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)

Reactive oxygen species, such as superoxide and nitric oxide (NO), have been postulated to underlie the pathogenesis of various diseases. About 3 to approximately 10% of the oxygen utilized by tissues is converted to its reactive intermediates that impair cells and tissues. However, only a limited information supporting this hypothesis is available predominantly because of the short half life of these intermediates. To elucidate the role of superoxides and related metabolites in the pathogenesis of various diseases, two superoxide dismutase derivatives were synthesized; one (SM-SOD) circulates bound to albumin and accumulates in tissues with decreased pH and the other (HB-SOD) binds to vascular endothelial cells by a heparin-inhibitable mechanism. NO was first recognized as a potent vasorelaxant. NO rapidly diffuses across cells and binds to various proteins, such as guanylate cyclase, thereby modulating cellular metabolism. Because NO also reacts with superoxide and molecular oxygen, the two molecules might be major determinants of its half life and strongly affect its biological functions. In fact, targeting HB-SOD to vascular endothelial cells increased the cGMP levels in arterial walls and normalized the blood pressure of animals with genetic and nongenetic hypertension. Thus, the imbalance between superoxide and NO seems to underlie the pathogenesis of hypertension. NO forms a dissociable complex with cytochrome c oxidase in mitochondria and regulates cellular energy metabolism particularly under physiologically low oxygen tensions. Thus, cross-talk between oxygen, NO and superoxide radicals might play a critical role in regulating circulation and energy metabolism. Oxidative stress causes an imbalance in this cross-talk and underlies the pathogenesis of various diseases.
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PMID:[Role of oxidative stress in health and disease]. 893 79

Hemeproteins play an important role in the signaling processes mediated by nitric oxide (NO). For example, the production of NO by nitric oxide synthase, the activation of guanylate cyclase by binding NO, and the scavenging of NO by hemoglobin, myoglobin, and cytochrome c oxidase all occur through unique mechanisms of interaction between NO and hemeproteins. Unlike carbon monoxide (CO) and oxygen (O2), which have been studied extensively, the reactions of NO with ferric and ferrous hemeproteins are not as well characterized. In this work, NO binding to myoglobin is studied using cryogenic optical spectroscopy and Fourier transform infrared spectroscopy (FTIR) in order to characterize the ligand-bound and photoproduct states involved in the interaction of NO with the heme iron and the distal pocket of the protein. For ferrous nitrosyl myoglobin (MbIINO), optical spectroscopy is used to show that the ligand-bound state can be converted to >95% stable photoproduct below 10 K. The Soret peak of the photoproduct is red-shifted by 4 nm relative to deoxy-myoglobin (Mb), similar to previous results for carbonmonoxy- (MbCO) and oxy-myoglobin (MbO2) (Miller et al., 1996). MbIINO completely rebinds by 35 K, indicating that the rebinding barrier for NO is lower than MbCO, consistent with room temperature picosecond kinetic measurements. For ferric nitrosyl myoglobin (MbIIINO), we find that the photoproduct yield at cryogenic temperatures is less than unity and dependent on the distal pocket residue. Native MbIIINO has a lower photoproduct yield than the mutant, MbIII(H64L)NO, where the distal histidine is replaced by leucine. The rebinding rates for the native and mutant species are similar to each other and to MbIINO. By using FTIR difference spectroscopy (photolyzed/unphotolyzed) of isotopically labeled ferrous nitrosyl myoglobin (MbIINO), the NO stretching frequencies in both the ligand-bound states and photoproduct states are determined. Two ligand-bound conformational states (1607 and 1613 cm-1) and two photoproduct conformational states (1852 and 1857 cm-1) are observed for MbIINO. This is the first direct observation of photolyzed NO in the distal pocket of myoglobin. The ligand-bound frequencies are consistent with a bent MbIINO moiety, where the unpaired pi*(NO) electron remains localized on NO, causing nu(N-O) to be approximately 300 cm-1 lower than MbIIINO. Similar to MbO2, we suggest that Nepsilon of the distal histidine is protonated, forming a hydrogen bond to the NO ligand. For native MbIIINO, a single ligand-bound conformational state with respect to nu(N-O) is observed at 1927 cm-1. This frequency decreases to 1904 cm-1 for the mutant, MbIII(H64L)NO, contrary to the increase of the carbon monoxide (CO) stretching frequency in the isoelectronic MbII(H64L)CO mutant versus native MbCO. For linear MbIIINO, we suggest that backbonding from the unpaired pi*(NO) electron to iron results in an increased positive charge on the NO ligand, Fe(delta-)-NO(delta+). This can be facilitated by tautomerism of the distal histidine, leaving Nepsilon of the imidazole ring unprotonated and able to accept positive charge from the Fe(delta-)-NO(delta+) moiety, resulting in a higher bond order (and a 23 cm-1 shift to higher frequency) for native MbIIINO versus MbIII(H64L)NO, where this interaction is absent. These different interactions between the distal histidine and the ferrous versus ferric species illustrate potential ways the protein can stabilize the bound ligand and demonstrate the versatile nature by which NO can bind to hemeproteins.
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PMID:Identification of conformational substates involved in nitric oxide binding to ferric and ferrous myoglobin through difference Fourier transform infrared spectroscopy (FTIR). 931 57

