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)

The mechanism of activation of soluble guanylate cyclase purified from bovine lung by phenylhydrazine is reported. Heme-deficient and heme-containing forms of guanylate cyclase were studied. Heme-deficient enzyme was activated 10-fold by NO but was not activated by phenylhydrazine. Catalase or methemoglobin enabled phenylhydrazine to activate guanylate cyclase 10-fold and enhanced activation by NO to over 100-fold. Heme-containing enzyme was activated only 3-fold by phenylhydrazine but over 100-fold by NO. Added hemoproteins enhanced enzyme activation by phenylhydrazine to 12-fold without enhancing activation by NO. Reducing or anaerobic conditions inhibited, whereas oxidants enhanced enzyme activation by phenylhydrazine plus catalase, and KCN had no effect. In contrast, enzyme activation by NO and NaN3 was inhibited by oxidants or KCN. NaN3 required native catalase, whereas phenylhydrazine also utilized heat-denatured catalase for enzyme activation. Thus, the mechanism of guanylate cyclase activation by phenylhydrazine differed from that by NO or NaN3. Guanylate cyclase activation by phenylhydrazine resulted from an O2-dependent reaction between phenylhydrazine and hemoproteins to generate stable iron-phenyl hemoprotein complexes. These complexes activated guanylate cyclase in the absence of O2, but lost activity after acidification, basification, or heating. Gel filtration of prereacted mixtures of [U-14C]phenylhydrazine plus hemoproteins resulted in co-chromatography of radioactivity, protein, and guanylate cyclase stimulating activity, and yielded a phenyl-hemoprotein binding stoichiometry of four under specified conditions (one phenyl/heme). [14C]Phenyl bound to heme-containing but not heme-deficient guanylate cyclase and binding correlated with enzyme activation. Moreover, reactions between enzyme and iron-[14C] phenyl hemoprotein complexes resulted in the exchange or transfer of iron-phenyl heme to guanylate cyclase and this correlated with enzyme activation.
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PMID:Guanylate cyclase from bovine lung. Evidence that enzyme activation by phenylhydrazine is mediated by iron-phenyl hemoprotein complexes. 614 58

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

Nitric oxide (.NO) is synthesized by the enzyme nitric oxide synthase (NOS). There are 2 constitutive forms of NOS (cNOS) and 1 inducible form (iNOS). Cells containing cNOS rapidly and transiently produce small amounts of NO in response to agonists that raise cytosolic levels of free Ca2+, whereas cells expressing inducible iNOS produce large amounts of .NO for extended periods after a lag of several hours during which time the enzyme is induced. Until recently, the 2 constitutive isoforms of NOS were thought to be confined to endothelial cells (eNOS) and brain (bNOS or nNOS). However, eNOS and bNOS have been identified in an increasing variety of additional cells. Many, if not most, types of cells are capable of expressing iNOS in response to cytokines, endotoxin, and phagocytosis. Regulation of iNOS occurs at transcriptional, translational, and posttranslational levels. Because .NO is rapidly diffusible and soluble in hydrophobic and aqueous environments, it is well suited to its role as an intercellular messenger with the unique ability to penetrate solid tissue. However, it is rapidly inactivated by hemoglobin. The biochemistry of .NO is dominated by its rapid reaction with oxygen and transitional metals, notably iron. The former reaction may be protective, as when neutralizing superoxide (.O2-), or harmful in forming additional highly damaging radicals such as peroxynitrite. Interaction of .NO with iron-containing proteins has a number of sequelae, including the activation of guanylate cyclase, inhibition of mitochondrial respiration, and inhibition of cell division. Nitric oxide has been implicated in a number of conditions of orthopaedic interest, including inflammation, arthritis, osteoporosis, sepsis, ligament healing, and aseptic loosening of joint prostheses.
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PMID:Nitric oxide and its role in orthopaedic disease. 754 92

