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)

Several reports have suggested that cylcic guanosine 3'-5' monophosphate (cGMP) and cyclic 3'-5' adenosine monophosphate (cAMP) are involved in the regulation of cellular proliferation. Following our previous reports on the cAMP system in human brain tumors, we decided to investigate the cGMP system in the same pathological tissues by studying the activity of guanylate cyclase and cGMP-phosphodiesterase (cGMP-PDE). We found that the activity of both enzymes is lower in neurinomas and glioblastomas than in meningiomas or in normal cerebral cortex. Furthermore, the subcellular distribution of guanylate cyclase in human cerebral cortex differs from that of neurinomas and glioblastomas. On the basis of such observations we have discussed the possibility that the regulatory mechanism of the enzymes related to the cyclic nucleotide metabolism is altered in brain tumors.
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PMID:Regulation of the cyclic guanosine 3'-5' monophosphate system in human brain tumors. 1 31

Ethionine-induced hepatomas are characterized by high adenylate cyclase activity and cyclic adenosine 3',5'-monophosphate content relative to those of surrounding liver or liver from pair-fed control rats. The present study examined the properties of the guanylate cyclase-cyclic guanosine 3',5'-monophosphate (cGMP) system of these tissues. cGMP levels of the ethionine-induced hepatomas, determined in both specimens quick-forzen in situ and after in vitro incubation of tissue slices, were approximately 2 times higher than those of surrounding liver or controls. Higher cGMP in the tumors was associated with an increase in whole homogenate, soluble, and particulate guanylate cyclase activities, as well as an increase in soluble cGMP-phosphodiesterase activity. 3-Isobutyl-1-methylxanthine, a potent inhibitor of cGMP-phosphodiesterase activity, potentiated the differences in cGMP between slices of the hepatomas and surrounding liver or control, suggesting that the higher steady-state cGMP content of the tumors reflected enhanced basal cGMP synthesis which was partially offset by increased nucleotide degradation. In the hepatomas, a greater proportion of the total guanylate cyclase activity was located in the particulate cell fraction (31%) as compared to the subcellular distribution of enzyme activity in either surrounding liver or controls (15% of total in the particulate fraction). Carbamylcholine, which increased cGMP 3-fold in surrounding liver and controls, failed to alter cGMP levels inslices of hepatoma. Further, the relative changes in both cGMP accumulation and guanylate cyclase activity of the tumors in response to NaN3, NH2OH, and NaNO2 were blunted compared to surrounding liver or controls, although in each instance a response was clearly evident. Ethionine-induced hepatomas are thus characterized by: (a) significant increases in cGMP content and in guanylate cyclase and cGMP-phosphodiesterase activities, (b) a change in the subcellular distribution of guanylate cyclase, and (c) altered responsiveness of the guanylate cyclase-cGMP system to several agonists.
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PMID:Increased guanylate cyclase activity and guanosine 3',5'-monophosphate content in ethionine-induced hepatomas. 1 87

Streptozotocin has been shown to induce the production of a variety of tumors in rats. The present report demonstrates that streptozotocin and 1-methyl-1-nitrosourea, a component of the streptozotocin molecule and a known carcinogen, stimulate the enzyme guanylate cyclase which catalyzes the production of guanosine 3',5'-monophosphate. At a maximal concentration of 3 mg/ml, these agents activated guanylate cyclase approximately 30-fold in liver, 20-fold in kidney, 15-fold in cerebellum. 15- to 30-fold in cerebrum, 4- to 20-fold inheart, 12-fold in brain stem, 10-fold in lung, and 2-fold in pancreas. Since recent evidence suggests a role for guanosine 3',5'-monophosphate in malignant transformation, the data may help explain the tumor-inducing capacity of these agents.
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PMID:Activation of guanylate cyclase by streptozotocin and 1-methyl-1-nitrosourea. 1 88