Nitric oxide (NO) binds to metalloproteins, and particularly to hemoproteins in both ferrous and ferric states, with association and dissociation rate constants which cover many orders of magnitude. These chemical properties often provide clear explanations of enzymatic specificity. A basic and straightforward description of the versatility of NO chemistry and of the biological relevance of NO effects, as understood by biochemists as opposed to physiologists, is presented. NO effects on hemoglobin and soluble guanylate cyclase, two proteins directly involved in arterio-venous oxygen transport at quite different biological levels, are compared. NO and other N-oxides also play primary roles in several mitochondrial functions. Specific interactions with cytochrome c oxidase and cytochrome c are reviewed, and the effects of NO and other N-oxides on other iron-cluster-containing components of mitochondrial respiration are discussed.
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PMID:Interactions of nitric oxide with hemoproteins: roles of nitric oxide in mitochondria. 1044 85

Two enzymes, the soluble guanylate cyclase and cytochrome c oxidase, have been shown to be exquisitely sensitive to nitric oxide (NO) at low physiological concentrations. Activation of the soluble guanylate cyclase by endogenous NO and the consequent increase in the second messenger cyclic GMP are now known to control a variety of biological functions. Cytochrome c oxidase (complex IV, the terminal enzyme of the mitochondrial respiratory chain) is inhibited by NO. We have shown that NO generated by vascular endothelial cells under basal and stimulated conditions modulates the respiration of these cells in response to acute changes in oxygen concentration. This action occurs at the level of complex IV and depends on influx of calcium. Thus, NO plays a physiological role in adjusting the capacity of this enzyme to use oxygen, allowing endothelial cells to adapt to acute changes in their environment. We have, in addition, studied the effect of long-term exposure to NO on different enzymes of the respiratory chain in a variety of cell lines. Our results show that, although NO inhibits complex IV in a way that is always reversible, prolonged exposure to NO results in a gradual and persistent inhibition of complex I that is concomitant with a reduction in the intracellular concentration of reduced glutathione. This inhibition appears to result from S-nitrosylation of critical thiols in the enzyme complex because it can be immediately reversed by exposing the cells to high intensity light or by replenishment of intracellular reduced glutathione. Furthermore, decreasing the concentration of reduced glutathione accelerates the process of persistent inhibition. Our results suggest that, although NO may regulate cell respiration physiologically by its action on complex IV, long-term exposure to NO leads to persistent inhibition of complex I and potentially to cell pathology.
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PMID:Nitric oxide and cell respiration: physiology and pathology. 1090 18