The N-methyl-D-aspartate (NMDA) receptor plays a key role in synaptic plasticity and is thought to underlie memory, learning and development of the nervous system. The NMDA receptor is a ligand-gated ion channel complex that contains distinct recognition sites for endogenous and exogenous ligands, including glutamate, glycine, Mg2+, Zn2+ and noncompetitive blockers such as MK-801. In the central nervous system, nitric oxide (NO) is produced in some neurons following activation of excitatory amino acids receptors, particularly those of the NMDA receptor. Nitric oxide is synthesized from a L-arginine by the cytoplasmic enzyme nitric oxide synthase (NOS) which is a calcium dependent enzyme, and this pathway is inhibited by the analogues of L-arginine such as NG-monomethyl-L-arginine (L-NMMA) and is augmented by NMDA receptor activation. Activation of the NMDA receptor results in the elevation of intracellular calcium ([Ca2+]i) which in turn activates NOS via the calcium-calmodulin complex. Nitric oxide is not a classical neurotransmitter in the central nervous system since it is not released by exocytosis and does not interact with a receptor protein but rather diffuses rapidly across the membrane and binds with the iron in heme-containing proteins. Nitric oxide can serve as both an oxidizing and reducing agent. It has strong affinity for heme proteins such as guanylyl cyclase, but there is evident that NO may have a regulatory role by oxidizing sulfhydryl groups of non-heme proteins such as those on the NMDA receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The generation of nitric oxide and its roles in neurotransmission and neurotoxicity. 754 46

Pretreatment of rat hepatocytes with low-dose nitrogen oxide (addition of SNAP in vitro or induction of nitric oxide synthase in vitro or in vivo) imparts resistance to killing and decrease in aconitase and mitochondrial electron transfer from a second exposure to a higher dose of SNAP. Induction of this resistance is prevented by cycloheximide, indicating upregulation of protective protein(s). Ferritin levels are increased as are non-heme iron-NO EPR signals. Tin-protoporphyrin (SnPP) prevents protection, suggesting involvement of hsp32 (heme oxygenase) and/or guanylyl cyclase (GC). Cross-resistance to H2O2 killing is also observed, which is also prevented by cycloheximide and SnPP. Thus, hepatocytes possess inducible protective mechanisms against nitrogen oxide and reactive oxygen toxicity.
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PMID:Nitrogen oxide-induced autoprotection in isolated rat hepatocytes. 758 41

The effects of sodium nitroprusside (SNP) on dopamine synthesis in a porcine renal epithelial cell line (LLC-PK1) were evaluated. Subsequent studies examined the actions of the degradation products of SNP (cyanide, ferrous ion and nitric oxide) on aromatic amino acid decarboxylase (AAAD) activity in tissue supernatants from LLC-PK1 cells and rat renal cortex. SNP (10-500 mumol/l) significantly inhibited dopamine production in LLC-PK1 cells in a dose-related manner. The activation of guanylate cyclase by nitric oxide was not found to be the mechanism whereby SNP inhibited dopamine synthesis in LLC-PK1 nor did the antioxidant glutathione attenuate the actions of SNP. Ferrous sulfate (0.5 mmol/l) and SNP (0.5 mmol/l) were found to inhibit dopamine synthesis in LLC-PK1 cells and to directly inhibit cytosolic AAAD activity from LLC-PK1 cells. A series of studies were conducted using AAAD from rat renal cortex and confirmed that SNP could directly inhibit the conversion of L-dopa to dopamine by AAAD. Furthermore, potassium ferricyanide (1 mmol/l) and potassium cyanide (1 mmol/l) could produce greater than 80% reductions in AAAD activity. Iron (0.5-1 mmol/l) was found to increase rat kidney AAAD activity. Kinetic analysis revealed that potassium cyanide was a potent (Ki = 40-50 mumol/l) noncompetitive/mixed noncompetitive inhibitor of AAAD. SNP was also found to be a noncompetitive inhibitor of AAAD with a Ki of approximately 300-500 mumol/l. In contrast, ferrous sulfate (0.5 mmol/l) was a competitive inhibitor (Ki = approximately 650 mumol/l) that actually increased the Vmax of AAAD. The results of these studies support that cyanide released from SNP can potently inhibit AAAD, although SNP has somewhat more complex interactions with AAAD due to the presence of ferrous ion.
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PMID:Mechanism of sodium nitroprusside-mediated inhibition of aromatic amino acid decarboxylase activity. 771 78

