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)

Nitric oxide (NO) is a mobile, highly reactive signal molecule, and changes the expression of specific genes in effector cells. Under physiological conditions, NO reacts with molecular oxygen and with reactive oxygen species (ROS) to produce intermediates known as reactive nitrogen species (RNS). The production of NO and RNS in the cell is controlled by hormones, neurotransmitters, cytokines, and growth factors. Hence NO and its derivatives act as secondary paracrinous factors and transmit the signal from NO-producing to neighboring cells. Intracellular reception of NO and RNS is due to Src-related tyrosine protein kinases, G-protein Ras, cytochrome oxidase, and guanylate cyclase. Receptor proteins mostly contain heme, active thiol, or iron-sulfur groups, and are both on the plasma membrane and in internal cell compartments. Many of the NO receptors are the key components of cell regulatory systems controlling the transcription factors AP-1, HIF-1, NF-kappa B, and p53 and the expression of their target genes. A distinguishing feature of NO signaling is that changes in redox potential of the cell switch the NO receptor and, consequently, modify the NO effect. Depending on the ROS level, NO activates different signal transduction pathways to induce (or suppress) different gene sets. The data considered indicate that antioxidants may be used to directionally change the transcriptional response of the cell to NO.
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PMID:[Redox-dependent regulation of gene expression induced by nitric oxide]. 1504 36

Heme oxygenase-1 (HO-1) catabolizes heme into CO, biliverdin, and free iron and serves as a protective enzyme by virtue of its anti-inflammatory, antiapoptotic, and antiproliferative actions. Previously, we have demonstrated that human CD4(+) T cells express HO-1 and that HO-1-overexpressing Jurkat T cells tend to display lower proliferative response. The aim of this study is to elucidate the mechanism(s) by which HO-1 can mediate its antiproliferative effect on CD4(+) T cells. Among the three HO-1 byproducts, only CO showed suppressive effect on T cell proliferation in response to anti-CD3 plus anti-CD28 Abs, mimicking the antiproliferative action of HO-1. CO blocked the cell cycle entry of T cells, which was independent of the guanylate cyclase/cGMP pathway. CO also suppressed the secretion of IL-2, and this suppressive effect of CO on IL-2 secretion mediated the antiproliferative action of CO. CO selectively inhibited the extracellular signal-regulated kinase pathway, which could explain the suppressive effects of CO on T cell proliferation and IL-2 secretion. Based on these findings, we suggest that HO-1/CO suppresses T cell proliferation and IL-2 secretion, possibly via its inhibition of extracellular signal-regulated kinase activation.
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PMID:Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. 1506 50

We have previously reported that, depending on the dose, nitric oxide (NO)-generating agents exert a dual facilitatory and inhibitory action on glutamatergic transmission on the rostral ventrolateral medulla (RVLM) neurons. The molecular mechanisms underlying the NO-mediated synaptic inhibition have not yet been defined. Here we show that the amplitude of excitatory postsynaptic currents (EPSCs) was reversibly reduced by the NO donors 3-morpholinylsydnoneimine (SIN-1) (1 mM) and spermine NONOate (1 mM). This effect was antagonized by an active peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride, G(i/o)-coupled receptor blockers, N-ethylmaleimide and pertussis toxin, A(1) adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine, or adenosine deaminase. However, NO-sensitive guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, GABA(B) receptor antagonist (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), or cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) had no effect on the inhibitory action of SIN-1 on EPSCs. Perfusion of adenosine mimicked and subsequently occluded the action of SIN-1. Inhibition of EPSC amplitude by SIN-1 was associated with an increase in the paired-pulse ratio of EPSCs. Furthermore, SIN reduced the frequency of spontaneous EPSCs without altering their amplitude of distribution. Pretreatment with N-type Ca(2+)-channel blocker omega-conotoxin GVIA selectively blocked SIN-1-induced inhibition of EPSCs. These results suggest that a higher dose of SIN-1 acts presynaptically to elicit a synaptic depression on the RVLM neurons through an inhibition of presynaptic N-type Ca(2+)-channel activity, leading to reduced glutamate release. The presynaptic action of SIN-1 is mediated by the formation of peroxynitrite, which subsequently acts to release adenosine to activate A(1) adenosine receptors.
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PMID:3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. 1532 40