We have localized 71% of the guanylate cyclase activity in the (G X 105,000) supernatent fraction of broken KB cells. The reaction follows Michaelis-Menten kinetics, the apparent Km for GTP is 0,5 mM, as long as GTP is lower than a limited concentration, then activity is inhibited. The ion Mn++ is an absolutely required activator, it does not change enzyme-substrate affinity. The enzyme shows several types of binding sites of Mn++. Guanylate cyclase, studied over a period of development of culture, shows, in KB cells without cell contact, an activity higher than that observed in confluent cells. This is not due to the fact of a change in enzyme-substrate affinity but to a modification of Mn++ influence.
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PMID:[Enzymatic characteristics of the guanylate cyclase of KB cells: their change as a function of the development of the cultures]. 1 95

A 37,000 X g supernatant fraction prepared from fat lung homogenate demonstrated a 2- to 3-fold increase in guanylate cyclase activity after incubation at 30 degrees for 30 min (preincubation). Treatment of the supernatant fraction with Triton X-100 increased activity to approximately the same extent as preincubation, but would not increase the activity after preincubation. By chromatography on Sepharose 2B, before and after preincubation, it was demonstrated that the increase in activity was only associated with the soluble guanylate cyclase, and not the particulate enzyme. Activation by preincubation required O2. It was completely inhibited by thiols such as 2-mercaptoethanol, and by bovine serum albumin, KCN, and sodium diethyldithiocarbamate. These inhibitors suggested a copper requirement for activation, and this was confirmed by demonstrating that 20 to 60 muM CuCl2 could relieve the inhibition by 0.1 mM sodium diethyldithiocarbamate. 2-Mercaptoethanol inhibition could also be reversed by removal of the thiol on a Sephadex G-25 column, however, this treatment partially activated the enzyme. Addition of 2-mercaptoethanol to a preincubated preparation would not reverse the activation. H2O2 was found to activate guanylate cyclase, either by its generation in the lung supernatant with glucose oxidase and glucose, or by its addition to a preparation in which the catalase was inhibited with KCN. KCN or bovine serum albumin was able to partially inhibit activation by glucose oxidase plus glucose, however, larger amounts of glucose oxidase could overcome that inhibition, indicating a catalytic role for Cu2+ at low H2O2 concentrations. No direct evidence for H2O2 formation during preincubation could be found, however, indirect evidence was obtained by the spectrophotometric detection of choleglobin formation from hemoglobin present in the lung supernatant fluid. The H2O2 is believed to result from the reaction of oxyhemoglobin with ascorbate.
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PMID:Activation of soluble guanylate cyclase from rat lung by incubation or by hydrogen peroxide. 1 60

Native soluble and particulate guanylate cyclase from several rat tissues preferred Mn2+ to Mg2+ as the sole cation cofactor. Wtih 4mM cation, activities with Mg2+ were less than 25% of the activities with Mn2+. The 1 mM NaN3 markedly increased the activity of soluble and particulate preparations from rat liver. Wtih NaN3 activation guanylate cyclase activities wite similar with Mn2+ and Mg2+. Co2+ was partially effective as a cofactor in the presence of NaN3, while Ca2+ was a poor cation with or without NaN3. Activities with Ba, Cu2+, or Zn2+ were not detectable without or with 1 mM NaN3. With soluble liver enzyme both manganese and magnesium activities were dependent upon excess Mn2+ or Mg2+ at a fixed MnGTP or MgGTP concentration of 0.4 mm; apparent Km values for excess Mn2+ and Mg2+ were 0.3 and 0.24 mM, respectively. After NaN3 activation, the activity was less dependent upon free Mn2+ and retained its dependence for free Mg2+, at 0.4 mM MgGTP the apparent Km for excess Mg2+ was 0.3 mM. The activity of soluble liver guanylate cyclase assayed with Mn2+ or Mg2+ was increased with Ca2+. After NaN3 activiation, Ca2+ had no effect or was somewhat inhibitory with either Mn2+. After NaN activation, Ca2+ had no effect or was somewhat inhibitory with either Mn2+ or Mg2+. The stimulatory effect of NaN2 on Mn2+-and Mg2+-dependent guanylate cyclase activity from liver or cerebral cortex supernatant fractions required the presence of the sodium azide-activator factor. With partially purified soluble liver guanylate cyclase and azide-activator factor, the concentration (1 mjM) of NaN3 that gave half-maximal activation with Mn2+ or Mg2+ was imilar. Thus, under some conditions guanylate cyclase can effectively use Mg2+ as a sole cation cofactor.
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PMID:Appearance of magnesium guanylate cyclase activity in rat liver with sodium azide activation. 1 77