1. The effect of copper on the activity of the S-nitrosothiol compounds S-nitrosocysteine (cysNO) and S-nitrosoglutathione (GSNO) was investigated, using the specific copper chelator bathocuproine sulphonate (BCS), and human washed platelets as target cells. 2. Chelation of trace copper with BCS (10 microM) in washed platelet suspensions reduced the inhibition of thrombin-induced platelet aggregation by GSNO; however, BCS had no significant effect on the anti-aggregatory action of cysNO. BCS inhibited cyclic GMP generation in response to both cysNO and GSNO. 3. The effect of BCS was rapid (within 30 s), and could be abolished by increasing the platelet concentration to 500 x 10(9) l-1. 4. In BCS-treated platelet suspensions, the addition of Cu2+ ions (0.37-2.37 microM) led to a restoration of both guanylate cyclase activation and platelet aggregation inhibition by GSNO. 5. The anti-aggregatory activity of GSNO was reduced in a concentration-dependent manner by the copper (I)-specific chelators BCS and neocuproine, and to a smaller extent by desferal. No effect was observed with the copper (II) specific chelator, cuprizone, the iron-specific chelator, bathophenanthroline sulphonate, or the broader-specificity copper chelator, D-penicillamine. 6. In both BCS-treated and -untreated platelet suspensions, cys NO was more potent than GSNO as a stimulator of guanylate cyclase. In BCS-treated platelet suspensions there was no significant difference between the anti-aggregatory potency of cysNO and GSNO; however, in untreated suspensions, GSNO was significantly more potent than cysNO. Thus, when copper was available, GSNO produced a greater inhibition of aggregation than cysNO, despite being a less potent activator of guanylate cyclase. 7. The breakdown of cysNO and GSNO was measured spectrophotometrically by decrease in absorbance at 334 nm. In Tyrode buffer, cysNO (10 microM) broke down at a rate of 3.3 microM min-1. BCS (10 microM)reduced this to 0.5 microM min-1. GSNO, however, was stable, showing no fall in absorbance over a period of 7 min even in the absence of BCS.8. We conclude that copper is required for the activity of both cysNO and GSNO, although its influence on anti-aggregatory activity is only evident with GSNO. The stimulatory effect of copper is unlikely to be explained solely by catalysis of S-nitrosothiol breakdown. The enhancement by copper of the anti-aggregatory activity of GSNO, relative to cysNO, suggests that copper may be required for biological activity of GSNO which is independent of guanylate cyclase stimulation.
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PMID:Copper chelation-induced reduction of the biological activity of S-nitrosothiols. 778 Jun 43

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

Carbon monoxide has been proposed as a possible neurotransmitter because of its ability to bind to the iron atom of the heme of guanylyl cyclase, which is similar to that of nitric oxide. To determine whether carbon monoxide exerts an effect on the penis, strips of rabbit corpus cavernosum were mounted in an organ bath for isometric tension studies and the effect of zinc deuteroporphyrin, an inhibitor of heme oxygenase which metabolizes hemoprotein and releases carbon monoxide, on relaxation induced by electrical field stimulation (neurally mediated) was determined. Also observed was relaxation induced by electrical field stimulation after incubation with atropine and guanethidine to isolate nonadrenergic noncholinergic neurotransmission. Zinc deuteroporphyrin (10(-6) M, 10(-5) M, 10(-4) M and 3 x 10(-4) M) did not affect relaxation induced by electrical field stimulation in the absence or presence of guanethidine and atropine. Therefore, it appears that carbon monoxide does not contribute to neurally mediated relaxation of the rabbit corpus cavernosum.
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PMID:Lack of effect of carbon monoxide inhibitor on relaxation induced by electrical field stimulation in corpus cavernosum. 787 13

Streptozotocin (STZ) is selectively toxic to insulin-secreting beta-cells of pancreatic islets and induces impairment of islet glucose oxidation and of glucose-induced insulin secretion. Similar effects are induced by Interleukin-1 (IL-1), and the deleterious effects of IL-1 on islets appear to be mediated by nitric oxide (NO). STZ contains a nitroso moiety and may liberate NO by processes analogous to those for the NO-releasing drug nitroprusside. NO is rapidly transformed to nitrite in aqueous solution, and NO activates heme-containing enzymes such as guanylyl cyclase and inhibits iron-sulfur enzymes such as mitochondrial aconitase. Data presented here indicate that incubation of rat islets with STZ at concentrations that impair insulin secretion results in generation of nitrite, stimulation of islet guanylyl cyclase and accumulation of cGMP, and inhibition of islet mitochondrial aconitase activity to a degree similar to that achieved by IL-1. Effects of STZ on beta-cells may be mediated by local liberation of NO from STZ within islets.
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PMID:Biochemical evidence for nitric oxide formation from streptozotocin in isolated pancreatic islets. 790 59


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