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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crude preparations of secretin or pancreozymin increased and at higher concentrations decreased guanylate cyclase (GTP pyophosphate-lyase, EC 4.6.1.2) activity from soluble and particulate fractions of rat liver homogenates. Partially purified and synthetic secretin were without effect as was the biologically active octapeptide fragment of pancreozymin. The active contaminants in these preparations survived boiling, saponification, and treatment with phospholipase A, trypsin and neuraminidase C. The activity was extractable with chloroform/methanol and did not survive ashing. Eight bile salt contaminants in crude secretin were obtained with thin-layer chromatography. Two of the contaminating bile salts that increased liver particulate guanylate cyclase activity were identified as taurodeoxycholate and either glycochenodeoxycholate or glycodeoxycholate; taurocholate was inhibitory. The sodium salts of cholate, deoxycholate, chenodeoxycholate and their glycine-or taurine-conjugated forms either increased or decreased particulate and soluble rat liver guanylate cyclase activity depending upon their concentration. Thus, the previously reported stimulatory and inhibitory effects of secretin and pancreozymin preparations on guanylate cyclase activity are probable attributable to their bile salt contaminants.
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PMID:Activation of liver guanylate cyclase by bile salts and contaminants in crude secretin and pancreozymin preparations. 1 19

We have examined the mechanism governing guanosine 3',5'-cyclic monophosphate (cGMP)-associated photoinduced relaxation elicited by long-wavelength ultraviolet (UV) light of endothelium-removed, isolated bovine pulmonary arteries. Hypoxia, produced by gassing of the organ bath solution with 95% N2-5% CO2, inhibited photorelaxation. Photorelaxation was also inhibited by cyanide (1 mM NaCN) but was potentiated by lactate (5 mM). Irradiation of bovine pulmonary arterial smooth muscle with UV light (or exposure to exogenous H2O2) stimulated cyanide-inhibitable oxidation of methanol to formaldehyde, suggesting that UV light increased H2O2 metabolism via catalase. The UV light-induced oxidation of methanol by pulmonary arterial smooth muscle was also inhibited by hypoxia. Consumption of O2 was detected when pulmonary arterial tissue was exposed to UV light, but cyanide failed to interfere with this effect, consistent with the photochemical reduction of O2 within vascular smooth muscle in a manner independent of mitochondrial respiration. We propose that photorelaxation is associated with the intracellular photochemical reduction of O2 to form H2O2, which elicits increases of vascular smooth muscle cGMP levels via the catalase-dependent activation of soluble guanylate cyclase. In addition, we hypothesize that the photooxidation of NAD(P)H could contribute to the generation of H2O2, since the enhancement of photorelaxation by lactate may originate from increased levels of NADH.
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PMID:Association of pulmonary artery photorelaxation with H2O2 metabolism by catalase. 192 95

Escherichia coli heat-stable enterotoxins (ST) are classified into STa and STb according to their physicochemical and biologic characteristics. STa induces diarrhea, activating the guanylate cyclase-cGMP system. ST-like enterotoxins can be produced by bacteria other than E. coli, including Klebsiella pneumoniae. A Klebsiella ST has previously been shown to share some chemical and immunologic characteristics with E. coli ST. Aiming to define better the nature of Klebsiella ST, we have screened 237 children with diarrhea and 179 controls for ST-producing Klebsiella, using the SMA. We detected 26 Klebsiella strains from patients, two of which were positive in the SMA, and 36 from controls, all negative for ST. A partial purification was performed using an acetone precipitation followed by ultrafiltration and gel filtration techniques. Klebsiella toxin was heat-stable, methanol-soluble, sensitive to mercaptoethanol, active at acid pH values, but not at pH greater than 8. The time course of Klebsiella toxin in the SMA resembled that of E. coli STa. Klebsiella ST caused reduced Na absorption and net Cl secretion in rabbit ileal mucosa mounted in Ussing chambers. It was found to increase the cGMP but not the cAMP concentration. Finally, Klebsiella ST did not react with anti-E. coli STa MAb in a competitive ELISA. We conclude that K. pneumoniae may induce diarrhea through the production of an STa similar but not identical to E. coli STa.
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PMID:Characteristics and mechanism of action of a heat-stable enterotoxin produced by Klebsiella pneumoniae from infants with secretory diarrhea. 247 15

