Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bordetella pertussis, the etiological agent of whooping cough, synthesizes a calmodulin-sensitive adenylate cyclase that is suspected to play a major role in the virulence of this bacterium. We show that adenylate cyclase synthesized as a 200-kilodalton protein is the product of the cyaA gene and that various virulent Bordetella species secrete this high-molecular-weight polypeptide without apparent proteolytic processing. When submitted to trypsin digestion, the 200-kilodalton protein was converted to a stable 45- to 50-kilodalton species. This corresponds to the size of the enzyme previously purified from a culture supernatant. The molecular heterogeneity reported for the various identified forms of adenylate cyclase could therefore result in part from proteolytic degradation or molecular aggregation of the major 200-kilodalton form of the enzyme.
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PMID:Synthesis and secretion of Bordetella pertussis adenylate cyclase as a 200-kilodalton protein. 232 14

Bordetella pertussis produces several potential virulence factors. One of these is an adenylate cyclase which penetrates eukaryotic cells, is activated by calmodulin and generates high levels of intracellular cAMP. We have found that pertussis infection in man leads to production of high titres (2000-8000) of anti-B. pertussis adenylate cyclase antibodies. Such antibodies also are produced after pertussis vaccination. They persist into adulthood, cross the placenta and disappear a few months after birth. The anti-adenylate cyclase antibodies found in human serum during pertussis infection do not neutralise the catalytic and penetrative activities of the enzyme.
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PMID:Antibodies to Bordetella pertussis adenylate cyclase are produced in man during pertussis infection and after vaccination. 237 55

The Bordetella pertussis cyaA gene encodes a virulence factor which is a bifunctional protein exhibiting calmodulin-sensitive adenylate cyclase and hemolytic activities (P. Glaser, H. Sakamoto, J. Bellahov, A. Ullmann, and A. Danchin, EMBO J. 7:3997-4004, 1988). We characterized the hemolytic and toxin activities of the 200-kilodalton (kDa) bifunctional (CyaA) protein and showed that, whether cell associated or secreted, the 200-kDa CyaA protein carries hemolytic and toxin functions. The catalytically active 45-kDa form of adenylate cyclase released by proteolytic digestion of the 200-kDa CyaA protein displayed neither hemolytic nor toxin activities. We constructed in-phase deletions in the 3' region of the cyaA gene, which presumably carries the hemolytic determinant, and showed that the resulting proteins exhibited wild-type adenylate cyclase activity and were secreted without processing into culture supernatants. The hemolytic activities of these mutant CyaA proteins were severely reduced, and their toxin activities were abolished. These results suggest that the structural integrity of the 200-kDa CyaA protein is necessary for toxin activity and that distinct structural determinants within the CyaA protein are involved in secretion, pore formation, and entry into target cells.
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PMID:Deletions affecting hemolytic and toxin activities of Bordetella pertussis adenylate cyclase. 240 63

Proliferation of Bordetella pertussis in the lungs of infant mice challenged by the intranasal route was examined. The bacteria rapidly proliferated in the lungs of mice challenged with a sublethal dose of a wild-type strain (BP338) or a filamentous hemagglutinin mutant (BPM409) from 500 at day 0 to 10(7) at day 15. The infection cleared in about 40 days. Pertussis toxin-deficient mutant BP357 gave a similar profile; however, the number of bacteria recovered was slightly reduced, suggesting that pertussis toxin is not essential for bacterial growth in the lungs. In contrast, adenylate cyclase toxin mutant BP348 was rapidly cleared from the lungs, with no viable bacteria remaining 10 days postchallenge, suggesting that the adenylate cyclase toxin is a colonization factor required for the bacteria to initiate infection.
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PMID:Adenylate cyclase toxin is critical for colonization and pertussis toxin is critical for lethal infection by Bordetella pertussis in infant mice. 240 70

This communication reports the effects of the exotoxin of Bordetella pertussis (pertussis toxin) on hamster brown fat cells. Pertussis toxin significantly increased the lipolytic and respiratory responses to isoproterenol but did not increase the basal rates of either of these processes. In contrast, the stimulation of respiration by the alpha-adrenergic agent phenylephrine was not altered by pertussis toxin. The inhibitory effects of adenosine on stimulated lipolysis, respiration, and adenylate cyclase activity were completely abolished by pertussis toxin, as was the ability of methylxanthines or adenosine deaminase to potentiate isoproterenol stimulation of respiration or lipolysis. These effects of pertussis toxin were associated with an ADP ribosylation of a single membrane protein having a molecular weight of approximately 41. These data demonstrate that pertussis toxin can prevent the inhibitory action of adenosine on brown fat cells and suggest that the effects of the nucleoside on these cells results from inhibition of adenylate cyclase. We further suggest that the enhanced responses to isoproterenol in pertussis-treated adipocytes results from a blockade of the action of endogenous adenosine. In addition to blocking adenosine action, pertussis toxin also abolished the antilipolytic effect of insulin. However, because the antilipolytic effect of insulin was prevented by adenosine deaminase and 3-isobutyl-1-methylxanthine and restored by 2-chloroadenosine, we conclude that insulin action on these cells is dependent on adenosine. Thus pertussis toxin blockade of insulin action appears to be secondary to blockade of adenosine action.
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PMID:Effects of pertussis toxin treatment on metabolism in hamster brown adipocytes. 241 1

