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

---

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

Monocyte chemoattracant-1 (MCP-1) stimulates leukocyte chemotaxis to inflammatory sites, such as rheumatoid arthritis, atherosclerosis, and asthma, by use of the MCP-1 receptor, CCR2, a member of the G-protein-coupled seven-transmembrane receptor superfamily. These studies identified a family of antagonists, spiropiperidines. One of the more potent compounds blocks MCP-1 binding to CCR2 with a K(d) of 60 nm, but it is unable to block binding to CXCR1, CCR1, or CCR3. These compounds were effective inhibitors of chemotaxis toward MCP-1 but were very poor inhibitors of CCR1-mediated chemotaxis. The compounds are effective blockers of MCP-1-driven inhibition of adenylate cyclase and MCP-1- and MCP-3-driven cytosolic calcium influx; the compounds are not agonists for these pathways. We showed that glutamate 291 (Glu(291)) of CCR2 is a critical residue for high affinity binding and that this residue contributes little to MCP-1 binding to CCR2. The basic nitrogen present in the spiropiperidine compounds may be the interaction partner for Glu(291), because the basicity of this nitrogen was essential for affinity; furthermore, a different class of antagonists, a class that does not have a basic nitrogen (2-carboxypyrroles), were not affected by mutations of Glu(291). In addition to the CCR2 receptor, spiropiperidine compounds have affinity for several biogenic amine receptors. Receptor models indicate that the acidic residue, Glu(291), from transmembrane-7 of CCR2 is in a position similar to the acidic residue contributed from transmembrane-3 of biogenic amine receptors, which may account for the shared affinity of spiropiperidines for these two receptor classes. The models suggest that the acid-base pair, Glu(291) to piperidine nitrogen, anchors the spiropiperidine compound within the transmembrane ovoid bundle. This binding site may overlap with the space required by MCP-1 during binding and signaling; thus the small molecule ligands act as antagonists. An acidic residue in transmembrane region 7 is found in most chemokine receptors and is rare in other serpentine receptors. The model of the binding site may suggest ways to make new small molecule chemokine receptor antagonists, and it may rationalize the design of more potent and selective antagonists.
...
PMID:Identification of the binding site for a novel class of CCR2b chemokine receptor antagonists: binding to a common chemokine receptor motif within the helical bundle. 1077 Sep 25

Pericardial disease is common in patients with renal disease. Approximately 20% of uremic patients requiring chronic dialysis develop uremic pericarditis or dialysis pericarditis. In all forms of uremic pericarditis, cardiac tamponade is the main danger. Pericardial contents are sterile unless secondarily infected. Differential diagnosis may be difficult, especially in mentally confused patients and because nonuremic intercurrent pericarditis of any cause is always possible. In uremic patients, frequent autonomic impairment and decreased cardiac adenylate cyclase limit heart rate increases during pericarditis, even during tamponade, so that the heart rate may be deceptively slow even with fever and hypotension. Adequate renal dialysis effectively ends uremic pericarditis. Several factors are associated with precipitating dialysis pericarditis and effusion, above all inadequate dialysis. Pericarditis in hepatorenal failure occurs at relatively low blood urea nitrogen levels and does not respond to dialysis.
...
PMID:Pericardial disease in renal patients. 1117 59

