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)

Low molecular mass dinitrosyl iron complexes (DNICs) are nitrosating agents and it is known that the dinitrosyl iron moiety can be transferred to proteins. The aim of the present study was to determine if the formation of protein-bound dinitrosyl iron can modulate ionic channel activity. In PC12 cells, dinitrosyl iron-thiosulfate (50 microM) caused irreversible activation of a depolarizing inward current (IDNIC). IDNIC was partially inhibited by the metal chelator diethyldithiocarbamate (DETC, 1 mM), but not by the reducing/denitrosylating agent dithiothreitol (DTT, 5 mM). The activation of IDNIC was not reproduced by application of nitric oxide (NO., 100 microM), S-nitrocysteine (200 microM) or ferrous iron-thiosulfate (50 microM), and was not prevented by the irreversible guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ, 1 microM). Similarly, intracellular perfusion of dinitrosyl iron-thiosulfate (100 microM) did not result in activation of IDNIC. Ion replacement experiments show that the DETC-sensitive component of IDNIC is a non-selective cationic current. In accordance, IDNIC was blocked by antagonists of receptor-operated calcium entry, gadolinium (25 microM) and SK&F 96365 (25 microM). Single-channel measurements from outside-out patches reveal that the DETC-sensitive component of IDNIC is an inward current carried by a cationic channel having a conductance of 50 pS. The present observations suggest that the formation of ion channel-bound dinitrosyl iron represents another mechanism of regulation of ion channel activity by NO.-related species, which may be particularly important in pathophysiological processes where NO. is overproduced.
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PMID:Novel activation of non-selective cationic channels by dinitrosyl iron-thiosulfate in PC12 cells. 1111 2

We have recently reported that the central heme oxygenase (HO) pathway has an important role in the genesis of lipopolysaccharide fever. However, the HO product involved, i.e., biliverdine, free iron, or carbon monoxide (CO), has not yet been identified with certainty. Therefore, in the present study, we tested the thermoregulatory effects of all HO products. Body core temperature (T(c)) and gross activity of awake, freely moving rats was measured by biotelemetry. Intracerebroventricular administration of heme-lysinate (152 nmol), which induces the HO pathway, evoked a marked increase in T(c), a response that was attenuated by intracerebroventricular pretreatment with the HO inhibitor zinc deuteroporphyrin 2,4-bis glycol (200 nmol), indicating that an HO product has a pyretic action in the central nervous system (CNS) of rats. Besides, heme-lysinate also increased gross activity, but no correlation was found between this effect and the increase in T(c). Moreover, intracerebroventricular biliverdine or iron salts at 152 nmol, a dose at which heme-lysinate was effective in increasing T(c), produced no change in T(c). Accordingly, intracerebroventricular treatment with the iron chelator deferoxamine elicited no change in basal T(c) and did not affect heme-induced pyresis. However, heme-induced pyresis was completely prevented by the soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. Because biliverdine and iron had no thermoregulatory effects and CO produces most of its actions via sGC, these data strongly imply that CO is the only HO product with a pyretic action in the CNS.
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PMID:Carbon monoxide is the heme oxygenase product with a pyretic action: evidence for a cGMP signaling pathway. 1120 74

Nitric oxide (NO) is a natural and stable free radical produced in soil and water by the bacteriological reduction of nitrites and nitrates and in animals by the enzyme oxidation of L-arginine. NO is biosynthesised by finely regulated enzymatic systems called NO-synthases and readily diffuses through tissues. It reacts rapidly with hemoproteins and iron-sulphur centers to form nitrosylated compounds. It oxidises more slowly to form nitrogen oxides that nitrosate thiols into thionitrite. NO is transported in these various forms and released spontaneously or through yet unclear mechanisms into most cells; it also regulates oxygen consumption at the mitochondrial respiratory chain level through interaction with cytochrome oxidase. In the cardiovascular system, NO lowers blood pressure by activating a hemoprotein, the guanylate cyclase present in muscle cells; through such interaction it acts also as a neuromediator and neuromodulator in the nervous system. However, many of NO's roles result from rapid coupling to other radicals; for example, it reacts with the superoxide anion (O2-) to form oxoperoxinitrate (ONOO-, also known as peroxynitrite). This strong oxidant of metallic centers, thiols, and antioxidants is also able to convert tyrosine to 3-nitrotyrosine and to act upon tyrosine residues contained in proteins. The biological aspects of the roles of NO are presented with particular respect to the rapid interactions of NO with hemoproteins' iron and other radicals. Concurrently, NO oxidation enables nitrosation reactions primarily of thiols but ultimately of nucleic bases. The thionitrite function (R-S-NO) thus formed and the dimerisation and nitration of tyrosine residues are protein post-translational modifications that are being investigated in animals.
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PMID:[Intervention by nitric oxide, NO, and its oxide derivatives particularly in mammals]. 1123 75

