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)

Chromatography of 105,000 x g supernatants of human and rat platelets on DEAE-cellulose yielded identical elution profiles containing 2 protein fractions (peaks I and II). Only peak II was found to possess guanylate cyclase activity. In the spectrum of the 105,000 x g supernatant of human platelets the absorption maximum was specified at 410 nm (the Soret band) which disappeared from the spectrum of the active protein fraction (peak II) but was detected in the nonactive fraction (peak I). The enzyme preparation was obtained in the heme-deficient form. In the experiments with rat platelets, the Soret band was absent from the corresponding spectra and the enzyme was not activated by sodium nitroprusside; i.e., in soluble guanylate cyclase of rat platelets, unlike the generally accepted notion, the heme is not a prosthetic group of the enzyme. It was shown that carnosine (beta-alanyl-L-histidine), a water-soluble antioxidant, inhibits guanylate cyclase activation by sodium nitroprusside. This inhibitory effect is caused by the interaction of carnosine with the guanylate cyclase heme and can be used for evaluating the degree of saturation of the enzyme with the heme. ADP-induced aggregation of human platelets (donors) is accompanied by a fall in the basal guanylate cyclase activity (with Mg2+) and the enhancement of the enzyme stimulation with sodium nitroprusside, protoporphyrin IX, arachidonic acid and L-arginine with simultaneous cGMP elevation in platelets. A hypothetic scheme of the regulatory role of cGMP in platelet aggregation is proposed. In the experiments with the acute myocardial ischemia of rats, 15 min after the surgery a sharp fall in the platelet guanylate cyclase activity accompanied by a decrease in the enzyme activity in the ischemic zone of the left ventricle of heart took place. The results provided evidence of the high sensitivity of platelet guanylate cyclase to pathological changes occurring in the myocardium at the earliest stages of the development of pathology.
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PMID:Soluble guanylate cyclase of platelets: function and regulation in normal and pathological states. 135 37

L-Arginine (L-Arg) is metabolized by nitric oxide synthase to the reactive intermediate nitric oxide. Since nitric oxide stimulates guanylyl cyclase and cGMP synthesis, L-Arg effects on cGMP accumulation in isolated pancreatic islets of the rat and RINm5F insulinoma cells were determined. Both L-Arg and glucose stimulation increased islet cGMP levels, and glucose potentiated the response to L-Arg alone. A competitive inhibitor of L-Arg metabolism to nitric oxide, NG-monomethyl-L-arginine, reduced glucose- and L-Arg-stimulated insulin release and glucose-induced increases in cGMP; however, basal insulin release was slightly increased. D-Arg and L-ornithine did not affect islet cGMP levels, although insulin release was stimulated. RINm5F cell cGMP levels and insulin release increased in response to L-Arg in a concentration- and time-related manner, whereas glucose and L-histidine were without effect. 8-Bromo-cGMP also slightly increased RINm5F cell insulin release. Sodium nitroprusside as a source of nitric oxide increased RINm5F cell cGMP production. Methylene blue and LY83583, inhibitors of soluble guanylyl cyclase activation, reduced RINm5F cell cGMP levels in the presence and absence of L-Arg; LY83583 also reduced glucose-stimulated cGMP levels in islets. Insulin release by glucose and L-Arg was also inhibited by methylene blue and LY83583 in islets. We conclude that glucose and L-Arg stimulate guanylyl cyclase activity and cGMP formation in beta-cells at least in part through metabolism to the reactive intermediate nitric oxide. However, neither nitric oxide nor cGMP synthesis is obligatory for insulin secretion.
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PMID:L-arginine stimulates cyclic guanosine 3',5'-monophosphate formation in rat islets of Langerhans and RINm5F insulinoma cells: evidence for L-arginine:nitric oxide synthase. 168 79