Noncovalent bonding interactions of nitric oxide (NO) with human serum albumin (HSA), human hemoglobin A, bovine myoglobin, and bovine cytochrome c oxidase (CcO) have been explored. The anesthetic nitrous oxide (NNO) occupies multiple sites within each protein, but does not bind to heme iron. Infrared (IR) spectra of NNO molecules sequestered within albumin, with NO present, support the binding of NO and NNO to the same sites with comparable affinities. Perturbations of IR spectra of the Cys(34) thiol of HSA indicate NO, NNO, halothane, and chloroform can induce similar changes in protein structure. Experiments evaluating the relative affinities of binding of NO and carbon monoxide (CO) to iron(II) sites of the hemeproteins led to evidence of NO binding to noniron, nonsulfur sites as well. With HbA, IR spectra of cysteine thiols and/or the iron(II) N-O stretching region denote changes in protein structure due to NO, NNO, or CO occupying noniron sites with an order of decreasing affinities of NO > NNO > CO. Loss of NO from some, not all, noniron sites in hemeproteins is very slow (t(1/2) approximately hours). These findings provide examples in which NO and anesthetics alter the structure and properties of protein similarly, and support the hypothesis that some physiological effects of NO (and possibly CO) result from anesthetic-like noncovalent bonding to sites within protein or other tissue components. Such bonding may be involved in mechanisms for control of oxygen transport, mitochondrial respiration, and activation of soluble guanylate cyclase by NO.
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PMID:Anesthetic-like interactions of nitric oxide with albumin and hemeproteins. A mechanism for control of protein function. 1127 8

Resonance Raman spectroscopy and step-scan Fourier transform infrared (FTIR) spectroscopy have been used to identify the ligation state of ferrous heme iron for the H93G proximal cavity mutant of myoglobin in the absence of exogenous ligand on the proximal side. Preparation of the H93G mutant of myoglobin has been previously reported for a variety of axial ligands to the heme iron (e.g., substituted pyridines and imidazoles) [DePillis, G., Decatur, S. M., Barrick, D., and Boxer, S. G. (1994) J. Am. Chem. Soc. 116, 6981-6982]. The present study examines the ligation states of heme in preparations of the H93G myoglobin with no exogenous ligand. In the deoxy form of H93G, resonance Raman spectroscopic evidence shows water to be the axial (fifth) ligand to the deoxy heme iron. Analysis of the infrared C-O and Raman Fe-C stretching frequencies for the CO adduct indicates that it is six-coordinate with a histidine trans ligand. Following photolysis of CO, a time-dependent change in ligation is evident in both step-scan FTIR and saturation resonance Raman spectra, leading to the conclusion that a conformationally driven ligand switch exists in the H93G protein. In the absence of exogenous nitrogenous ligands, the CO trans effect stabilizes endogenous histidine ligation, while conformational strain favors the dissociation of histidine following photolysis of CO. The replacement of histidine by water in the five-coordinate complex is estimated to occur in < 5 micros. The results demonstrate that the H93G myoglobin cavity mutant has potential utility as a model system for studying the conformational energetics of ligand switching in heme proteins such as those observed in nitrite reductase, guanylyl cyclase, and possibly cytochrome c oxidase.
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PMID:A photolysis-triggered heme ligand switch in H93G myoglobin. 1131 54

Nitric oxide (NO(*)) signaling is diverse, and involves reaction with free radicals, metalloproteins, and specific protein amino acid residues. Prominent among these interactions are the heme protein soluble guanylate cyclase and cysteine residues within several proteins such as caspases, the executors of apoptosis. Another well characterized site of NO(*) binding is the terminal complex of the mitochondrial respiratory chain, cytochrome c oxidase, although the downstream signaling effects of this interaction remain unclear. Recently, it has been recognized that the intracellular formation of hydrogen peroxide (H(2)O(2)) by controlled mechanisms contributes to what we term "redox tone," and so controls the activity and activation thresholds of redox-sensitive signaling pathways. In this hypothesis paper, it is proposed that NO(*)-dependent modulation of the respiratory chain can control the mitochondrial generation of H(2)O(2) for cell signaling purposes without affecting ATP synthesis.
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PMID:Hypothesis: the mitochondrial NO(*) signaling pathway, and the transduction of nitrosative to oxidative cell signals: an alternative function for cytochrome C oxidase. 1184 27

