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)

Saccharomyces cerevisiae was inoculated into a dilute synthetic minimal medium with glycerol as the carbon source. The number of live cells in the cultures was determined by colony counts on agar plates. Untreated control cells had doubled in number about once at the end of the first week and had gone through eight doublings by the end of the second week. Addition of either 8-bromo-cyclic guanosine monophosphate (8-bromo-cGMP) or human recombinant insulin, made the cells go through 12 and 10 doublings, respectively, by the end of the first week. In contrast, 8-bromo-cyclic adenosine monophosphate (8-bromo-cAMP) had only slight stimulating effects on cell multiplication, but if it was combined with phorbol-12-myristate-13-acetate (PMA) the cells went through about 12 doublings during the first week. Addition of LY 83583, an inhibitor of soluble guanylate cyclase, prevented cell proliferation. Further addition of 8-bromo-cGMP bypassed this inhibition. Singly, bradykinin or PMA did not affect cell multiplication. However, when these two compounds were combined, the cells went through about 10 doublings during the first week. Neither bradykinin, nor PMA had any releasing effect on the inhibition of LY 83583. These results indicate the existence of several routes leading to cell proliferation in wildtype S. cerevisiae cells.
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PMID:Resumption of rapid proliferation from lag phase in cultures of Saccharomyces cerevisiae in poor nutrient conditions. Effect of surface and intracellular signalling mechanisms. 1045 42

Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric (alpha/beta) haem protein that converts GTP to cGMP2-4. Here we report the discovery of a regulatory site on sGC. Using photoaffinity labelling, we have identified the cysteine 238 and cysteine 243 region in the alpha1-subunit of sGC as the target for a new type of sGC stimulator. Moreover, we present a pyrazolopyridine, BAY 41-2272, that potently stimulates sGC through this site by a mechanism that is independent of NO. This results in antiplatelet activity, a strong decrease in blood pressure and an increase in survival in a low-NO rat model of hypertension, and as such may offer an approach for treating cardiovascular diseases.
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PMID:NO-independent regulatory site on soluble guanylate cyclase. 1124 81

We have studied the effect of nitric oxide (NO) and hydrogen peroxide (H(2)O(2)), two reactive oxygen species (ROS) on histamine release (HR) from RBL-2H3 cells, a rat mucosal-type mast cell line. Marked HR was elicited by antigen (DNP-HSA), calcium ionophore A23187, sodium fluoride or phospholipase C, but not with compound 48/80 or 1,2-dioctanoyl-sn-glycerol. The NO-synthase substrate L-arginine and its inactive enantiomer (D-arginine), each on its own, induced a small but significant increase in HR above the basal level. However, the NO-donors (sodium nitroprusside or NaNO(3)) or the NO-synthase inducer lipopolysaccharide did not induce HR. Moreover, methylene blue (MB), which inhibits guanylate cyclase and N(omega)-nitro-L-arginine (L-NA), an inhibitor of NO synthase, were also without effect on either the basal HR or the L-arginine-induced HR. HR induced by A23187, DNP-HSA, sodium fluoride or phospholipase C was markedly reduced by MB, but mildly by L-NA (both at 1-100 microM). H(2)O(2) (0.01-1.0 mM) on its own did not induce HR, but it had a potent inhibitory effect on DNP-HSA- or A23187-induced HR, which was not reversed by L-NA (1-100 microM). Taken together, it seems that neither the stimulatory nor the inhibitory effects of the NO-related compounds on HR can be attributed to NO, but rather to other mechanisms. The inhibition of HR by H(2)O(2) also does not involve NO and suggests a negative feedback regulatory role for the peroxide in the allergic inflammation.
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PMID:Effects of nitric oxide and hydrogen peroxide on histamine release from RBL-2H3 cells. 1172 90

