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:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a previous report we described that adenosine-induced apoptosis of HL-60 cells was blocked by the pretreatment of cells with a potent inhibitor (3-aminobenzamide) of poly(ADP-ribose) polymerase (PARP). The pretreatment of the cells with nicotinamide, another inhibitor of the enzyme, also suppressed most effectively the adenosine-induced apoptosis. This inhibition was reversible and observed during apoptosis mediated by other known apoptosis inducers such as actinomycin D and staurosporine (group I inducers), but nicotinamide was ineffective on the apoptosis mediated by VM 26, camptothecin and A23187 (group II inhibitors). In addition to the enzyme inhibition, a down-regulation of the enzyme level caused by the pretreatments of cells with differentiation-inducing agents, retinoic acid (RA) and dimethylsulfoxide (DMSO) also resulted in a marked resistance of the cells to the apoptosis inducers. A pretreatment of the cells for a limited time of 24 hrs. by these agents decreased the PARP level to 66-75% of the untreated cells and the cells showed a quite similar resistance to the group I apoptosis inducers like the cells treated with the enzyme inhibitors, whereas they were still sensitive to the group II inhibitors. A more prolonged treatment for 48 hrs. of the cells with RA and DMSO resulted in further down-regulation of the cellular PARP reaching respectively 50 and 43% of control cells and at this stage, the cells became resistant to all the inducers of both groups. These results suggest that the pathway, by which both groups of the inducers initiate and progress apoptosis, is not identical but include at least two different processes which are differently affected by PARP-inhibition or by different levels of cellular PARP.
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PMID:Inhibition and down-regulation of poly(ADP-ribose) polymerase results in a marked resistance of HL-60 cells to various apoptosis-inducers. 853 70

SKI-1 is a 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU)-resistant glioma cell line and SK-MG-1 is a BCNU-sensitive glioma cell line. Both cell lines do not express O6-methylguanine-DNA methyl transferase (MGMT) and exhibit comparable levels of 3-methyladenine DNA glycosylase. In order to detect DNA binding proteins involved in alternative DNA repair mechanisms of BCNU damage, we performed Southwestern analysis using a DNA probe damaged with BCNU and nuclear protein extracts from SKI-1 and SK-MG-1 cell lines. Both cell lines express a protein of M(r) 116,000 that is able to bind to BCNU-damaged DNA with higher specificity than to undamaged DNA. This protein was identified as poly(ADP-ribose) polymerase (PARP). Using glioma extracts depleted of PARP or using antibody to block the DNA binding domain of PARP no other protein binding to BCNU-treated probe was observed. Addition of methoxyamine, an inhibitor of DNA strand breaks, led to a significant reduction of PARP binding to BCNU-treated DNA. BCNU treatment of both glioma cell lines led to reduced nicotinamide adenine dinucleotide levels, indicating activation of PARP. Thus, the recognition and binding of PARP to BCNU-induced DNA nicks with concomitant PARP activation may be important processes that are involved in the initial stage of DNA repair of BCNU lesions in glial cells.
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PMID:Identification of a 116 kDa protein able to bind 1,3-bis(2-chloroethyl)-1-nitrosourea-damaged DNA as poly(ADP-ribose) polymerase. 853 47

Mono ADP-ribosyltransferases catalyze the transfer of the ADP-ribose moiety of nicotinamide adenine dinucleotide (NAD) to proteins. It was reported by Wang et al (J Immunol 153:4048, 1994) that incubation of mouse cytotoxic T lymphocytes (CTL) with NAD resulted in the ADP-ribosylation of membrane proteins and inhibition of cell proliferation and cytotoxicity. Treatment of CTL with phosphatidylinositol-specific phospholipase C (PI-PLC) before incubation with NAD prevented the inhibitory effects of NAD on the cells, consistent with the removal of a glycosylphosphatidylinositol (GPI)-anchored ADP-ribosyltransferase on the lymphocyte surface. We have identified and cloned a GPI-linked ADP-ribosyltransferase from Yac-1 mouse T-cell lymphoma cells. The deduced amino acid sequence of the Yac-1 transferase was 70% and 41% identical to those of the rabbit skeletal muscle and chicken heterophil, respectively. It contained three noncontiguous sequences similar to those found in several of the bacterial toxin and vertebrate ADP-ribosyltransferases. Based on crystallography of the bacterial toxins, these regions are believed to form, in part, the catalytic site consistent with a common mechanism for the ADP-ribose transfer reaction. In rat mammary adenocarcinoma (NMU) cells transformed with the Yac-1 transferase cDNA, transferase activity was present on the cell surface and was released into the medium by treatment of cells with PI-PLC. Thus, we have cloned a novel gene that has properties identical to the transferase detected in CTL, and may be involved in the NAD-dependent regulation of proliferation and cytotoxicity.
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PMID:Molecular characterization of a glycosylphosphatidylinositol-linked ADP-ribosyltransferase from lymphocytes. 870 49