A series of tricyclic imidazo[2,1-i]purinones and ring-enlarged analogues derived from xanthine derivatives have been prepared as adenosine receptor (AR) antagonists. In comparison with xanthines, the tricyclic compounds exhibit increased water solubility due to a basic nitrogen atom, which can be protonated under physiological conditions. Substituents were introduced that confer high affinity for A(2A) or A(3) ARs, respectively. A new capillary electrophoresis method was developed for the determination of the enantiomeric purity of selected chiral products using native and modified beta-cyclodextrins as chiral discriminators. The compounds were investigated in radioligand binding assays at rat brain A(1) and A(2A) ARs. Selected compounds were additionally investigated in radioligand binding assays at human recombinant A(3) ARs and in functional studies (adenylate cyclase assays) at A(1) ARs of rat fat cell membranes, A(2A) ARs of rat PC 12 cell membranes, and mouse A(2B) ARs of NIH 3T3 cell membranes. Structure-activity relationships were similar to those of corresponding xanthine derivatives. The 2-styrylimidazopurinones were less potent at A(2A) ARs as compared to 8-styrylxanthine derivatives. The most potent compound at A(2A) ARs was (S)-1,4-dimethyl-8-ethyl-2-styryl-imidazo[2,1-i]purinone (S-25) exhibiting a K(i) value of 424 nM at rat A(2A) ARs. The compound was highly selective for A(2A) receptors vs A(1) and A(3) ARs. Selectivity vs A(2B) ARs, however, was low. Among the 1-unsubstituted 2-phenyl-imidazo[2,1-i]purin-5-one derivatives, very potent and highly selective antagonists for human A(3) ARs were identified. The most potent A(3) antagonist of the present series was (R)-4-methyl-8-ethyl-2-phenyl-imidazo[2,1-i]purin-5-one (R-24) exhibiting a K(i) value of 2.3 nM and high selectivity for A(3) receptors vs all other AR subtypes.
...
PMID:Imidazo[2,1-i]purin-5-ones and related tricyclic water-soluble purine derivatives: potent A(2A)- and A(3)-adenosine receptor antagonists. 1213 54

The regulatory control of pertussis vaccines, as for other biological products, requires that they conform to specified standards of safety and efficacy. The current potency test for whole cell vaccines, the intracerebral mouse protection test (AMPT) is still the only such assay that has shown a correlation with protection in children. An alternative in vivo assay based on non-lethal aerosol challenge of mice has been assessed as a replacement for the current AMPT. An in vitro assay based on determination of reactive nitrogen/oxygen intermediates produced as a result of macrophage activation has also been investigated as a potential replacement for the in vivo challenge test. On the other hand, for safety testing, an enzymatic-HPLC coupled assay using a fluorescein-labelled G alpha(i3)C20 peptide to measure the enzymatic ribosylation activity of active pertussis toxin was evaluated for its suitability as a replacement for the current histamine sensitisation test (HIST). An assay for adenylate cyclase toxin (ACT)-related toxicity, based on measuring the ACT-induced oxidative burst in macrophage-like cell cultures has also been investigated. Although some questions still need to be answered in relation to the development of suitable replacements for in vivo tests of pertussis vaccines, the prospects for further improvements are promising.
...
PMID:Developments in reduction and replacement of in vivo toxicity and potency tests for pertussis vaccines. 1267 25

Schizosaccharomyces pombe utilizes two opposing signaling pathways to sense and respond to its nutritional environment. Glucose detection triggers a cyclic AMP signal to activate protein kinase A (PKA), while glucose or nitrogen starvation activates the Spc1/Sty1 stress-activated protein kinase (SAPK). One process controlled by these pathways is fbp1+ transcription, which is glucose repressed. In this study, we isolated strains carrying mutations that reduce high-level fbp1+ transcription conferred by the loss of adenylate cyclase (git2delta), including both wis1- (SAPK kinase) and spc1- (SAPK) mutants. While characterizing the git2delta suppressor strains, we found that the git2delta parental strains are KCl sensitive, though not osmotically sensitive. Of 102 git2delta suppressor strains, 17 strains display KCl-resistant growth and comprise a single linkage group, carrying mutations in the cgs1+ PKA regulatory subunit gene. Surprisingly, some of these mutants are mostly wild type for mating and stationary-phase viability, unlike the previously characterized cgs1-1 mutant, while showing a significant defect in fbp1-lacZ expression. Thus, certain cgs1- mutant alleles dramatically affect some PKA-regulated processes while having little effect on others. We demonstrate that the PKA and SAPK pathways regulate both cgs1+ and pka1+ transcription, providing a mechanism for cross talk between these two antagonistically acting pathways and feedback regulation of the PKA pathway. Finally, strains defective in both the PKA and SAPK pathways display transcriptional regulation of cgs1+ and pka1+, suggesting the presence of a third glucose-responsive signaling pathway.
...
PMID:Suppressors of an adenylate cyclase deletion in the fission yeast Schizosaccharomyces pombe. 1518 83