Vascular relaxation to GTN (nitroglycerin) and other antianginal nitrovasodilators requires bioactivation of the drugs to NO or a related activator of sGC (soluble guanylate cyclase). Conversion of GTN into 1,2-GDN (1,2-glycerol dinitrate) and nitrite by mitochondrial ALDH2 (aldehyde dehydrogenase 2) may be an essential pathway of GTN bioactivation in blood vessels. In the present study, we characterized the profile of GTN biotransformation by purified human liver ALDH2 and rat liver mitochondria, and we used purified sGC as a sensitive detector of GTN bioactivity to examine whether ALDH2-catalysed nitrite formation is linked to sGC activation. In the presence of mitochondria, GTN activated sGC with an EC50 (half-maximally effective concentration) of 3.77+/-0.83 microM. The selective ALDH2 inhibitor, daidzin (0.1 mM), increased the EC50 of GTN to 7.47+/-0.93 microM. Lack of effect of the mitochondrial poisons, rotenone and myxothiazol, suggested that nitrite reduction by components of the respiratory chain is not essential to sGC activation. However, since co-incubation of sGC with purified ALDH2 led to significant stimulation of cGMP formation by GTN that was completely inhibited by 0.1 mM daidzin and NO scavengers, ALDH2 may convert GTN directly into NO or a related species. Studies with rat aortic rings suggested that ALDH2 contributes to GTN bioactivation and showed that maximal relaxation to GTN occurred at cGMP levels that were only 3.4% of the maximal levels obtained with NO. Comparison of sGC activation in the presence of mitochondria with cGMP accumulation in rat aorta revealed a slightly higher potency of GTN to activate sGC in vitro compared with blood vessels. Our results suggest that ALDH2 catalyses the mitochondrial bioactivation of GTN by the formation of a reactive NO-related intermediate that activates sGC. In addition, the previous conflicting notion of the existence of a high-affinity GTN-metabolizing pathway operating in intact blood vessels but not in tissue homogenates is explained.
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PMID:Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. 1537 79

Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and non-esterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.
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PMID:[Natriuretic peptides: a new lipolytic pathway in human fat cells]. 1563 22

GTN (nitroglycerin; glycerol trinitrate) causes dilation of blood vessels via activation of nitric oxide (NO)-sensitive sGC (soluble guanylate cyclase), a heterodimeric haem protein that catalyses the conversion of GTP into cGMP. Activation of sGC by GTN requires enzymatic or non-enzymatic bioactivation of the nitrate. Based on insufficient NO release and lack of spectroscopic evidence for formation of NO-sGC, the cysteine (Cys)-dependent activation of sGC by GTN was proposed to occur in an NO-independent manner. This extraordinary claim is questioned by the present findings. First, the effect of GTN/Cys was blocked by the NO scavenger oxyhaemoglobin, the superoxide-generating compound flavin mononucleotide and the haem-site sGC inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one). Secondly, at equi-effective concentrations, GTN/Cys and the NO donor 2,2-diethyl-1-nitroso-oxyhydrazine released identical amounts of NO. Finally, at sufficiently high rates of NO release, activation of sGC by GTN/Cys was accompanied by a shift of the Soret band from 431 to 399 nm, indicating formation of NO-sGC. In the absence of Cys, GTN caused haem oxidation, apparent as a shift of the Soret band to 392 nm, which was accompanied by inactivation of the NO-stimulated enzyme. These results suggest that the effect of GTN/Cys is the result of an activation/inactivation equilibrium that is controlled by the rate of NO release and haem oxidation.
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PMID:Effects of nitroglycerin/L-cysteine on soluble guanylate cyclase: evidence for an activation/inactivation equilibrium controlled by nitric oxide binding and haem oxidation. 1590 91

Nitric oxide (NO) is an endogenous compound, which plays a fundamental role in the modulation of the function of the cardiovascular system, where it induces vasorelaxing and antiplatelet responses, mainly through the stimulation of guanylate cyclase and the increase of cGMP. Many drugs of common, time-honoured clinical use (for example, glycerol trinitrate and all the vasodilator nitrites and nitrates) act via the release of exogenous NO, thus mimicking the effects of the endogenous factor. In the last few years, a revision of the "one-compound-one-target" paradigm has led pharmacologists and pharmaceutical chemists to develop new classes of molecules which combine different pharmacodynamic properties. This innovative pharmacological/pharmaceutical strategy has produced hybrid drugs, with a dual mechanism of action: a) the slow release of nitric oxide and b) another fundamental pharmacodynamic profile. These drugs have been obtained by inserting appropriate NO-donor chemical groups (i.e. nitrate esters, nitrosothiols, etc.), linked to a known drug, by means of a variable spacer moiety. These new pharmacodynamic hybrids present the advantage of combining a basic mechanism of action (for example, cyclooxygenase inhibition, beta-antagonism or ACE inhibition) with a slow release of NO, which may be useful either to reduce adverse side effects (for example, the gastrotoxicity of NSAIDs), or to improve the effectiveness of the drug (for example, conferring direct vasorelaxing and antiplatelet effects on an ACE-inhibitor). The aim of this review is to present the chemical features of NO-releasing hybrids of cardiovascular drugs, and to explain the pharmacological improvements obtained by the addition of the NO-donor properties.
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PMID:NO-releasing hybrids of cardiovascular drugs. 1652 54