1. The role of the endothelium in mediating relaxation to acetylcholine, the calcium ionophore A23187, vasoactive intestinal peptide and peptide histidine methionine was studied using isolated human blood vessels. 2. Segments of renal, colic, pulmonary, uterine, transverse cervical, brachial, coronary and coeliac branch arteries, and saphenous veins, were obtained from surgical resection material for use in tissue bath studies. 3. Acetylcholine or A23187 produced endothelium-dependent relaxation in isolated vessels from all vascular beds studied. Coronary arteries, however, differed in their response to acetylcholine which produced predominantly a contractile response, either alone or after initial relaxation. 4. Vasoactive intestinal peptide and peptide histidine methionine produced endothelium-dependent relaxation in coeliac branch arteries. However, these peptides relaxed isolated pulmonary arteries independently of endothelium. 5. Endothelium-dependent relaxation in response to acetylcholine and A23187 was antagonized by nordihydroguaretic acid, a lipoxygenase inhibitor, and methylene blue and haemoglobin, inhibitors of soluble guanylate cyclase. In these respects the endothelium-dependent responses of human arteries to acetylcholine and A23187 resemble those described in other species.
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PMID:Endothelium-dependent relaxation in isolated human arteries and veins. 311 75

hGBP1 is an interferon-induced 67-kDa protein of human cells that readily binds to agarose-immobilized GTP, GDP, and GMP but not to other nucleotides. We cloned hGBP1 cDNA into a histidine-tagging vector, produced recombinant hGBP1 with 6 extra histidine residues at its N terminus in Escherichia coli, and purified this protein to near homogeneity from bacterial lysates. Purified hGBP1 hydrolyzed radiolabeled GTP but failed to hydrolyze ATP, UTP, or CTP at significant rates. Unexpectedly, the principal product of the GTP hydrolysis reaction was GMP rather than GDP. Although significant amounts of GDP were produced when the reaction was performed at 15 degrees C, GDP could not serve as substrate or as inhibitor of hGBP1. hGBP1 lacked guanylate cyclase and guanylyltransferase activity. Degradation of GTP to GMP most likely occurred via two consecutive cleavages of single phosphate groups, because pyrophosphate was not a reaction product, and because hGBP1 failed to hydrolyze GTP gamma S. In vitro modification assays with radiolabeled mevalonic acid and farnesyl pyrophosphate showed that the CaaX motif at the C terminus of hGBP1 functions as an isoprenylation signal. Thus, hGBP1 is a GTPase with novel biochemical properties that may be membrane-associated in eukaryotic cells.
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PMID:The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP. 751 61

Vasoactive intestinal peptide (VIP) and peptide histidine-isoleucine (PHI) receptors and the signaling pathways to which they are coupled were characterized in dispersed gastric smooth muscle cells. Radioligand binding using 125I-labeled VIP and PHI identified 4 classes of receptors: VIP-preferring and PHI-preferring receptors recognized by both ligands and readily desensitized by the preferred ligand, and VIP-specific and PHI-specific receptors recognized by only 1 ligand and resistant to desensitization. All except VIP-specific receptors were coupled to adenylate cyclase. VIP-specific receptors mediated a G protein-coupled Ca2+ influx that led to activation of NO synthase (NOS), NO-dependent activation of soluble guanylate cyclase, and activation of guanosine 3',5'-cyclic monophosphate (cGMP) kinase resulting in muscle relaxation. The entire cascade was blocked by Ca2+ channel and/or calmodulin antagonists. The NOS inhibitor NG-nitro-L-arginine abolished L-[3H]citrulline (coproduct of NO synthesis) and cGMP generation and partly inhibited (52 +/- 4%) relaxation. The components of response mediated by VIP-specific receptors (increase in [Ca2+]i, L-[3H]citrulline, and cGMP) were preserved after desensitization. Insertion of guanosine 5'-O-(beta-thio)diphosphate into reversibly permeabilized muscle cells abolished responses mediated by VIP-preferring and VIP-specific receptors. VIP stimulated both adenosine 3',5'-cyclic monophosphate (cAMP)-kinase and cGMP-kinase activities consistent with stimulation of cAMP and cGMP. Both kinases contributed to relaxation that was partly inhibited by cAMP-kinase [H-89 and (R)-p-adenosine 3',5'-cyclic monophosphorothioate] and cGMP-kinase (KT-5823) inhibitors and abolished by a combination of the 2 types of inhibitors. We conclude that VIP-specific receptors mediate a G protein-coupled Ca2+ influx leading to activation of a constitutive Ca2+/calmodulin-dependent NOS and generation of NO, which is partly responsible for relaxation in smooth muscle.
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PMID:VIP-mediated G protein-coupled Ca2+ influx activates a constitutive NOS in dispersed gastric muscle cells. 769 77