In the filamentous, nitrogen-fixing cyanobacterium Anabaena sp. PCC7120, red light (630 nm) decreased, whereas far-red light (720 nm) increased cellular adenosine 3',5'-cyclic monophosphate (cAMP) content. To find a red and far-red light photoreceptor that triggers the cAMP signal cascade, we disrupted 10 open reading frame having putative chromophore-binding GAF domains. The response of the cellular cAMP concentration to red and far-red light in each open reading frame disruptant was determined. It was found that only the mutant of the gene all2699 failed to respond to far-red light. The open reading frame named as aphC encoded a protein with 920 amino acids including GAF domains similar to those involved in Cph2, a photoreceptor of Synechocystis sp. PCC6803. To determine which adenylate cyclase (AC) is responsible for far-red light signal, we disrupted all AC genes and found that CyaC was the candidate. The enzymatic activity of CyaC might be controlled by a far-red light photoreceptor through the phosphotransfer reaction. The site-specific mutant of the Asp59 residue of the receiver (R1) domain of CyaC lost its light-response capability. It was suggested that the far-red light signal was received by AphC and then transferred to the N-terminal response regulator domain of CyaC. Then its catalytic activity was stimulated, which increased the cellular cAMP concentration and drove the subsequent signal transduction cascade.
...
PMID:A phytochrome-like protein AphC triggers the cAMP signaling induced by far-red light in the cyanobacterium Anabaena sp. strain PCC7120. 1562 25

Cellular cAMP was rapidly increased in the nitrogen-fixing cyanobacterium, Anabaena sp. PCC 7120, by the addition of 200 mM NaCl to the culture medium. Other alkaline-metal chlorides such as KCl or LiCl caused a lesser increase. The increase in cellular cAMP was transient and diminished when an adenylate cyclase, CyaC, which contains the conserved domains of the bacterial two-component regulatory system, was disrupted. DNA microarray analysis showed that expression of a gene cluster containing all5347 and alr5351 (hglE) was upregulated by NaCl in the wild-type strain but not in the cyaC mutant. Primer extension analysis indicated that transcription levels of all5347 and hglE were rapidly increased in response to the NaCl addition, and that these genes have NaCl-dependent transcription start sites. It was concluded that NaCl induced expression of genes related to heterocyst envelope formation in this cyanobacterium, possibly via a CyaC-cAMP signal transduction system.
...
PMID:NaCl enhances cellular cAMP and upregulates genes related to heterocyst development in the cyanobacterium, Anabaena sp. strain PCC 7120. 1618 71

Strains of Enterobacter cloacae show promise as biological control agents for Pythium ultimum-induced damping-off on cucumber and other crops. Enterobacter cloacae M59 is a mini-Tn5 Km transposon mutant of strain 501R3. Populations of M59 were significantly lower on cucumber roots and decreased much more rapidly than those of strain 501R3 with increasing distance from the soil line. Strain M59 was decreased or deficient in growth and chemotaxis on most individual compounds detected in cucumber root exudate and on a synthetic cucumber root exudate medium. Strain M59 was also slightly less acid resistant than strain 501R3. Molecular characterization of strain M59 demonstrated that mini-Tn5 Km was inserted in cyaA, which encodes adenylate cyclase. Adenylate cyclase catalyzes the formation of cAMP and cAMP levels in cell lysates from strain M59 were approximately 2% those of strain 501R3. Addition of exogenous, nonphysiological concentrations of cAMP to strain M59 restored growth (1 mM) and chemotaxis (5 mM) on synthetic cucumber root exudate and increased cucumber seedling colonization (5 mM) by this strain without serving as a source of reduced carbon, nitrogen, or phosphorous. These results demonstrate a role for cyaA in colonization of cucumber roots by Enterobacter cloacae.
...
PMID:Mutation in cyaA in Enterobacter cloacae decreases cucumber root colonization. 1702 89

