto moiety and the reduction of NAD(+) to NADH. This enzyme has been shown to use alpha-ketoglutarate as an oxidant to regenerate the oxidized dinucleotide. For this investigation, three different crystal structures were determined: the enzyme with bound NAD(H), the enzyme in a complex with NAD(H) and alpha-ketoglutarate, and the enzyme in a complex with NAD(H) and its substrate (UDP-N-acetyl-d-glucosaminuronic acid). The tetrameric enzyme assumes an unusual quaternary structure with the dinucleotides positioned quite closely to one another. Both alpha-ketoglutarate and the UDP-linked sugar bind in the WlbA active site with their carbon atoms (C-2 and C-3', respectively) abutting the re face of the cofactor. They are positioned approximately 3 A from the nicotinamide C-4. The UDP-linked sugar substrate adopts a highly unusual curved conformation when bound in the WlbA active site cleft. Lys 101 and His 185 most likely play key roles in catalysis.
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PMID:Structural and functional studies of WlbA: A dehydrogenase involved in the biosynthesis of 2,3-diacetamido-2,3-dideoxy-D-mannuronic acid . 2069 May 87

Bordetella pertussis employs numerous strategies to evade the immune system, including the ability to resist killing via complement. Previously we have shown that B. pertussis binds a complement regulatory protein, C1 esterase inhibitor (C1inh) to its surface in a Bvg-regulated manner (i.e. during its virulence phase), but the B. pertussis factor was not identified. Here we set out to identify the B. pertussis C1inh-binding factor. Using a serum overlay assay, we found that this factor migrates at approximately 100 kDa on an SDS-PAGE gel. To identify this factor, we isolated proteins of approximately 100 kDa from wild type strain BP338 and from BP347, an isogenic Bvg mutant that does not bind C1inh. Using mass spectrometry and bioinformatics, we identified the autotransporter protein Vag8 as the putative C1inh binding protein. To prove that Vag8 binds C1inh, vag8 was disrupted in two different B. pertussis strains, namely BP338 and 18-323, and the mutants were tested for their ability to bind C1inh in a surface-binding assay. Neither mutant strain was capable of binding C1inh, whereas a complemented strain successfully bound C1inh. In addition, the passenger domain of Vag8 was expressed and purified as a histidine-tagged fusion protein and tested for C1inh-binding in an ELISA assay. Whereas the purified Vag8 passenger bound C1inh, the passenger domain of BrkA (a related autotransporter protein) failed to do so. Finally, serum assays were conducted to compare wild type and vag8 mutants. We determined that vag8 mutants from both strains were more susceptible to killing compared to their isogenic wild type counterparts. In conclusion, we have discovered a novel role for the previously uncharacterized protein Vag8 in the immune evasion of B. pertussis. Vag8 binds C1inh to the surface of the bacterium and confers serum resistance.
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PMID:Bordetella pertussis autotransporter Vag8 binds human C1 esterase inhibitor and confers serum resistance. 2169 23


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