Human fat cell lipolysis was considered until recently to be an exclusive cAMP/protein-kinase A (PKA)-regulated metabolic pathway under the control of catecholamines and insulin. Moreover, exercise-induced lipid mobilization in humans was considered to mainly depend on catecholamine action and interplay between fat cell beta- and alpha2-adrenergic receptors controlling adenylyl cyclase activity and cAMP production. We have recently demonstrated that natriuretic peptides stimulate lipolysis and contribute to the regulation of lipid mobilization in humans. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulate lipolysis in human isolated fat cells. Activation of the adipocyte plasma membrane type A guanylyl cyclase receptor (NPR-A), increase in intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) levels and activation of hormone-sensitive lipase mediate the action of ANP. ANP does not modulate cAMP production and PKA activity. Increment of cGMP induces the phosphorylation of hormone-sensitive lipase and perilipin A via the activation of a cGMP dependent protein kinase-I (cGK-I). Plasma concentrations of glycerol and nonesterified fatty acids are increased by i.v. infusion of ANP in humans. Physiological relevance of the ANP-dependent pathway was demonstrated in young subjects performing physical exercise. ANP plays a role in conjunction with catecholamines in the control of exercise-induced lipid mobilization. This pathway becomes of major importance when subjects are submitted to chronic treatment with a beta-blocker. Oral beta-adrenoceptor blockade suppresses the beta-adrenergic component of catecholamine action in fat cells and potentiates exercise-induced ANP release by the heart. These findings may have several implications whenever natriuretic peptide secretion is altered such as in subjects with left ventricular dysfunction, congestive heart failure and obesity.
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PMID:[Natriuretic peptides: a new lipolytic pathway in human fat cells]. 1659 2

Bioactivation of nitroglycerin (GTN) into an activator of soluble guanylate cyclase (sGC) is essential for the vasorelaxant effect of the drug. Besides several enzymes that catalyze GTN bioactivation, the reaction with cysteine is the sole nonenzymatic mechanism known so far. Here we show that a reaction with ascorbate results in GTN bioactivation. In the absence of ascorbate, GTN did not affect the activity of purified sGC. However, the enzyme was activated to approximately 20% of maximal NO-stimulated activity by GTN in the presence of 10 mM ascorbate with an EC(50) value of 27.3 +/- 4.9 microM GTN. The EC(50) value of ascorbate was 0.11 +/- 0.011 mM. Activation of sGC was sensitive to oxyhemoglobin, superoxide, and a heme-site enzyme inhibitor. GTN had no effect when ascorbate was replaced by 1000 U of superoxide dismutase per milliliter. Ascorbate is known to reduce inorganic nitrite to NO. In the presence of 10 mM ascorbate, approximately 30 microM nitrite caused the same increase in sGC activity as 0.3 mM GTN. Determination of ascorbate-driven 1,2- and 1,3-glycerol dinitrate formation indicated that a 140 nM concentration of products was generated from 0.3 mM GTN within 10 min, excluding nitrite as a relevant intermediate. Our results suggest that a reaction between GTN and ascorbate or an ascorbate-derived species yields an activator of sGC with NO-like chemical properties. This reaction may contribute to GTN bioactivation in blood vessels under conditions of GTN tolerance and ascorbate supplementation.
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PMID:Bioactivation of nitroglycerin by ascorbate. 1744 67

Metabolism of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation. The link between nitrite formation and activation of soluble guanylate cyclase (sGC) is still unclear. To test the hypothesis that the ALDH2 reaction is sufficient for GTN bioactivation, we measured GTN-induced formation of cGMP by purified sGC in the presence of purified ALDH2 and used a Clark-type electrode to probe for nitric oxide (NO) formation. In addition, we studied whether GTN bioactivation is a specific feature of ALDH2 or is also catalyzed by the cytosolic isoform (ALDH1). Purified ALDH1 and ALDH2 metabolized GTN to 1,2- and 1,3-GDN with predominant formation of the 1,2-isomer that was inhibited by chloral hydrate (ALDH1 and ALDH2) and daidzin (ALDH2). GTN had no effect on sGC activity in the presence of bovine serum albumin but caused pronounced cGMP accumulation in the presence of ALDH1 or ALDH2. The effects of the ALDH isoforms were dependent on the amount of added protein and, like 1,2-GDN formation, were sensitive to ALDH inhibitors. GTN caused biphasic sGC activation with apparent EC(50) values of 42 +/- 2.9 and 3.1 +/- 0.4 microm in the presence of ALDH1 and ALDH2, respectively. Incubation of ALDH1 or ALDH2 with GTN resulted in sustained, chloral hydrate-sensitive formation of NO. These data may explain the coupling of ALDH2-catalyzed GTN metabolism to sGC activation in vascular smooth muscle.
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PMID:Bioactivation of nitroglycerin by purified mitochondrial and cytosolic aldehyde dehydrogenases. 1845 Jul 47


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