The paper gives data on the role of heme in the functioning soluble forms of guanylate cyclase (of human platelets, rat heart and platelets), on the mechanism of nitrogen oxide-induced heme-dependent activation of enzymes, on the role of platelet guanylate cyclase in the regulation of human platelet aggregation/disaggregation and on the mechanism of antihypertensive and antiaggregatory action of enzyme activators. The instability of relationships of the protein molecule of human platelet guanylate cyclase and heme (regarded as a prosthetic group of the enzyme) results in heme loss during purification of the enzyme and preparation of a heme-deficient agent having a drastically reduced ability to sodium nitroprusside activation. Soluble rat platelet guanylate cyclase was found to be present in these cell originally in a heme-deficient form, it was not activated by sodium nitroprusside and, unlike the routine concepts, heme is not a moiety of this enzyme molecule. The water soluble antioxidant carnosine (beta-alanyl-L-histidine) inhibits sodium nitroprusside activation of guanylate cyclase by interacting with the heme of enzyme of the NO group of nitroprusside and may be useful to reveal the degree of htmt saturation of guanylate cyclase. The study of the mechanism of activation of guanylate cyclase by nitroso complexes of transition metals (Fe, Cr, Co) showed that their realization of antihypertensive effects required only heme-dependent activation of the enzyme. ADF-induced aggregation of human (donor) platelets is followed by stimulation of guanylate cyclase by various activators (despite heme involvement in the mechanism of activation) with concurrent elevations of platelet cGMP levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Soluble forms of guanylate cyclases: mechanism of activation by nitrogen oxide and role in platelet aggregation]. 775 30

In either sperm whale or horse heart myoglobin, binding of NO and lowering of solution pH work together to weaken, and ultimately break, the bond between iron and the proximal histidine. This is reminiscent of the reaction observed at neutral pH in the case of guanylate cyclase, the heme enzyme that catalyzes the conversion of GTP to cGMP. Bond breaking is characterized by a spectral change from a nine-line to a three-line ESR signal and accompanied by a shift from 420 to 387 nm in the UV-vis spectrum of the Soret band maximum. Analysis of the pH-dependent spectral changes shows that they are reversible, at least within a few hours, that the transition is cooperative, involving six protons during pH lowering but only two as it is raised, and that the pK is about 4.7. Different proteins exhibit different pK values, which are generally lower than that for "chelated" protoheme. The pK differences reflect the extra bond stability afforded by the protein structure. Investigations of thermal and photochemical NO displacement by CO suggest that the local pocket around the ligand, although significantly altered (according to circular dichroism investigations), nonetheless still imposes a barrier against the outward diffusion of ligand into the solvent. Nanosecond and picosecond flash photolysis shows that in proteins at low pH there is an extremely efficient geminate recombination of the ligand with the four-coordinated species through a single-exponential process. This occurs to a significantly larger extent than for the case of NO-"chelated" protoheme (where no distal barrier for ligand is present). At neutral pH, when the proximal histidine bond is intact, the geminate recombination for NO takes longer and displays multiexponential kinetics. Altogether, these results suggest that, even though distal effects probably also play a role, proximal effects make an important contribution in modulating ligand-iron bond formation.
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PMID:Myoglobin-NO at low pH: free four-coordinated heme in the protein pocket. 787 45