Methylprednisolone sodium succinate (MPSS) administered during reperfusion may improve myocardial function. These effects have been related to adrenergic stimulation. The present study investigated (1) the effects of ischemia and reperfusion on the beta-adrenergic response system and (2) the ability of MPSS to modify the ischemic effects on the beta-adrenergic system. Isolated perfused rat hearts were used. The ischemic protocol consisted of aerobic perfusion (20 minutes) followed by total, global normothermic (37 degrees C) ischemia (30 minutes) and reperfusion (30 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). The non-ischemic protocol consisted of aerobic perfusion (20 minutes) followed by aerobic perfusion (20 minutes) with MPSS (0, 100, 500, or 1,000 mg/L). At the end of the experiments all hearts were rapidly frozen in liquid nitrogen. Crude sarcolemmal membranes were prepared and stimulated at the beta-receptor, at the coupling (G.- or N-) protein, or directly at the adenylate cyclase enzyme (AC). Results were assessed by cyclic adenosine monophosphate (cAMP) production. Tissue specimens were analyzed for myocardial content of cAMP and methylprednisolone (MP). In the ischemic protocol, the responsiveness of the beta-adrenergic system was significantly reduced at the G.-protein level. The treatment with MPSS (100 or 500 mg/L) during reperfusion preserved the beta-adrenergic response. MPSS (1,000 mg/L) offered no protection. In the non-ischemic protocol, MPSS reduced the response of the beta-adrenergic system in a dose-dependent manner at the same level. The hearts in the ischemic protocol had significantly higher contents of MP than the hearts in the non-ischemic protocol at corresponding concentrations of MPSS. The present study suggests that postischemic cardiac failure may result in part from beta-adrenergic dysfunction. This loss of function, probably at the level of the protein connecting the receptor and AC, can successfully be prevented by an optimal dose of MPSS during reperfusion after ischemia.
...
PMID:Steroids protect the beta-adrenergic system during reperfusion after ischemia: effects of methylprednisolone on the beta-adrenergic response system. 1717 88

In yeast the Protein Kinase A (PKA) pathway can be activated by a variety of nutrients. Fermentable sugars, like glucose and sucrose, trigger a spike in the cAMP level, followed by activation of PKA and phosphorylation of target proteins causing a.o. mobilization of reserve carbohydrates, repression of stress-related genes and induction of growth-related genes. Glucose and sucrose are sensed by a G-protein coupled receptor system that activates adenylate cyclase and also activates a bypass pathway causing direct activation of PKA. Addition of other essential nutrients, like nitrogen sources or phosphate, to glucose-repressed nitrogen- or phosphate-starved cells, also triggers rapid activation of the PKA pathway. In these cases cAMP is not involved as a second messenger. Amino acids are sensed by the Gap1 transceptor, previously considered only as an amino acid transporter. Recent results indicate that the amino acid ligand has to induce a specific conformational change for signaling. The same amino acid binding site is involved in transport and signaling. Similar results have been obtained for Pho84 which acts as a transceptor for phosphate activation of the PKA pathway. Ammonium activation of the PKA pathway in nitrogen-starved cells is mediated mainly by the Mep2 transceptor, which belongs to a different class of transporter proteins. Hence, different types of sensing systems are involved in control of the yeast PKA pathway by nutrients.
...
PMID:Novel mechanisms in nutrient activation of the yeast protein kinase A pathway. 1859 14


<< Previous 1 2 3 4 5 6 7 Next >>

---