Resonance Raman (RR) spectra of soluble guanylate cyclase (sGC) reported by five independent research groups have been classified as two types: sGC(1) and sGC(2). Here we demonstrate that the RR spectra of sGC isolated from bovine lung contain only sGC(2) while both species are observed in the spectra of the CO-bound form (CO-sGC). The relative populations of the two forms were altered from an initial composition in which the CO-sGC(2) form predominated, with the Fe-CO (nu(Fe)(-)(CO)) and C-O stretching modes (nu(CO)) at 472 and 1985 cm(-)(1), respectively, to a composition dominated by the CO-sGC(1) form with nu(Fe)(-)(CO) and nu(CO) at 488 and 1969 cm(-)(1), respectively, following the addition of a xenobiotic, YC-1. Further addition of a substrate, GTP, completed the change. GDP and cGMP had a significantly weaker effect, while a substrate analogue, GTP-gamma-S, had an effect similar to that of GTP. In contrast, ATP had a reverse effect, and suppressed the effects of YC-1 and GTP. In the presence of both YC-1 and GTP, vinyl vibrations of heme were significantly influenced. New CO isotope-sensitive bands were observed at 521, 488, 363, and 227 cm(-)(1). The 521 cm(-)(1) band was assigned to the five-coordinate (5c) species from the model compound studies using ferrous iron protoporphyrin IX in CTAB micelles. Distinct from the 472 cm(-)(1) species, both the 488 and 521 cm(-)(1) species were apparently un-photodissociable when an ordinary Raman spinning cell was used, indicating rapid recombination of photodissociated CO. On the basis of these findings, binding of YC-1 to the heme pocket is proposed.
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PMID:Resonance Raman evidence for the presence of two heme pocket conformations with varied activities in CO-bound bovine soluble guanylate cyclase and their conversion. 1565 50

Accumulating evidence suggests that suberythemogenic ultraviolet A (UVA) (320-400 nm) exposure protects against the immunosuppressive effect of ultraviolet B (290-320 nm) radiation or its epidermal photoproduct, cis-urocanic acid (cis-UCA). In skin, UVA photoimmunoprotection is mediated by the inducible antioxidant stress enzyme, heme oxygenase-1 (HO-1), which degrades heme into carbon monoxide (CO), iron, and biliverdin (reduced to bilirubin), and is important for cell survival under conditions of oxidative stress. The identity of the HO enzymatic product(s) that provide the immunoprotection is unknown. Here we examine the potential of CO to fulfill this role in hairless mouse skin, utilizing a novel CO-releasing molecule (CO-RM) to deliver CO to the skin topically. The CO-RM released CO gradually from the lotion vehicle during 3 h following its preparation, and between 50 and 500 microM, concentration-dependently protected mice against the suppression of contact hypersensitivity by either solar-simulated UV radiation (SSUVR) or cis-UCA, whereas aged CO-depleted CO-RM was inactive. Thus, the CO-RM treatment mimicked UVA-photoimmunoprotection, and identified HO-released CO as the protective mediator, providing evidence that the murine cutaneous immune system is modulated by this gaseous messenger. Preliminary evidence for involvement of guanylyl cyclase was obtained by treatment of the mouse with its specific inhibitor 1H-(1,2,4)oxadiazolo-(4,3-1)quinoxaline-1-one, which abrogated UVA photoimmunoprotection.
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PMID:Ultraviolet A (320-400 nm) modulation of ultraviolet B (290-320 nm)-induced immune suppression is mediated by carbon monoxide. 1573 7

Hemoglobins (Hbs), generally defined as 5 or 6 coordinate heme proteins whose primary function is oxygen transport, are now recognized to occur in virtually all phyla of living organisms. Historically, study of their function focused on oxygen as a reversibly bound ligand of the ferrous form of the protein. Other diatomic ligands like carbon monoxide and nitric oxide were considered "non-physiological" but useful probes of structure-function relationships in Hbs. This investigatory landscape changed dramatically in the 1980s when nitric oxide was discovered to activate a heme protein, cyclic guanylate cyclase. Later, its activation was likened to Perutz' description of Hb's allosteric properties being triggered by a ligand-dependent "out-of-plane/into-plane" movement of the heme iron. In 1996, a functional role for nitric oxide in human and mammalian Hbs was demonstrated and since that time, the interest in NO as a physiologically relevant Hb ligand has greatly increased. Concomitantly, non-oxygen binding properties of Hbs have challenged the view that Hbs arose for their oxygen storage and transport properties. In this focused review we discuss some invertebrate Hbs' functionally significant reactions with nitric oxide and how strategic positioning of a few residues in the heme pocket plays an large role in the interplay of diatomic ligands to ferrous and ferric heme iron in these proteins.
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PMID:Invertebrate hemoglobins and nitric oxide: how heme pocket structure controls reactivity. 1581 7