The effects of a variety of purine and pyrimidine nucleotides were tested for their capacity to inhibit mammalian soluble guanylate cyclase activity. Adenosine 5'-tetraphosphate (ATetP), ATP, ADP, AMP, guanosine 5'-tetraphosphate (GTetP) and GDP were found to inhibit soluble guanylate cyclase activity from rat lung and other mammalian tissues. The corresponding cytosine and thymine nucleotides showed little or no inhibitory activity, except for thymidine 5'-tetraphosphate, which inhibited glanylate cyclase activity but to a lesser extent than did the purine nucleoside tetraphosphates. ATetP and GTetP were found to be potent inhibitors of soluble guanylate cyclase activity from rat, guinea pig and mouse lung, rat heart and rat brain. Both purine nucleoside tetraphosphates were competitive inhibitors of the rat lung soluble enzyme. ATetP and GTetP had Ki values of 1 muM and 2.5 muM, respectively. The experimental data suggest that purine nucleoside tetraphosphates, and perhaps other purine nucleotides, may play a biologic role in modulating mammalian soluble guanylate cyclase activity.
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PMID:Inhibition of mammalian soluble guanylate cyclase activity by adenosine 5'-tetraphosphate, guanosine 5'-tetraphosphate and other nucleotides. 1 93

Hydroxylamine actived guanylate cyclase in particulate fraction of cerebral cortex of rat. Activation was most remarkable in crude mitochondrial fraction. When the crude mitochondrial fraction was subjected to osmotic shock and fractionated, guanylate cyclase activity recovered in the subfractions as assayed with hydroxylamine was only one-third of the starting material. Recombination of the soluble and the particulate fractions, however, restored guanylate cyclase activity to the same level as that of the starting material. When varying quantities of the particulate and soluble fractions were combined, enzyme activity was proportional to the quantity of the soluble fraction. Heating of the soluble or particulate fraction at 55 degrees for 5 min inactivated guanylate cyclase. The heated particulate fraction markedly activated guanylate cyclase activity in the native soluble fraction, while the heated soluble fraction did not stimulate enzyme activity in the particulate. The particulate fraction preincubated with hydroxylamine at 37 degrees for 5 min followed by washing activated guanylate cyclase activity in the soluble fraction in the absence of hydroxylamine. Further fractionation of the crude mitochondrial fraction revealed that the factor(s) needed for the activation by hydroxylamine is associated with the mitochondria. The mitochondrial fraction of cerebral cortex activated guanylate cyclase in supernatant of brain, liver, or kidney in the presence of hydroxylamine. The mitochondrial fraction prepared from liver or kidney, in turn, activated soluble guanylate cyclase in brain. Activation of guanylate cyclase by hydroxylamine was compared with that of sodium azide. Azide activated guanylate cyclase in the synaptosomal soluble fraction, while hydroxylamine inhibited it. The particulate fraction preincubated with azide followed by washing did not stimulate guanylate cyclase activity in the absence of azide. The activation of guanylate cyclase by hydroxylamine is not due to a change in the concentration of the substrate GTP, Addition of hydroxylamine did not alter the apparent Km value of guanylate cyclase for GTP. Guanylate cyclase became less dependent on manganese in the presence of hydroxylamine. Thus the activation of guanylate cyclase by hydroxylamine is due to the change in the Vmax of the reaction.
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PMID:Activation of guanylate cyclase in cerebral cortex of rat by hydroxylamine. 1 73

