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)

Current information is reviewed on the mechanism of secretion in small intestine, including how it is altered by cyclic 3',5'-adenosine monophosphate and on the structures and properties of cholera and both heat-labile and heat-stable Escherichia coli enterotoxins. Two separate active ion transport processes are altered by cyclic 3',5'-adenosine monophosphate: 1) coupled absorption of NaCl is inhibited in villus cells and 2) active anion secretion is stimulated, probably in crypt cells. Cholera and heat-labile E. coli toxins exert their secretory effect by stimulating intestinal mucosal adenylate cyclase. This stimulation results from the A1 subunit catalyzed transfer of adenosine diphosphate ribose from NAD to a membrane-bound guanosine triphosphatase, thereby inhibiting the enzyme, which normally represses adenylate cyclase. Heat-stable E. coli enterotoxin stimulates intestinal mucosal guanylate cyclase, which appears to be the basis for its enterotoxicity.
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PMID:Mechanisms of action of cholera and Escherichia coli enterotoxins. 3 66

Vero cell cytotoxins and cytotonic enterotoxins produced by E. coli are toxic proteins, which have been implicated in a number of specific diseases in humans and animals. Nomenclature for these toxins is complicated by the existence of different names for the same toxin. The Vero cell cytotoxins are called verotoxins because they are lethal for Vero cells in culture; they are also known as Shiga-like toxins (SLTs) because they are clearly related to Shiga toxin in structure, amino acid sequence, mechanism of action, and biological activity. SLTs belong to two classes. SLT-I is identical with Shiga toxin and is in a class by itself (class I). The other SLTs are closely related to each other and form a second class (class II). Class II SLTs include SLT-II, SLT-IIv, SLT-IIvha, SLT-IIvhb, and SLT-IIva. All SLTs that have been investigated are A-B subunit protein toxins, whose A subunits possess N-glycosidase activity against 28S rRNA and cause inhibition of protein synthesis in eukaryotic cells. These toxins are enterotoxic as well as cytotoxic. SLTs produced in the intestine are absorbed into the blood stream and affect vascular endothelial cells in target organs. They may also have a direct toxic effect on enterocytes. Diseases in which E. coli SLTs have been implicated include diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome in humans and edema disease in pigs. Variation in receptor specificities among SLTs may be the reason for different disease syndromes in different host species. The E. coli enterotoxins belong to three distinct classes: heat-labile enterotoxin (LT), heat-stable enterotoxin type I or type a (STI, STa), and heat-stable enterotoxin type II or type b (STII, STb). There is clear evidence that these cytotonic enterotoxins play an essential role in diarrheal disease. LT is an A-B subunit protein toxin, closely related to cholera toxin. Following binding of LT to receptors in enterocytes the A subunit is internalized. The enzymatically active A subunit transfers ADP-ribose from NAD to a GTP-dependent adenylate cyclase regulatory protein, thereby elevating intracellular levels of adenylate cyclase. The increased levels of cyclic AMP cause stimulation of A kinase and lead to hypersecretion of electrolytes and fluid. STI is a small peptide of 18 or 19 amino acids. It binds to receptors in enterocytes and stimulates particulate guanyl cyclase. Elevated intracellular cyclic GMP stimulates G kinase, resulting in increased Cl- secretion and impaired absorption of Na+Cl-. STII is a peptide toxin whose mechanism of action is unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Escherichia coli cytotoxins and enterotoxins. 139 38

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

The heat-stable enterotoxin (STa) of E. coli activates intestinal guanylate cyclase and leads to increased cGMP levels by an as yet undetermined mechanism. In comparing this cGMP system to other known toxin-mediated alterations in cAMP metabolism, we observed that pertussis toxin caused lower levels of intestinal cGMP synthesis in response to purified STa. Another participant in ADP-ribosylation reactions, NAD, enhanced the ability of STa to activate guanylate cyclase, yet had no effect on basal enzyme activity. Niacinamide and isoniacinamide also had no effect on basal activity, but attenuated the STa activation. These results are discussed in relation to current models of hormone/toxin-sensitive adenylate cyclase, and may suggest an involvement of guanine-nucleotide-binding proteins in intestinal cGMP metabolism.
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PMID:Activation of guanylate cyclase by E. coli heat-stable enterotoxin (STa). Modulation by NAD and pertussis toxin. 287 59