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

Heme oxygenase (HO) is the rate-limiting enzyme for the degradation of heme, a prooxidant, coming from a multitude of heme-containing proteins/enzymes. With the action of cytochrome P(450) reductase, HO cleaves the heme ring into biliverdin which is converted into bilirubin, both have been shown to have intrinsic radical scavenger activities. Iron is also released from the heme core and in its free form can act as a catalyst for oxidative stress damage or can be sequested by several iron-binding proteins. Under physiological conditions, the newly generated iron can be neutralized within the cell. The third product of the opening of the porphyrin ring is carbon monoxide, which role has been puzzling. It has been reported as a potential neuromodulator, it modulates guanylate cyclase activity and has vasodilation, anti-inflammatory and antiapoptotic effects. In the brain, HO2 accounts for the vast majority of HO activity. By decreasing HO2 activity, one would expect more neuronal damage after oxidative stress injury with possible direct implications to acute and chronic neurodegenerative disorders. Pharmacological ways to increase neuronal HO activity is likely to have therapeutic applications.
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PMID:Decreased activity of the antioxidant heme oxygenase enzyme: implications in ischemia and in Alzheimer's disease. 1205 65

To investigate whether nitric oxide (*NO) is neurotoxic or neuroprotective in the brain, we compared the in vivo role of S-nitroso-N-acetylpenicillamine (SNAP) with that of sodium nitroprusside (SNP) on ferrous citrate-induced oxidative stress and neuronal loss in the rat nigrostriatal dopaminergic system. It is known that light irradiation releases *NO from its donor compounds; these irradiated *NO donors were used as sham controls in this study. Intranigral infusion of ferrous citrate (4.2 nmol) into the rat midbrain substantia nigra compacta area caused acute lipid peroxidation in the substantia nigra and chronic dopamine depletion in the caudate nucleus. Coinfusion of freshly prepared SNAP (0-8.4 nmol) or *NO (about 2 nmol), but not SNP, rescued iron-induced dopamine depletion in the rat brain in vivo. In fact, SNP produced prooxidative effects similar to ferrous citrate both in vivo and in vitro, since SNP is a redox iron complex. Consistently, *NO and SNAP inhibited, whereas SNP potentiated, *OH generation and lipid peroxidation evoked by ferrous citrate in vitro. We previously reported that freshly prepared, but not irradiated, S-nitroso-L-glutathione (GSNO) protected brain dopamine neurons against oxidative stress in vivo. As well as these antioxidative properties, our recent reports (see (Ref. 1)) indicate that *NO/GSNO activated guanylyl cyclase, increased cGMP and that could lead to PKG-mediated expression of MnSOD, Bcl-2, and thioredoxin for preconditioning neuroprotection against 1-methyl-4-phenylpyridinium (MPP(+)).(1) In conclusion, *NO and S-nitrosothiols (e.g., GSNO and SNAP) can scavenge reactive oxygen species and activate the heme moiety of guanylyl cyclase, resulting in protection of brain dopamine neurons through both antioxidative and antiapoptotic mechanisms.
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PMID:Contradictory effects of sodium nitroprusside and S-nitroso-N-acetylpenicillamine on oxidative stress in brain dopamine neurons in vivo. 1207 63