Harmaline increases cerebellar 3':5'-cyclic guanosine monophosphate (cGMP) content in a dose-related manner; this increase is prevented by a pretreatment with 3-acetylpyridine (3-AP) (0.66 mmol/kg) which destroys climbing fibers and inhibits harmaline-induced tremor. The cerebellar cGMP content increases after isoniazid; this response remains unchanged in rats pretreated with 3-AP. Since isoniazid decreases cerebellar gamma-aminobuturic acid (GABA) levels, the increase in cGMP content might reflect a reduction in the availability of GABA at the level of postsynaptic receptors. Apomorphine (a dopamine receptor agonist) and haloperidol (a dopamine receptor blocker) increase or decrease the cGMP content of cerebellar cortex, respectively. Neither drug changes the guanylate cyclase activity of cerebellar homogenates; moreover their action on cerebellar cGMP content persists after 3-AP. Chloropromazine, like haloperidol, decreases the cerebellar cGMP content. The increase in cerebellar cGMP content elicited by apomorphine can be differentiated from that elicited by harmaline or isoniazid; presumably apomorphine indirectly activates mossy fibers. The decrease in cerebellar cGMP content elicited by haloperidol can be differentiated from that elicited by diazepam; perhaps haloperidol reduces the mossy fiber input to the cerebellum. We suggest that the cGMP content of cerebellar cortex fluctuates in response to changes in the afferent stimulatory input to the cerebellum; it increases when the activity of either climbing or mossy fibers is increased; it decreases when either of these two stimulatory inputs is reduced.
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PMID:Pharmacologically induced changes in the 3':5'-cyclic guanosine monophosphate content of rat cerebellar cortex: difference between apomorphine, haloperidol and harmaline. 1 99

Guanylate cyclase from human platelets was over 90% soluble, even when assayed in the presence of Triton X-100. A time-dependent increase in activity occurred when the enzyme was incubated at 37 degrees and this spontaneous activation was prevented by dithiothreitol. Arachidonic acid stimulated the soluble enzyme activity approximately 2- to 3-fold. Linear double reciprocal plots of guanylate cyclase activation as a function of arachidonic acid concentration were obtained with a Ka value of 2.1 muM. A Hill coefficient of 0.98 was obtained indicating that one fatty acid binding site is present for each catalytic site. Concentrations of arachidonic acid in excess of 10 muM caused less than maximal stimulation. Dihomo-gamma-linolenic acid and two polyunsaturated 22 carbon fatty acids stimulated the activity of guanylate cyclase to the same degree as did arachidonic acid. The methyl ester of arachidonic acid was much less effective. Diene, monoene, and saturated fatty acids of various carbon chain lengths as well as prostaglandins E1, E2, and F2alpha, had little or no effect. These data indicate that the structural determined required for stimulation by fatty acids of soluble platelet guanylate cyclase is a 1,4,7-octatriene group with its first double bond in the omega6 position. This structural group is similar to the substrate specificity determinants of fatty acid cyclooxygenase, the first enzyme of the prostaglandin synthetase complex. However, conversion of arachidonic acid to a metabolite of the cyclooxygenase pathway did not appear to be required for activation of the cyclase since activation occurred in the 105,000 X g supernatant fraction and pretreatment of this fraction with aspirin did not alter the ability of arachidonic acid to activate guanylate cyclase. Kinetic studies showed that the stimulation of guanylate cyclase by arachidonic acid is primarily an effect on maximal velocity. Arachidonic acid did not alter the concentration of free Mn2+ required for optimal activity. It is concluded that the activity of the soluble form of guanylate cyclase in cell-free preparations of human platelets can be increased by a lipid-protein interaction involving specific polyunsaturated fatty acids.
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PMID:Stimulation of human platelet guanylate cyclase by fatty acids. 1 50


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