As noted previously, in N1E-115 neuroblastoma cells, carbamylcholine, a muscarinic cholinergic agonist, increased cGMP over 15-fold and decreased basal and prostaglandin E1 (PGE1)-stimulated cAMP content. In contrast to the stimulatory effects of PGE1 on cAMP, which were immediate, the carbamylcholine-induced decrease in basal and PGE1-stimulated cAMP exhibited a delay. The delay in carbamylcholine inhibition was independent of the extent of adenylate cyclase activation. Although basal cAMP content was suppressed within 30 sec after addition of carbamylcholine, inhibition was not maximal for at least 2 min following agonist addition; the delay was similar in cells exposed to PGE1 for 10 min prior to carbamylcholine but could be eliminated by incubation of the cells with muscarinic cholinergic agonist for 5 min prior to addition of prostaglandin. N1E-115 neuroblastoma cells possess a 41,000-Da membrane protein believed to be a component of the inhibitory GTP-binding protein of adenylate cyclase that is ADP ribosylated by pertussis toxin. Incubation of the cells with pertussis toxin prior to the addition of carbamylcholine reduced the maximal extent of inhibition of cAMP content and prevented the [32P]ADP-ribosylation of a 41,000-Da protein by toxin and [32P]NAD in membrane preparations from these cells. Incubation of cells with pertussis toxin, however, did not significantly alter the dose-response curve for carbamylcholine effects on cGMP. Even high concentrations of carbamylcholine, effective in stimulating cGMP, had minimal effects on cAMP content in toxin-treated cells; thus, ADP-ribosylation of Gi converts the adenylate cyclase but not the guanylate cyclase system to an agonist-insensitive state.
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PMID:Effects of pertussis toxin on cAMP and cGMP responses to carbamylcholine in N1E-115 neuroblastoma cells. 299 40

Lactate was found to produce a relaxation of isolated endothelium-removed calf pulmonary arteries precontracted with 20-30 mM K+. Examination of the mechanism of this response indicates that it appears to be O2 dependent and mediated via guanosine 3',5'-cyclic monophosphate (cGMP), since it is reduced by hypoxia (N2 atmosphere, PO2 = 8-10 Torr) and because the relaxation was both eliminated by inhibition of soluble guanylate cyclase activation with methylene blue and enhanced by an antagonist of cGMP-selective phosphodiesterases (M & B 22948). Relaxation to lactate is not mediated via prostaglandin formation or arginine-derived nitric oxide, since indomethacin or nitro-L-arginine, respectively, did not alter the response. Lucigenin-elicited chemiluminescence, a potential detector of superoxide anion, was significantly increased by lactate only after inhibition of Cu-Zn-superoxide dismutase (via pretreatment with diethyldithiocarbamate). Pyruvate (5 mM) produced only minimal relaxation and did not significantly increase chemiluminescence. In the homogenate fraction of the arterial smooth muscle, NAD plus lactate or NADH was required to observe increased chemiluminescence. The calf pulmonary arterial smooth muscle contraction to hypoxia and relaxation to posthypoxic reoxygenation was observed to be increased by lactate, associated with a reduced level tone generation under O2 but not N2 atmosphere. Thus lactate, but not pyruvate, appears to cause a cGMP-mediated relaxation in the calf pulmonary artery through an increased intracellular H2O2 generation via the NADH-dependent production of superoxide anion, and activation of this relaxing mechanism modulates O2-elicited tone responses.
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PMID:O2-dependent modulation of calf pulmonary artery tone by lactate: potential role of H2O2 and cGMP. 838 45

Our previous studies in isolated endothelium-removed calf pulmonary arteries suggest that PO2-elicited responses are primarily mediated through modulation of guanosine 3',5'-cyclic monophosphate via changes in the generation of H2O2 originating from superoxide anion (O2-.) produced by NADH oxidase activity. In the present study we examined the importance of this mechanism in PO2-elicited responses of endothelium-removed calf coronary arteries. NADH oxidase activity was found to be the major source of O2-. in the homogenate of endothelium-removed calf coronary arteries detected by lucigenin-elicited chemiluminescence. Precontracted endothelium-removed calf coronary arteries show a relaxation to hypoxia, and reoxygenation causes a transient additional relaxation before the recovery of normoxic levels of force. Under these conditions the detection of O2-. was decreased by hypoxia and a transient overproduction was observed during reoxygenation. The relaxation to reoxygenation, but not to hypoxia, was significantly inhibited by a scavenger of O2-. that prevents the formation of H2O2 (nitro blue tetrazolium), an inhibitor of NAD(P)H oxidases and other O2(-.)-generating flavoproteins (diphenyliodonium), and inhibition of the stimulation of soluble guanylate cyclase (LY-83583). A scavenger of O2-. that promotes H2O2 formation (Tiron) did not inhibit the PO2-elicited responses examined. Hypoxia and diphenyliodonium (but not Tiron) decreased the metabolism of endogenous H2O2 by catalase (as measured by the H2O2-dependent co-oxidation of methanol to formaldehyde by catalase), and reoxygenation caused a stimulation of H2O2 metabolism by catalase. The presence of endothelium resulted in minor modifications of the PO2 responses, which were partially mediated via prostaglandins and nitric oxide on the basis of the effects of indomethacin and nitro-L-arginine, respectively. These results suggest that in calf coronary arteries the stimulation of guanylate cyclase via H2O2 originating from NADH-derived O2-(.) production contributes to the transient relaxation to posthypoxic reoxygenation, but not the response to hypoxia.
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PMID:Oxygen-elicited responses in calf coronary arteries: role of H2O2 production via NADH-derived superoxide. 878 Feb 2