In hypoxanthine (guanine) phosphoribosyltransferase- (HPRT; EC 2.4.2.8) deficient lymphoblasts, ATP but not nicotinamide-adenine dinucleotide coenzyme concentrations are reduced by limited nutrition. Such reduced ATP concentrations are correlated with reduced poly(ADP-ribose) synthetase (polyADPRT; EC 2.4.2.30) activity; this reduces the breakdown of nicotinamide-adenine dinucleotide coenzymes and thus explains their normal intracellular concentrations. Since reductions in poly(ADP-ribose) synthetase activity reduce DNA repair, alterations in DNA could accumulate even in non-multiplying cells such as neurons, especially in the continuously active 'respiratory centre'. Our Lesch-Nyhan patients suffered respiratory deaths between 15 and 20 years of age.
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PMID:Lesch-Nyhan syndrome and its pathogenesis: normal nicotinamide-adenine dinucleotide but reduced ATP concentrations that correlate with reduced poly(ADP-ribose) synthetase activity in HPRT-deficient lymphoblasts. 875 Jun 13

The crystal structures of the catalytic fragment of chicken poly(ADP-ribose) polymerase [NAD+ ADP-ribosyltransferase; NAD+:poly(adenosine-diphosphate-D-ribosyl)-acceptor ADP-D-ribosyltransferase, EC 2.4.2.30] with and without a nicotinamide-analogue inhibitor have been elucidated. Because this enzyme is involved in the regulation of DNA repair, its inhibitors are of interest for cancer therapy. The inhibitor shows the nicotinamide site and also suggests the adenosine site. The enzyme is structurally related to bacterial ADP-ribosylating toxins but contains an additional alpha-helical domain that is suggested to relay the activation signal issued on binding to damaged DNA.
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PMID:Structure of the catalytic fragment of poly(AD-ribose) polymerase from chicken. 875 99

Autoimmune processes are involved in pancreatic beta-cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against the 37/ 40 K antigen appear in the circulation years before clinical onset and permit increasingly precise disease prediction. A cellular immune response causes pancreatic infiltration, while macrophages and Th-cells appear to be implicated-via local release of cytokines-in beta-cell destruction. Generation of free radicals, DNA strand breaks, activation of the enzyme poly (ADP-ribose) polymerase (PARP), and depletion of intracellular nicotinamide adenine dinucleotide (NAD) appear to be common factors in beta-cell death, whether mediated by oxygen radicals, nitric oxide, or streptozotocin. Nicotinamide, a soluble B group vitamin which offers protection against these toxic stimuli, is at high doses a free radical scavenger, a potent inhibitor of PARP, and protects against depletion of intracellular NAD. A sound scientific rationale therefore exists for its use in human prediabetes, and promising pilot studies have been performed in ICA-positive first-degree relatives and school children. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial.
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PMID:Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide. 880 29

The vitamin nicotinamide can protect against oxidative stress-induced apoptosis in the brain when used as a precursor for nicotinamide adenine dinucleotide (NAD+). The intracerebroventricular administration of tertiary-butylhydroperoxide (t-buOOH) to mice was used to simulate physiologic oxidative stress and apoptosis which may occur in some neurodegenerative conditions. t-buOOH produced characteristic apoptotic nuclear degeneration in neurons with extensive fragmentation of DNA. In this report we show that the elevation of NAD+ by nicotinamide prevents DNA fragmentation during apoptosis or necrosis in the brain as stimulated by t-buOOH administration. NAD+ levels can be increased by 50% in the brain. This may prevent the critical depletion of NAD+ by poly(ADP-ribose) polymerase (PARP) and provide additional substrate during the repair of DNA. Nicotinamide may be of particular interest in the treatment of neurodegeneration.
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PMID:Nicotinamide as a precursor for NAD+ prevents apoptosis in the mouse brain induced by tertiary-butylhydroperoxide. 884 80