Certain enteropathogenic bacteria, including strains of Escherichia coli, Klebsiella pneumoniae and Yersinia enterocolitica, elicit their diarrhoeagenic effects by elaborating small molecular weight, heat-stable enterotoxins (STs). Structural and functional characteristics indicate that ST peptides are heterogeneous and two major subtypes, STa and STb, have been identified. Molecules of STa, unlike those of STb, are methanol-soluble and elicit their pathogenic effects by activating host cell guanylate cyclase activity and thereby increasing tissue cyclic GMP content: this increase in cyclic GMP causes fluid secretion. STa binds to specific proteinaceous receptors on intestinal cells but the nature of STa-receptor coupling to guanylate cyclase is poorly understood. The actions of STa, including binding to its receptor, activation of guanylate cyclase and stimulation of electrolyte transport, are rapid, reversible and tissue-specific. STa activates only particulate and not soluble guanylate cyclase. It alters the Vmax but not the apparent Km of this enzyme for Mg-GTP or Mn-GTP. At concentrations above 0.5-1 mM, calcium inhibits the STa activation of guanylate cyclase. The effects of calmodulin antagonists such as chlorpromazine on the activation of guanylate cyclase by STa are less clear. Inhibitors of phospholipid and arachidonic acid cascade pathways interfere with both basal and STa-stimulated guanylate cyclase. Membrane integrity is essential for STa activation of guanylate cyclase and the STa-receptor complex may activate the enzyme by intramembrane protein-protein interactions and/or perturbations. Interference with membrane phospholipid could alter such coupling.
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PMID:Toxins which activate guanylate cyclase: heat-stable enterotoxins. 286 Oct 70

Fluid secretion by the Malpighian tubules (MTs) of Locusta is drastically reduced in the absence of extracellular calcium. Verapamil (10(-4) M) inhibits basal secretion, whereas the ionophore A23187 (10(-5) M) elevates the secretory rate. Cyclic guanosine monophosphate (cGMP) stimulates fluid secretion at a concentration of 10(-3) M. A factor extractable in methanol from the storage lobes of the corpora cardiaca stimulates increased guanylate cyclase activity in MTs, resulting in a 10-fold elevation in intracellular cGMP levels. Attempts to separate the factor stimulating guanylate cyclase by high-performance size-exclusion chromatography proved unsuccessful. Neither 5-hydroxytryptamine (5-HT) (10(-4) M) nor A23187 (10(-5) M) are able to elevate intracellular cGMP levels. Elevations of both intracellular cAMP and cGMP levels in response to diuretic hormone (DH) are potentiated in the absence of extracellular calcium. Consistent with these elevations are increases in the rates of fluid secretion by tubules deprived of extracellular calcium. It is concluded that, although calcium has an important role in the regulation of fluid secretion, its role in the mechanism of hormone-stimulated secretion may be modulatory rather than regulatory.
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PMID:The role of calcium in diuretic hormone action on locust Malpighian tubules. 298 34

Heat-stable enterotoxin (ST) of Escherichia coli increased guanylate cyclase activity in homogenates of rat and rabbit intestinal mucosa and stimulated intestinal fluid secretion in suckling mice. The ST effect on guanylate cyclase was dose-dependent, occurred without a time lag, and was confined to the particulate fraction. ST activation of guanylate cyclase was tissue-specific; ST did not alter activity of soluble or particulate rat liver, lung, heart, kidney, or cerebral cortex enzyme. The ST activity on guanylate cyclase and secretion was methanol-soluble and alkali-labile, and its effects were not altered by phentolamine, propranolol, or atropine. Monosialoganglioside did not reduce ST-induced secretion. However, indomethacin and butylated hydroxyanisole decreased the ST effect on both guanylate cyclase and secretion. Fluid secretion with ST sppears to result from specific activation of particulate intestinal guanylate cyclase. While adrenergic and cholinergic events are probably not involved in this process, the effects of ST may be mediated through prostaglandin synthesis or oxidative mechnanisms.
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PMID:Activation of intestinal guanylate cyclase by heat-stable enterotoxin of Escherichia coli: studies of tissue specificity, potential receptors, and intermediates. 610 30

The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a delay of about 20 min, they evolved [3H]methanol. This evolution, and the amount of [3H] methanol liberated by treatment with base, was inhibited in a dose-dependent fashion by the cyclic nucleotide phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine, papaverine, dipyridamole, and RA233 (2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d] pyrimidine). Each of these compounds increased the incorporation of [3H]methionine into platelets. The effects of RA233 were studied in more detail. Inhibition of [3H]methanol production was not potentiated by stimulators of the adenylate cyclase or the guanylate cyclase. The majority of the base-labile radioactivity was trichloroacetic acid precipitable. Thin layer chromatography of extracts of platelets incubated with L-[35S]methionine showed that RA233 did not induce a cellular accumulation of [35S]S-adenosylhomocysteine, and that it actually increased the amount of cellular [35S]S-adenosylmethionine. Discontinuous polyacrylamide gel electrophoresis at acid pH using the cationic detergent benzyldimethyl-n-hexadecylammonium chloride of platelets incubated with [3H]methionine showed incorporation of radioactivity into more than 30 protein bands, including one which co-migrates with calmodulin. The incorporation into the majority of these bands was inhibited by RA233 in a dose-dependent fashion. It is suggested that caution should be used in ascribing the pharmacological effects of known phosphodiesterase inhibitors to increases in cyclic nucleotides, because some of these effects could be due to inhibition of protein carboxyl methylation.
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PMID:Inhibitors of cyclic nucleotide phosphodiesterases inhibit protein carboxyl methylation in intact blood platelets. 619 23