In primary cocultures of neurons and glial cells prepared from the neonatal rat brain, lipopolysaccharide (LPS) reduced the numbers of neuronal cells but the effects were markedly inhibited by NG-monomethyl-L-arginine, indicating the involvement of NO and LPS-induced NO synthase in neuronal death. LPS stimulated the expression of inducible NOS (iNOS) in preparations of primary cultured microglias/astrocytes, but not in primary cultured neurons. In addition, LPS caused DNA fragmentation only in NG108-15 cells but not in primary cultured astrocytes as well as astrocytes in cocultures of the two cell types, suggesting that NOS induces the apoptosis of neurons but not glial cells. We then examined the NO-induced neuronal death in NG108-15 cells using NO donors. SNP, and NO donor, caused NO-2 accumulation in the reaction medium and lactate dehydrogenase (LDH) leakage from NG108-15 cells. Although SNP stimulated guanylyl cyclase and accumulated cGMP, cGMP analogs did not affect LDH leakage. In addition, SNP induced chromosomal condensation and fragmentation of nuclei in NG108-15 cells. Gel electrophoretic analysis of cellular DNA extracted from SNP-treated cells, confirmed the internucleosomal DNA fragmentation typical of apoptosis in this culture. SNP increased the amount of radioisotopic labeled glyceraldehyde-3 phosphate dehydrogenase (GAPDH) in the presence of [32P]NAD and inhibited the enzyme activity. The results suggested that SNP-induced cell death is partly due to the NO-induced inhibition of GAPDH, perhaps by stimulating the binding of NAD to GAPDH.
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PMID:Neuronal apoptosis by glial NO: involvement of inhibition of glyceraldehyde-3-phosphate dehydrogenase. 918 51

We have previously reported that inhibition of Cu/Zn superoxide dismutase (SOD) in endothelium-removed bovine pulmonary arteries (BPA) attenuates nitrovasodilator-elicited relaxation and that a NADH oxidase linked to the redox status of cytosolic NADH is the major detectable source of superoxide (O-2) production in this tissue. In the present study, we investigated whether NADH oxidase-derived O-2 participated in inhibition of nitrovasodilator-elicited relaxation and soluble guanylate cyclase (sGC) stimulation. Lactate (10 mM) and pyruvate (10 mM) were employed to increase and decrease, respectively, NADH-dependent O-2 production in the BPA presumably by modulating cytosolic NAD(H) through the lactate dehydrogenase reaction. A 30-min pretreatment with 10 mM diethyldithiocarbamate (DETCA) was used to inhibit Cu/Zn SOD, and S-nitroso-N-acetylpenicillamine (SNAP) was employed as a source of nitric oxide (NO). Lactate or pyruvate did not alter relaxation to NO. However, when the response to NO was inhibited by DETCA, lactate potentiated and pyruvate reduced the inhibitory effects of DETCA. SOD attenuated the inhibitory effects of DETCA plus lactate. In the presence of 10 microM SNAP, the activity of sGC in a BPA homogenate preparation (which was reconcentrated to approximate tissue conditions) was not altered by SOD. However, NADH (0.1 mM) decreased sGC activity by 70%, and this effect of NADH was attenuated in the presence of SOD. Thus cytosolic NADH redox and Cu/Zn SOD activity have important roles in controlling the inhibitory effects of O-2 derived from NADH oxidase on sGC activity and cGMP-mediated relaxation to nitrovasodilators in BPA.
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PMID:Regulation of NO-elicited pulmonary artery relaxation and guanylate cyclase activation by NADH oxidase and SOD. 1033 Feb 36

Observations that physiological levels of O2 control the rates of production of reactive O2 species by systems including NAD(P)H oxidases and that certain of these species have signalling mechanisms that regulate vascular tone has resulted in consideration of these systems in processes that mediate the sensing of changes in P(O2). Evidence exists for the participation of hydrogen peroxide-dependent regulation of prostaglandin production and soluble guanylate cyclase activity, resulting from the metabolism of peroxide by cyclooxygenase and catalase, respectively, in P(O2)-elicited signalling mechanisms that regulate vascular force generation. A microsomal NADH oxidase whose activity is controlled by the redox status of cytosolic NAD(H) appears to function as a P(O2) sensor in bovine pulmonary and coronary arteries where changes in O2 levels control the production of superoxide anion-derived hydrogen peroxide and a cGMP-mediated relaxation response. Interactions with nitric oxide and superoxide anion, and the activity of glutathione peroxidase appear to influence the function of these O2 sensing systems, and some of these interactions, along with the activation of other oxidases, may contribute to alterations in P(O2) sensing mechanisms under pathophysiological conditions that affect vascular function.
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PMID:Roles for NAD(P)H oxidases and reactive oxygen species in vascular oxygen sensing mechanisms. 1038 36


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