Soluble guanylate cyclase (sGC), the mammalian receptor for nitric oxide (NO), is a heme protein with a histidine as the proximal ligand. Formation of a five-coordinate heme-NO complex with the associated Fe-His bond cleavage is believed to trigger a conformational change that activates the enzyme and transduces the NO signal. Cytochrome c' (cyt c') is a protobacteria heme protein that has several similarities with sGC, including the ability to form a five-coordinate NO adduct and the fact that it does not bind oxygen. Recent crystallographic characterization of cyt c' from Alcaligenes xylosoxidans (AXCP) has yielded the discovery that exogenous ligands are able to bind to the Fe center from either side of the porphyrin plane. In this paper, we explore the molecular basis of the NO interaction with AXCP using hybrid quantum-classical simulation techniques. Our results suggest that Fe-His bond breaking depends not only on the iron-histidine bond strength but also on the existence of a local minimum conformation of the protein with the histidine away from the iron. We also show that AXCP is a useful paradigm for NO interaction with heme proteins, particularly regarding the activation/deactivation mechanism of sGC. The results presented here fully support a recently proposed model of sGC activation in which NO is not only the iron ligand but also catalyzes the activation step.
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PMID:Nitric oxide interaction with cytochrome c' and its relevance to guanylate cyclase. Why does the iron histidine bond break? 1591 62

In the cardiovascular system, nitric oxide (NO) is involved in the short and long-term regulation of haemodynamics, and in a number of their pathological alterations. Investigation into the biochemistry of NO-synthase isoforms has confirmed that they also all produce superoxide anion (O(*)). The free radical NO can interact with many targets on which novel information has been recently obtained. The major results of these interactions are not only the well known activation of guanylyl cyclase, but also the formation of potentially cytotoxic peroxynitrite (ONOO(-)), and the formation of S-nitrosothiols and non-haem iron-dinitrosyl dithiolate complexes. Tissue O(2), O(*), low molecular weight thiols and transition metals (especially FeII) play a pivotal role in directing NO towards targets responsible for biological effects, or storage or release from these stores. In addition, circulating forms of NO have been proposed with S-nitrosation of blood proteins. All these mechanisms provide potential pharmacological targets for future therapeutic strategies.
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PMID:Molecular mechanisms underlying the role of nitric oxide in the cardiovascular system. 1599 28

The role of nitric oxide in cellular signaling in the past 22 years has become one of the most rapidly growing areas in biology with more than 20,000 publications to date. Nitric oxide is a gas and free radical with an unshared electron that can regulate an ever-growing list of biological processes. In many instances nitric oxide mediates its biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis from GTP. However, the list of effects of nitric oxide that are independent of cyclic GMP is also growing at a rapid rate. For example, nitric oxide can interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids and other molecules. Some of these reactions result in the oxidation of nitric oxide to nitrite and nitrate to terminate its effect, while other reactions can lead to altered protein structure, function, and/or catalytic capacity. These diverse effects of nitric oxide that are either cyclic GMP dependent or independent can alter and regulate important physiological and biochemical events in cell regulation and function. Nitric oxide can function as an intracellular messenger, an autacoid, a paracrine substance, a neurotransmitter, or as a hormone that can be carried to distant sites for effects. Thus, it is a unique simple molecule with an array of signaling functions. However, as with any messenger molecule, there can be too little or too much of the substance and pathological events result. Some of the methods to regulate either nitric oxide formation, metabolism, or function have been in clinical use for more than a century as with the use of organic nitrates and nitroglycerin in angina pectoris that was initiated in the 1870's. Current and future research with nitric oxide and cyclic GMP will undoubtedly expand the clinicians' therapeutic armamentarium to manage a number of important diseases by perturbing nitric oxide and cyclic GMP formation and metabolism. Such promise and expectations have obviously fueled the interests in these signaling molecules for a growing list of potential therapeutic applications.
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PMID:Discovery of some of the biological effects of nitric oxide and its role in cell signaling. 1613 22

Many biological functions of heme oxygenase (HO), such as cytoprotection against oxidative stress, vasodilation, neurotransmission in the central or peripheral nervous systems, and anti-inflammatory, anti-apoptotic, or anti-proliferative potential, have been attributed to its enzymatic byproduct carbon monoxide (CO), although roles for biliverdin/bilirubin and iron have also been proposed. In addition to these well-characterized effects, recent findings reveal that HO-derived CO may act as an oxygen sensor and circadian modulator of heme biosynthesis. In lymphocytes, CO may participate in regulatory T cell function. A number of the known signaling effects of CO depend on stimulation of soluble guanylate cyclase and/or activation of mitogen-activated protein kinases (MAPK). Furthermore, modulation of caveolin-1 status may serve as an essential component of certain aspects of CO action, such as growth control. In this review, we summarize recent findings of the beneficial or detrimental effects of endogenous CO with an emphasis on the signaling pathways and downstream targets that trigger the action of this gas.
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PMID:CO as a cellular signaling molecule. 1640 11


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