Analysis of adenylate cyclase (ACase) activity in broken cell preparations usually involves conversion of [alpha-32P]ATP to [32P]cyclic AMP (cAMP) followed by purification of cAMP by liquid chromatographic methods. An automated, preparative reverse-phase HPLC procedure was developed that purifies cAMP rapidly and decreases variability and background. It permits the separation procedure to be validated rapidly prior to use with actual samples, and is readily adaptable for assaying guanylate cyclase, phosphodiesterases (PDE), or a variety of other related nucleotide-metabolizing enzymes. For ACase assays, 4.5% ZnSO4-10% Ba(OH)2 is added to the incubation mixture, and following centrifugation, the supernatant is injected on an HPLC apparatus fitted with a Waters Z-Module containing a 10-microns C18 reverse-phase cartridge. Using a mobile phase of 0.15 M sodium acetate-20% methanol (pH 5.0) at a flow rate of 4 ml/min, cAMP is eluted at k' greater than 1.25, whereas k' less than 0.5 for all other adenine nucleotides, permitting collection of the cAMP fraction after running the other nucleotides to waste. The method was validated by characterizing dopamine-sensitive ACase in homogenates of striatum from Sprague-Dawley rats. Basal activity (177 +/- 16 pmol/mg protein/min), the stimulation by dopamine (186 +/- 19 pmol/mg/min), the apparent Km for dopamine (5.0 +/- 1.5 microM), and expected effects of varying magnesium, EGTA, and GTP were similar to available data. However, it was found that isobutylmethylxanthine (IBMX) or theophylline, usually included in the incubation mixture as PDE inhibitors, markedly inhibited the synthesis of cAMP in both the presence and absence of dopamine. A consequence of this inhibition was a marked change in the apparent Km of dopamine calculated from a Lineweaver-Burk plot. The use of IBMX to inhibit PDEs was compared with an alternate strategy, the addition of excess exogenous cAMP. Simultaneous analysis of PDE and ACase activity was accomplished by including [3H]cAMP in the incubation and quantifying the amounts of [3H]cAMP hydrolyzed and [32P]cAMP synthesized. Without IBMX, a concentration of 1 mM exogenous cAMP was sufficient to prevent significant loss of [3H]cAMP. In the absence of exogenous cAMP, 0.5 mM IBMX did not completely prevent the breakdown of [3H]cAMP, whereas 2.5 mM IBMX did. Although there was 25% less [3H]cAMP recovered in the presence of 0.5 mM IBMX than with 2.5 mM IBMX, there was no difference in the amount of [32P]cAMP formed (either with or without dopamine).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:An improved, automated adenylate cyclase assay utilizing preparative HPLC: effects of phosphodiesterase inhibitors. 631 7

Catalase promotes the H2O2-dependent oxidation of phenylhydrazine to benzene but simultaneously is subject to a pseudo-first order inactivation process. Each inactivation event is subtended by catalytic turnover of three molecules of phenylhydrazine and 52 molecules of H2O2. The dimethyl ester of N-phenylprotoporphyrin IX is extracted with acidic methanol from the inactivated enzyme, but the prosthetic heme with a phenyl sigma-bonded to the iron atom is obtained by gentle extraction with 2-butanone. The absolute chirality of N-ethylprotoporphyrin IX isolated from catalase inactivated with ethylhydrazine confirms that the prosthetic heme has the same chiral orientation in the active site as it does in hemoglobin. The known inactivation of methemoglobin by phenylhydrazine is shown to depend on H2O2 but not oxygen. The results demonstrate that the H2O2-dependent oxidation of phenylhydrazine by catalase and other hemoproteins results in sigma-coordination of a phenyl residue to the prosthetic heme iron. This process may play a role not only in phenylhydrazine-mediated erythrocyte lysis but also in the activation of guanylate cyclase.
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PMID:Inactivation of catalase by phenylhydrazine. Formation of a stable aryl-iron heme complex. 688 92

Nitrososydnone-5-imines and Thiazole-2-nitrosimines are susceptible to photolytic cleavage of the = N-NO bond. This can be achieved with a tungsten lamp. In water the corresponding syndnone imine salts are formed in 90% yield at 37 degrees C. Only at higher temp. (70 degrees C) ring opening is observed. In methanol about 25% of sydnones are obtained. On the other hand NO. and N2O were detected in the head space of the reaction vials when oxygen was excluded. The formation of N2O from nitrososydnone imine was increased up to elevenfold by glutathione while the amount of NO. was decreased. In the presence of light and thiols soluble guanylate cyclase (s-GC) was stimulated. The results suggest that the nitroxylate anion NO- plays an important role in the stimulation of s-GC.
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PMID:New NO-donors with antithrombotic and vasodilating activities, IV: Chemical reactivity of nitrosimines and its implications for their pharmacologic properties. 791 76


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