Soluble guanylyl cyclase [GTP pyrophosphate-lyase (cyclizing); EC 4.6.1.2] is a hemoprotein that exists as a heterodimer; the heme moiety has been proposed to bind nitric oxide, resulting in a dramatic activation of the enzyme. Mutation of six conserved His residues reduced but did not abolish nitric oxide stimulation whereas a change of His-105 to Phe in the beta 1 subunit yielded a heterodimer that retained basal cyclase activity but failed to respond to nitric oxide. Heme was not detected as a component of the mutant heterodimer and protophorphyrin IX failed to stimulate enzyme activity. The activity of the His mutant was almost identical to that of the wild-type enzyme in the presence of KCN, suggesting that disruption of heme binding is the principal effect of the mutation. Thus, the mutation provides a means to inhibit the nitric oxide-sensitive guanylyl cyclase signaling pathway.
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PMID:Mutation of His-105 in the beta 1 subunit yields a nitric oxide-insensitive form of soluble guanylyl cyclase. 790 39

Nitric oxide (.NO) is a recently discovered signaling agent which plays a role in many biological processes such as vasodilation and neuronal synaptic transmission. The only receptor characterized thus far for .NO is the soluble form of guanylate cyclase (sGC). .NO increases the Vmax of sGC by 100-200-fold, probably by interacting with a heme moiety on the enzyme. Although several procedures exist for purifying sGC, these procedures result in preparations with low heme contents. Using a novel procedure, the enzyme has been purified to homogeneity from bovine lung with a heme content of approximately 1 heme/heterodimer. The UV-visible spectrum of the enzyme contains a Soret peak centered at 431 nm and a single broad alpha/beta peak at 555 nm indicative of a 5-coordinate ferrous heme with histidine as the axial ligand. The heme moiety does not bind oxygen but will readily bind .NO to form a 5-coordinate complex or carbon monoxide (CO) to form a 6-coordinate complex. Oxidation of the heme with ferricyanide shifts the Soret to 393 nm, due most likely to the formation of a 5-coordinate ferric heme. In the ferric state, the heme will apparently not bind water but will bind cyanide with reduced affinity compared to methemoglobin and metmyoglobin. Purified enzyme containing 1 heme/heterodimer is activated 130-fold by .NO and 4.4-fold by CO.
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PMID:Soluble guanylate cyclase from bovine lung: activation with nitric oxide and carbon monoxide and spectral characterization of the ferrous and ferric states. 791 35

The lability of the bond between the protein molecule of human platelet guanylate cyclase and heme (the prosthetic group of the enzyme) has been established. It was shown that soluble rat platelet guanylate cyclase exists in these cells originally in a heme-deficient form. The data obtained suggest that in contrast with the generally accepted view, heme is not the prosthetic group of this enzyme. The water-soluble antioxidant carnosine (beta-alanyl-L-histidine) inhibits the guanylate cyclase activation by sodium nitroprusside. This inhibitory effect is caused by carnosine interaction with the guanylate cyclase heme and can be used for evaluating the degree of the heme deficiency of the enzyme. Analysis of the mechanism of guanylate cyclase activation by nitroso complexes of some transient metals (Fe, Co, Cr) differing in the degree of NO oxidation demonstrated that the essential requirement for the realization of the hypotensive effect of these compounds is the activation of guanylate cyclase solely via a heme-dependent mechanism. The ADP-induced aggregation of human platelets (donors) is accompanied by enhanced stimulation of guanylate cyclase by various activators with a simultaneous increase in the intraplatelet cGMP level. This stimulation occurs irrespective of the involvement of the guanylate cyclase heme in the mechanism of enzyme regulation. It is concluded that guanylate cyclase acts via a negative feedback mechanism to control over platelet aggregation and mediates a signal to deaggregation. A hypothetic scheme for the regulatory role of cGMP in platelet aggregation is proposed.
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PMID:[Soluble platelet guanylate cyclase: significance of heme in regulating enzymatic activity and the role of the enzyme in platelet aggregation]. 791 45


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