Carbon monoxide (CO), a gaseous second messenger, arises in biological systems during the oxidative catabolism of heme by the heme oxygenase (HO) enzymes. HO exists as constitutive (HO-2, HO-3) and inducible isoforms (HO-1), the latter which responds to regulation by multiple stress-stimuli. HO-1 confers protection in vitro and in vivo against oxidative cellular stress. Although the redox active compounds that are generated from HO activity (i.e. iron, biliverdin-IXalpha, and bilirubin-IXa) potentially modulate oxidative stress resistance, increasing evidence points to cytoprotective roles for CO. Though not reactive, CO regulates vascular processes such as vessel tone, smooth muscle proliferation, and platelet aggregation, and possibly functions as a neurotransmitter. The latter effects of CO depend on the activation of guanylate cyclase activity by direct binding to the heme moiety of the enzyme, stimulating the production of cyclic 3':5'-guanosine monophosphate. CO potentially interacts with other intracellular hemoprotein targets, though little is known about the functional significance of such interactions. Recent progress indicates that CO exerts novel anti-inflammatory and anti-apoptotic effects dependent on the modulation of the p38 mitogen activated protein kinase (MAPK)-signaling pathway. By virtue of these effects, CO confers protection in oxidative lung injury models, and likely plays a role in HO-1 mediated tissue protection.
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PMID:Heme oxygenase/carbon monoxide signaling pathways: regulation and functional significance. 1216 41

Soluble guanylate cyclase (sGC) is a ferrous iron hemoprotein receptor for nitric oxide (NO). NO binding to the heme activates the enzyme 300-fold. sGC as isolated is five-coordinate, ferrous with histidine as the axial ligand. The NO-activated enzyme is a five-coordinate nitrosyl complex where the axial histidine bond is broken. Past studies using rapid-reaction kinetics demonstrated that both the formation of a six-coordinate intermediate and the conversion of the intermediate to the activated five-coordinate nitrosyl complex depended on the concentration of NO. A model invoking a second NO molecule as a catalyst for the conversion of the six-coordinate intermediate to the five-coordinate sGC-NO complex was proposed to explain the observed kinetic data. A recent study [Bellamy, T. C., Wood, J. & Garthwaite, J. (2002) Proc. Natl. Acad. Sci. USA 99, 507-510] concluded that a simple two-step binding model explains the results. Here we show through further analysis and simulations of previous data that the simple two-step binding model cannot be used to describe our results. Instead we show that a slightly more complex two-step binding model, where NO is used as a ligand in the first step and a catalyst in the second step, can describe our results quite satisfactorily. These new simulations combined with the previous activation data lead to the conclusion that the intermediate six-coordinate sGC-NO complex has substantial activity. The model derived from our simulations also can account for the slow deactivation of sGC that has been observed in vitro.
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PMID:Revisiting the kinetics of nitric oxide (NO) binding to soluble guanylate cyclase: the simple NO-binding model is incorrect. 1220 5

Chlorite dismutase (EC 1.13.11.49), an enzyme capable of reducing chlorite to chloride while producing molecular oxygen, has been characterized using EPR and optical spectroscopy. The EPR spectrum of GR-1 chlorite dismutase shows two different high-spin ferric heme species, which we have designated 'narrow' (gx,y,z = 6.24, 5.42, 2.00) and 'broad' (gz,y,x = 6.70, 5.02, 2.00). Spectroscopic evidence is presented for a proximal histidine co-ordinating the heme iron center of the enzyme. The UV/visible spectrum of the ferrous enzyme and EPR spectra of the ferric hydroxide and imidazole adducts are characteristic of a heme protein with an axial histidine co-ordinating the iron. Furthermore, the substrate analogs nitrite and hydrogen peroxide have been found to bind to ferric chlorite dismutase. EPR spectroscopy of the hydrogen peroxide adduct shows the loss of both high-spin and low-spin ferric signals and the appearance of a sharp radical signal. The NO adduct of the ferrous enzyme exhibits a low-spin EPR signal typical of a five-co-ordinate heme iron nitrosyl adduct. It seems that the bond between the proximal histidine and the iron is weak and can be broken upon binding of NO. The midpoint potential, Em(Fe3+/2+) = -23 mV, of chlorite dismutase is higher than for most heme enzymes. The spectroscopic features and redox properties of chlorite dismutase are more similar to the gas-sensing hemoproteins, such as guanylate cyclase and the globins, than to the heme enzymes.
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PMID:Spectroscopic characterization and ligand-binding properties of chlorite dismutase from the chlorate respiring bacterial strain GR-1. 1235 22


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