Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
 6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ten years ago, the term "oxidative stress" (sigma -O2) was created to define oxidative damage inflicted to the organism. This definition brings together processes involving reactive oxygen species production and action such as free radical production during univalent reduction of oxygen within mitochondria, activation of NADPH-dependent oxidase system on the membrane surface of neutrophils, flavoprotein-catalyzed redox cycling of xenobiotics and exposure to chemical and physical agents in the environment. Since the discovery of the nitric oxide biosynthetic pathway, the deleterious effects of uncontrolled nitric oxide generation are generally classified as oxidative stress. Indeed, products of the reaction of NO and superoxide lead to oxidants such as peroxinitrite, nitrogen dioxide and hydroxyl radical, which are involved in mechanisms of cell-mediated immune reactions and defence of the intracellular environment against microbiol invasion. However NO can also regulate many biological reactions and signal transduction pathways that lead to a variety of physiological responses such as blood pressure, neurotransmission, platelet aggregation, endothelin generation or smooth muscle cell proliferation. Then the uncontrolled NO production can lead to a variety of physiological and pathophysiological responses similar to a Nitric Oxide Stress: activation of guanylate cyclase and production of cGMP: overstimulation of the inducible L-arginine to L-citrulline and NO pathway by bactericidal endotoxins and cytokines has been shown to promote undesired increases in vasodilatation, which may account for hypotension in septic shock and cytokine therapy. stimulation of auto-ADP-ribosylation and modification of SH-groups of glyceraldehyde-3-phosphate dehydrogenase in a cGMP-independent mechanism: by this way, NO in excess can strongly inhibits this important glycolytic enzyme and reduce the cellular energy production. inhibition of ribonucleotide reductase: extensive inhibition of this key enzyme in DNA synthesis in the presence of large amounts of NO could lead to important antiproliferative effects; inhibition of cytochrome P450-dependent metabolism: in Kupffer cells and hepatocytes, LPS-induced overproduction of NO has been shown to inhibit cytochrome P450-dependent metabolism and to mediate the suppression of hepatic metabolism. Moreover, NO synthetized in the peripheral nervous system is known to mediate nonadrenergic noncholinergic (NANC) neurotransmission. Overstimulation of NO synthases might therefore contribute to pathophysiological states such as: gastrointestinal motility, reflux oesophagitis, asthma, adult respiratory distress syndrome (ARDS) and chronic pulmonary artery hypertension. To these NO-mediated biological functions, one could add the biological effects of NO-derivatives such as N-nitrosocompounds, which act as carcinogenic agents, or C-nitrosocompound which were recently used as "zinc-ejecting" agents to inhibit HIV-1 infectivity of human T-lymphocytes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Does nitric oxide stress exist?]. 852 Oct 87

Peroxynitrite is a reactive oxidant produced from nitric oxide (NO) and superoxide, which reacts with proteins, lipids, and DNA under conditions of inflammation and shock. Here we overview the role of peroxynitrite in circulatory shock and inflammation. Immunohistochemical and biochemical evidence demonstrate production of peroxynitrite in endotoxic and hemorrhagic shock, chronic bowel inflammation, and in various forms of ischemia-reperfusion injury. The reactivity and decomposition of peroxynitrite is determined by the chemical environment, and the ratio of superoxide versus NO. Peroxynitrite can initiate toxic oxidative reactions in vitro and in vivo. Initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3-phosphate dehydrogenase, inhibition of membrane Na+/K+ ATP-ase activity, inactivation of membrane sodium channels, and other oxidative protein modifications contribute to the cytotoxic effect of peroxynitrite. In addition, peroxynitrite is a potent trigger of DNA strand breakage, with subsequent activation of the nuclear enzyme poly-ADP ribosyl synthetase, with eventual severe energy depletion of the cells. Pharmacological evidence suggests that the peroxynitrite-poly-ADP ribosyl synthetase pathway importantly contributes to the cellular injury in endotoxic shock, inflammatory pancreatic islet cell destruction, and central nervous system ischemia. The proposal that peroxynitrite is a major cytotoxic mediator would change the interpretation of previous data on the effects of NO donors, NO synthase inhibitors, and superoxide neutralizing strategies in shock and inflammation.
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PMID:The pathophysiological role of peroxynitrite in shock, inflammation, and ischemia-reperfusion injury. 885 40

The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
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PMID:Troglitazone inhibits fatty acid oxidation and esterification, and gluconeogenesis in isolated hepatocytes from starved rats. 886 61