Treatment of C57B1/6 mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) reduced striatal dopamine and cortical noradrenaline levels by 77-83% and 43-46%, respectively, at 7 days post-treatment. Co-treatments with five different inhibitors of poly(ADP-ribose) polymerase (PARP), including benzamide, significantly prevented the MPTP-induced catecholamine depletions. Benzamide was present in the striatum, 30 min after single i.p. injection, at low millimolar concentrations known to selectively inhibit PARP in vitro. The protective activities of benzamide and its derivatives paralleled their in vitro efficacies and potencies both as neuroprotective agents and as inhibitors of PARP, while the activity of 1,5-dihydroxyisoquinoline, a structurally-unrelated compound, did not. In naive animals, the PARP inhibitors by themselves did not alter striatal dopamine levels at 7 days post-treatment. However, in acute studies, 1,5-dihydroxyisoquinoline and nicotinamide caused marked alterations in striatal dopamine metabolite levels; on the contrary, benzamide and its amino-derivatives showed little or no effect on dopamine metabolism. These results indicate that, although these compounds might act at other sites in addition to PARP, PARP inhibitors possess neuroprotective potential in vivo and suggest a role for PARP in MPTP neurotoxicity.
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PMID:Poly(ADP-ribose) polymerase inhibitors protect against MPTP-induced depletions of striatal dopamine and cortical noradrenaline in C57B1/6 mice. 887 97

Autoimmune processes are involved in pancreatic beta cell destruction in type 1 diabetes. Autoantibodies including islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA), and antibodies directed against protein tyrosine phosphatase/IA2 (IA2-Ab) appear in the circulation years before clinical onset and permit increasingly precise disease prediction. Increasing knowledge of the pathogenesis of type 1 diabetes in animal models and humans suggests that progression to disease is not inevitable in those with indications of autoimmune processes directed against islet beta cells, and that these processes may prove vulnerable to intervention. The conditions therefore exist for screening and attempted intervention in pre-type 1 diabetes. This review will discuss the theoretical and practical background to a major controlled trial using one of a number of interventions currently under consideration. Nicotinamide, a soluble B group vitamin, has for many years been known to protect beta cells against a variety of noxious stimuli. It is at high doses a free radical scavenger, a potent inhibitor of the enzyme poly (ADP-ribose) polymerase (PARP), and prevents depletion of intracellular NAD. Although its benefits have been marginal or absent in recently diagnosed patients, promising pilot studies have been performed in ICA positive first degree relatives and schoolchildren. No serious side effects have been reported from its use at the doses proposed in man or other species. There is therefore a sound case for submitting this agent to a controlled clinical trial, which, in view of the numbers involved, has necessarily been launched on an international collaborative basis.
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PMID:Theory and practice of nicotinamide trials in pre-type 1 diabetes. 888 46

The role of the tryptophan residues in the substrate-binding and catalytic mechanism of an enzymatically active C-terminal fragment of Pseudomonas aeruginosa exotoxin A was studied by individually or jointly replacing these residues with phenylalanine. Substitution of W-466 decreased the ADP-ribosyltransferase and NAD(+)-glycohydrolase activities by 20- and 3-fold, respectively. In contrast, substitution of W-417 or W-558 with phenylalanine both resulted in a 3-fold decrease in ADP-ribosyltransferase activity with, however, only a decrease by 40% and 70% in NAD(+)-glycohydrolase activity, respectively. Simultaneous replacement of W-466 and W-558 resulted in a 200-fold decrease in ADP-ribosyltransferase and an 6-fold decrease in NAD(+)-glycohydrolase activities, suggesting that W-466 may play a minor role in the transfer of ADP-ribose to the eEF-2 protein. Chemical modification of the tryptophan residues in the wild-type toxin fragment by N-bromosuccinimide revealed the presence of a single residue important for enzymatic activity, W-466, with a minor contribution from W-558. Additionally, tryptophan residues, W-305 and W-417, were refractory to oxidation by N-bromosuccinimide, which likely indicated the buried nature of these residues within the protein structure. Titration of the wild-type toxin fragment with NAD+ resulted in the quenching of the intrinsic tryptophan fluorescence to 58% of the initial value. Titration of the various single and a double tryptophan replacement mutant protein(s) indicated that W-558 and W-466 are responsible for the substrate-induced fluorescence quenching, with the former being responsible for the largest fraction of the observed quenching in the wild-type toxin. Consequently, a molecular mechanism is proposed for the substrate-induced fluorescence quenching of both W-466 and W-558. Furthermore, molecular modeling of the recent crystal structures for both exotoxin A (domain III fragment) and diphtheria toxin, combined with a variety of previous results, has led to the proposal for a catalytic mechanism for the ADP-ribosyltransferase reaction. This mechanism features a SN1 attack (instead of the previously purported SN2 mechanism) by the diphthamide residue (nucleophile) of eukaryotic elongation factor 2 on the C-1 of the nicotinamide ribose of NAD+, which results in an inversion of configuration likely due to steric constraints within the NAD(+)-toxin-elongation factor 2 complex.
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PMID:Investigation into the catalytic role for the tryptophan residues within domain III of Pseudomonas aeruginosa exotoxin A. 895 60


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