2',5'-Dideoxyadenoside (DDA) inhibited both anti-IgE and ionophore A23187 induced histamine secretion from human basophils. Whereas DDA inhibited IgE-dependent histamine secretion when added at all times prior to challenge, release induced by A23187 was inhibited only with simultaneous addition of DDA and secretagogue. Dipyridamole, but not theophylline, abrogated DDA mediated inhibition of histamine release suggesting an intracellular mechanism of action of DDA. The observations that 2'-deoxyadenosine and 9-beta-D-arabinofuranosyladenine also inhibited release suggest that the its inhibitory effect was enhanced by manganese and reversed by islet activating protein from Bordetella pertussis suggest that DDA inhibits basophil histamine release by interacting with a guanine nucleotide binding protein which may be linked to either adenylate cyclase or other second messenger system(s).
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PMID:Inhibition of immunological and nonimmunological histamine release from human basophils by adenosine analogues that act at P-sites. 242 53

Bordetella pertussis and Bacillus anthracis, two taxonomically distinct bacteria, secrete adenylate cyclase toxins that are activated by the eukaryotic protein calmodulin. The two enzymes contain a well-conserved stretch of 24 amino acid residues [Escuyer et al. (1988) Gene 71, 293-298]. Antibodies have been obtained against two synthetic heptadecapeptides, covering part of the conserved sequences. The anti-peptide antibodies specifically reacted in Western blots with the rat brain adenylate cyclase as well as with the two bacterial enzymes. Anti-rat brain adenylate cyclase serum contained antibodies that were retained by the immobilized peptides, and the affinity-purified antibodies yielded the same recognition pattern of the eukaryotic enzyme as did the unfractionated serum. These results indicate that the eukaryotic adenylate cyclase contains an epitope closely related to that specified by the conserved bacterial sequence. The synthetic peptides and the bacterial adenylate cyclases appeared to compete for ATP (KD of the ATP-peptide complex ca. 0.2 mM), suggesting that the conserved sequence may be part of the substrate binding site in these two enzymes.
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PMID:Identification of a common domain in calmodulin-activated eukaryotic and bacterial adenylate cyclases. 247 Apr 5

We used an immunoblotting technique to compare the serum antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), a 69-kilodalton (kDa) adenylate cyclase-associated protein (69 KD protein), and Bordetella pertussis outer membrane proteins (OMPs) following either B. pertussis infection or immunization with whole-cell pertussis vaccine. Infection and vaccination induced nearly equally intense antibody responses to PT and to FHA, but vaccination induced stronger antibody responses to the 69 KD protein and to many OMPs. The importance of serum antibody responses to the 69 KD protein and to B. pertussis OMPs other than PT and FHA in conferring immunity to pertussis after vaccination is unknown. Serum antibody responses to PT following either infection or vaccination were almost exclusively to the 28-kDa enzymatic subunit (S1) and only rarely and weakly to the lesser molecular weight binding subunits (S2-S5).
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PMID:Human serum antibody responses to Bordetella pertussis infection and pertussis vaccination. 253 79

The structural organization of the low molecular mass form (43 kDa) of Bordetella pertussis adenylate cyclase was dissected taking advantage of the known sequence of the bacterial cya gene (Glaser, P., Ladant, D., Sezer, O., Pichot, F., Ullmann, A., and Danchin, A. (1988) Mol. Microbiol. 2, 19-30) and its low content of Trp and Met residues. Cleavage of the 43-kDa protein and of its complementary tryptic fragments (T25 and T18 peptides) with N-chlorosuccinimide and cyanogen bromide followed by sodium dodecyl sulfate-polyacrylamide gel analysis of digestion products allowed the following conclusions: (i) the catalytically active 43-kDa form of B. pertussis adenylate cyclase is within the first 400 residues of the protein encoded by the cya gene. T25 occupies the N-terminal domain of the protein (residues 1-235/237). Isolated T25 fragment exhibits a low but measurable enzymatic activity which indicates that it harbors the catalytic site; (ii) T18 which is the main calmodulin-binding domain, occupies the C-terminal segment of protein (residues 236/238-399) and is devoid of catalytic properties; (iii) the two complementary peptides T25 and T18 reassociated only in the presence of calmodulin, leading to significant recovery of the original activity. These results demonstrate that both fragments of the 43-kDa form of adenylate cyclase are essential for a high level of enzymatic activity.
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PMID:Characterization of the calmodulin-binding and of the catalytic domains of Bordetella pertussis adenylate cyclase. 253 1

Penetration of Bordetella pertussis adenylate cyclase into CHO cells was monotonically inhibited by polylysines, with a minimum degree of polymerization of greater than 6 and less than or equal to 9 to 10. Above this level, inhibitory potency per lysyl residue was independent of polymer length; 50% inhibition was obtained with 60 microM lysine monomer. Other polycations were also potent inhibitors. The adenylate cyclase itself showed a biphasic (stimulation-inhibition) response, with a similar independence of polymer length above a certain minimum. Half-maximal inhibitory concentrations for cyclic AMP accumulation corresponded to half-maximal stimulatory concentrations of poly-L-lysine for the cyclase. The inhibitory effect of polylysines on cyclic AMP accumulation was not reversed by washing or enzymatic removal of neuraminic acid. We conclude that charge-charge interactions play an important role in the penetration of B. pertussis adenylate cyclase into host cells.
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PMID:Modulation of invasiveness and catalytic activity of Bordetella pertussis adenylate cyclase by polycations. 253 95


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