We examined the alteration of endogenous mono ADP-ribosylation in the hippocampus of amygdaloid kindled rats to clarify the neurochemical basis of epilepsy. A significant increase of the ADP-ribosylation on the 38 kDa protein was observed in the hippocampal membrane of the kindled rat. Several antiepileptics (phenytoin, phenobarbital, carbamazepine, sodium valproate) significantly decreased the ADP-ribosylation on the 38 kDa protein and effaced the increase in the kindled group. The ADP-ribosylation was largely increased by sodium nitroprusside, a nitric oxide generating compound, in both the kindled and control groups. Carbamazepine could not affect the ADP-ribosylation in the presence of sodium nitroprusside. Twenty amino acids from the N-terminus of the ADP-ribosylated 38 kDa protein were determined by sequential analysis. The sequence was completely identical to that of glyceraldehyde-3-phosphate dehydrogenase. These results indicate that the endogenous mono-ADP-ribosylation which increased in the kindled group and decreased by the antiepileptics might be a specific reaction associated with the mechanisms of epileptogenesis.
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PMID:The contribution of endogenous mono-ADP-ribosylation to kindling-induced epileptogenesis. 903 98

To clarify the mechanisms of nitric oxide (NO)-induced cell death in human neuronal cells, we examined effects of NO donors such as sodium nitroprusside (SNP) and S-nitroso-N-acetylpenicillamine (SNAP) on activities of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and poly(ADP-ribose) polymerase (PARP) in human neuroblastoma cell line, SH-SY5Y. SNP-induced [32P]ADP-ribosylation of 113-kDa and 37-kDa proteins in SH-SY5Y cells. Treatment with PARP inhibitors such as 3-aminobenzamide and 1,5-isoquinolinediol partially prevented SNAP-induced cell death of SH-SY5Y. In purified GAPDH (37-kDa protein), SNP- and SNAP-induced enhancement of [32P]ADP-ribosylation, and inhibition of GAPDH activity. These results suggest that NO-induced cell death in human neuroblastoma SH-SY5Y cells possibly involves in covalent modifications such as ADP-ribosylation in PARP and GAPDH.
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PMID:Possible involvement of ADP-ribosylation of particular enzymes in cell death induced by nitric oxide-donors in human neuroblastoma cells. 904 62

Tocolytic therapy with beta-adrenergic receptor agonists is a standard regimen to prevent preterm birth. Agonists exposure of beta-adrenergic receptors causes receptor desensitization in other organs, and this may limit the therapeutic value of beta-adrenergic receptor agonists. To study the effects of prolonged beta-adrenergic agonist treatment in human myometrium, we obtained biopsies during Caesarean section of 14 pregnant patients who had received fenoterol for at least 5 days and 14 untreated pregnant controls. The densities of total beta-adrenergic receptors, which are mainly of the beta 2-subtype as assessed by [125I]iodo-cyanopindolol binding in crude membrane fractions, were more than 50% smaller in women receiving fenoterol, whereas alpha 2-adrenergic receptor densities were similar. Gs and Gi G-protein alpha-subunit densities were unaltered as assessed by Western blotting and pertussis toxin-catalyzed [32P]ADP-ribosylation. beta-Adrenergic receptor kinase (beta ARK) activity, as determined using bovine rhodopsin as the substrate, was the same in the two groups. Adenylyl cyclase activities in the presence of guanine nucleotides, NaF, forskolin, or Mn+2 were also not altered by fenoterol treatment. The messenger RNA (mRNA) concentrations of beta 2-adrenergic receptors, beta ARK-I and glyceraldehyde-3-phosphate dehydrogenase (as a reference), as determined by quantitative PCR, were unaffected by fenoterol treatment. We conclude that tocolysis with fenoterol results in a selective down-regulation of myometrial beta-adrenergic receptors, which is not associated with a reduction in the respective mRNA concentrations or alterations of alpha 2-adrenergic receptors, Gs and Gi alpha-subunits, or beta ARK activity or mRNA.
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PMID:Tocolytic therapy with fenoterol induces selective down-regulation of beta-adrenergic receptors in human myometrium. 910 Jun 1

Brefeldin A, a toxin inhibitor of vesicular traffic, induces the selective mono-ADP-ribosylation of two cytosolic proteins, glyceraldehyde-3-phosphate dehydrogenase and the novel GTP-binding protein BARS-50. Here, we have used a new quantitative assay for the characterization of this reaction and the development of specific pharmacological inhibitors. Mono-ADP-ribosylation is activated by brefeldin A with an EC50 of 17.0 +/- 3.1 microg/ml, but not by biologically inactive analogs including a brefeldin A stereoisomer. Brefeldin A acts by increasing the Vmax of the reaction, whereas it does not influence the Km of the enzyme for NAD+ (154 +/- 13 microM). The enzyme is an integral membrane protein present in most tissues and is modulated by Zn2+, Cu2+, ATP (but not by other nucleotides), pH, temperature, and ionic strength. To identify inhibitors of the reaction, a large number of drugs previously tested as blockers of bacterial ADP-ribosyltransferases were screened. Two classes of molecules, one belonging to the coumarin group (dicumarol, coumermycin A1, and novobiocin) and the other to the quinone group (ilimaquinone, benzoquinone, and naphthoquinone), rather potently and specifically inhibited brefeldin A-dependent mono-ADP-ribosylation. When tested in living cells, these molecules antagonized the tubular reticular redistribution of the Golgi complex caused by brefeldin A at concentrations similar to those active in the mono-ADP-ribosylation assay in vitro, suggesting a role for mono-ADP-ribosylation in the cellular actions of brefeldin A.
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PMID:Characterization of chemical inhibitors of brefeldin A-activated mono-ADP-ribosylation. 916 51