In order for nitric oxide (NO) to function as a biological messenger it has to be inactivated, but little is known of how this is achieved. In cells from the brain, we have recently shown the existence of a powerful NO sink that 'shapes' NO signals for targeting its receptor, soluble guanylate cyclase, whilst simultaneously preventing NO rising to toxic concentrations [Griffiths and Garthwaite (2001) J. Physiol. (Cambridge, U.K.) 536, 855-862]. In the present study, the properties of this sink were investigated further. Inactivation of NO was preserved in rat brain homogenates. In both cerebellar cell suspensions and brain homogenates, NO inactivation required O(2) and, from measurements in homogenates, the principal end-product was NO(-)(3), which is also the main product of endogenously formed NO in vivo. Direct chemical reaction with O(2), superoxide anions or haemoglobin was not responsible. Consumption of NO was, however, inhibited by heat or protease treatment. Pharmacological tests were negative for several candidate enzymes, namely cytochrome c oxidase, H(2)O(2)-dependent haem peroxidases, prostaglandin H synthase, 12/15-lipoxygenase and a flavohaemoglobin-like NO dioxygenase. The capacity of the NO sink in cells was limited because regeneration of the activity was slow (2 h). It is concluded that NO is consumed in the brain through a novel protein, ultimately forming NO(-)(3), and that the slow regeneration of the activity provides a scenario for NO to become toxic.
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PMID:Nitric oxide inactivation in brain by a novel O2-dependent mechanism resulting in the formation of nitrate ions. 1185 55

Nitric oxide (NO) signal transduction may involve at least two targets: the guanylyl cyclase-coupled NO receptor (NO(GC)R), which catalyzes cGMP formation, and cytochrome c oxidase, which is responsible for mitochondrial O(2) consumption and which is inhibited by NO in competition with O(2). Current evidence indicates that the two targets may be similarly sensitive to NO, but quantitative comparison has been difficult because of an inability to administer NO in known, constant concentrations. We addressed this deficiency and found that purified NO(GC)R was about 100-fold more sensitive to NO than reported previously, 50% of maximal activity requiring only 4 nm NO. Conversely, at physiological O(2) concentrations (20-30 microM), mitochondrial respiration was 2-10-fold less sensitive to NO than estimated beforehand. The two concentration-response curves showed minimal overlap. Accordingly, an NO concentration maximally active on the NO(GC)R (20 nm) inhibited respiration only when the O(2) concentration was pathologically low (50% inhibition at 5 microM O(2)). Studies on brain slices under conditions of maximal stimulation of endogenous NO synthesis suggested that the local NO concentration did not rise above 4 nm. It is concluded that under physiological conditions, at least in brain, NO is constrained to target the NO(GC)R without inhibiting mitochondrial respiration.
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PMID:Differential sensitivity of guanylyl cyclase and mitochondrial respiration to nitric oxide measured using clamped concentrations. 1208 82

The mechanisms of nitric oxide (NO) signaling include binding to the iron centers in soluble guanylate cyclase and cytochrome c oxidase and posttranslational modification of proteins by S-nitrosation. Low levels of NO control mitochondrial number in cells, but little is known of the impact of chronic exposure to high levels of NO on mitochondrial function in endothelial cells. The focus of this study is the interaction of NO with mitochondrial respiratory complexes in cell culture and the effect this has on iron homeostasis. We demonstrate that chronic exposure of endothelial cells to NO decreased activity and protein levels of complexes I, II, and IV, whereas citrate synthase and ATP synthase were unaffected. Inhibition of these respiratory complexes was accompanied by an increase in cellular S-nitrosothiol levels, modification of cysteines residues, and an increase in the labile iron pool. The NO-dependent increase in the free iron pool and inhibition of complex II was prevented by inhibition of mitochondrial protein synthesis, consistent with a major contribution of the organelle to iron homeostasis. In addition, inhibition of mitochondrial protein synthesis was associated with an increase in heat shock protein 60 levels, which may be an additional mechanism leading to preservation of complex II activity.
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PMID:Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins. 1469 Dec 59


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