Brefeldin A (BFA), a fungal metabolite that inhibits membrane transport, potently stimulates an endogenous ADP-ribosylation reaction that selectively modifies two cytosolic proteins of 38 and 50 kDa on an amino acid residue different from those used by all known mADPRTs. The 38-kDa substrate was identified as the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), whereas the 50-kDa substrate (BARS-50) was characterized as a novel guanine nucleotide binding protein. Thus, BARS-50 is able to bind GTP and its ADP-ribosylation is inhibited by the beta gamma subunit of GTP-binding (G) proteins. Moreover, BARS-50 was demonstrated to be a group of closely related proteins that appear to be different from all the known G proteins. A partially purified BARS-50 was obtained from rat brain cytosol, which was then used for microsequencing and in functional studies. A similar procedure led to the purification of native (non-ADP-ribosylated) BARS-50. The possible role of the BFA-dependent ADP-ribosylation and of BARS-50 in the maintenance of Golgi structure and function was addressed by examining which of the effects of BFA may be modified by inhibiting this reaction. We find that the BFA-dependent transformation of the Golgi stacks into a tubular reticular network is prevented when the BFA-dependent ADP-ribosylation activity was blocked by specific inhibitors thus indicating that BFA-dependent ADP-ribosylation of cytosolic proteins participate in the dynamic regulation of intracellular transport.
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PMID:Possible role of BARS-50, a substrate of brefeldin A-dependent mono-ADP-ribosylation, in intracellular transport. 919 72

We have recently described a novel enzymatic mono-ADP-ribosyl transfer reaction induced by brefeldin A, a well characterized inhibitor of vesicular traffic, which selectively modifies two cytosolic proteins of 38 kDa (p38) and 50 kDa (BARS-50). p38 was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme and a multifunctional protein involved in several cellular processes; BARS-50 might be a novel G protein, since it is able to bind GTP and the beta gamma subunit of G proteins. We have characterized this enzymatic activity and screened in vitro the effects of different drugs belonging to the coumarine (dicumarol, coumermicin A1 and novobiocin) and quinone (ilimaquinones, benzoquinones and naphtoquinones) class. These drugs blocked the BFA-dependent mono-ADP-ribosylation, showed remarkable effects on Golgi morphology in control cells, and antagonized the tubular reticular redistribution of the Golgi complex in brefeldin A treated cells (see papers of Corda and Colanzi in this issue) suggesting a possible role for ADP-ribosylation in both the cellular effects of brefeldin A and the maintenance of the structure/function of the Golgi complex.
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PMID:Characterization of the endogenous mono-ADP-ribosylation stimulated by brefeldin A. 919 74

A gel penetration technique, that measures the dilution undergone by protein equilibrium on a short tightly packed gel column, has been employed to determine the molecular masses of aldolase (160 kDa), glyceraldehyde-3-phosphate dehydrogenase (GPDH; 145 kDa) in the absence and presence of each other and of other proteins. The dilution factor (concentration of protein applied/concentration of protein after equilibration) was found to be inversely related to the molecular mass of the protein. In equimolar mixtures of aldolase and GPDH, 0.5-2.5 microM each, the two enzymes exhibited a common molecular mass value of 309-316 kDa. These enzymes did not undergo any self association or disassociation in this concentration range. Moreover, their molecular masses were unaffected by the presence of other proteins tested. When the concentration of one of these enzymes (aldolase or GPDH) was held constant and that of the other varied, the dilution factor of the former was decreased as the concentration of the latter was increased until it corresponded to a molecular mass of ca. 310 kDa at equimolar concentrations of the two enzymes. Further increase in the concentration of the variable enzyme had no effect. It has been suggested that aldolase and GPDH form a 1:1 complex of dissociation constant equal to or less than 5 x 10(-8) M. The complex was found to dissociate in the presence of KCl, (NH4)2SO4, ATP and NADH whereas its formation was favoured by fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, NAD+, ADP, AMP and phosphate ions.
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PMID:Interactions of aldolase and glyceraldehyde-3-phosphate dehydrogenase: molecular mass studies. 924 8


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