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)

This report demonstrates that incubation of cytotoxic T cells with NAD causes suppression of their ability to proliferate in response to stimulator cells or to lyse targets. Effects are evident after incubation for 3 h with concentrations of NAD as low as 1 microM and are sustained for many hours after removal of NAD from culture media. Suppression is a result of the failure of CTL to form specific conjugates with targets as well as a lower level of activation in response to TCR-mediated stimulation, although TCR-mediated transmembrane signaling is demonstrable. Metabolites of NAD such as nicotinamide, ADP-ribose, and cyclic-ADP-ribose have no detectable effect, indicating that NAD-glycohydrolase or ADP-ribose cyclase do not mediate suppression. Incubation of intact CTL with [32P]NAD leads to incorporation of 32P into a particulate, subcellular fraction, a reaction that is not inhibitable by ADP-ribose. Hydroxylamine, but not mercuric ion releases [32P]ADP-ribose, whereas phosphodiesterase releases [32P]AMP from the particulate subcellular fraction, suggesting that labeling is a result of enzymatic mono-ADP-ribosylation of arginines. In support of this, treatment of intact CTL with phosphatidylinositol-specific phospholipase C releases an arginine-specific ADP-ribosyltransferase and causes insensitivity to ecto-NAD suppression. These results suggest that a GPI-anchored ADP-ribosyltransferase uses ecto-NAD to ADP-ribosylate proteins that regulate CTL function.
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PMID:Regulation of cytotoxic T cells by ecto-nicotinamide adenine dinucleotide (NAD) correlates with cell surface GPI-anchored/arginine ADP-ribosyltransferase. 793 Jun 12

NAD:arginine ADP-ribosyltransferases catalyze the ADP-ribosylation of arginine residues in proteins. Coding region nucleic acid and deduced amino acid sequences of a human skeletal muscle ADP-ribosyltransferase cDNA were, respectively, 80.8% and 81.3% identical to those of the rabbit skeletal muscle transferase. A human transferase-specific cDNA probe detected major mRNA of 1.2 kb (mouse and rat), 3.0 kb (rabbit), 3.8 kb (monkey), and 5.7 kb (human) upon Northern analysis. Polyclonal anti-rabbit ADP-ribosyltransferase antibodies reacted with 36,000 M(r) proteins in partially purified transferase preparations from bovine, dog, and rabbit heart muscle and a 40,000 M(r) protein from human skeletal muscle. The human muscle ADP-ribosyltransferase cDNA, like the previously cloned rabbit muscle transferase, predicts predominantly hydrophobic amino- and carboxy-terminal amino acid sequences, which is characteristic of glycosylphosphatidylinositol (GPI)-anchored proteins. On immunoblots of partially purified rabbit and human skeletal muscle ADP-ribosyltransferases, anti-cross-reacting determinant antibodies detected at 36,000 and 40,000 M(r), respectively, phosphatidylinositol-specific, phospholipase C-sensitive, GPI-anchored proteins. These data are consistent with the conclusion that GPI-anchored skeletal and cardiac muscle ADP-ribosyltransferases are conserved across mammalian species.
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PMID:Immunological and structural conservation of mammalian skeletal muscle glycosylphosphatidylinositol-linked ADP-ribosyltransferases. 794 88

Several low molecular weight G proteins have been identified, but their functional roles remain unclear. To clarify the involvement of low molecular weight G protein in receptor-stimulated turnover of polyphosphoinositide (PI) turnover, influences of botulinum toxins on serotonin (5-HT)-stimulated Cl- current mediated by PI turnover were investigated using Xenopus oocytes injected with rat brain mRNA. Treatment with botulinum toxin C, D or purified ADP-ribosyltransferase of botulinum toxin (botulinum toxin C3 enzyme) inhibited the 5-HT-induced Cl- current in oocytes, and ADP-ribosylated 23 kDa proteins. Both botulinum toxin C3 enzyme-induced inhibition of the current and ADP-ribosylation were suppressed by pretreatment with antibotulinum toxin C3 enzyme antibody. Botulinum toxin D treatment of oocytes was ineffective in the response of Cl- current induced by injection of 50 pmol inositol 1,4,5-trisphosphate and 50 pmol Ca2+. It is suggested that low molecular weight G proteins ADP-ribosylated by botulinum toxin C3 enzyme are involved in phospholipase C activation in Xenopus oocytes.
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PMID:Inhibitory effects of botulinum toxin on 5-HT1C receptor-induced Cl- current in Xenopus oocytes. 813 79

RT6.2 is a 26-kDa alloantigen expressed only on post-thymic T cells and attached to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. It has been reported that expression of RT6.2 in animal models may correlate with lymphopenia and genetically-induced insulin-dependent diabetes mellitus. Its physiological function is unclear. Since RT6.2 has significant amino acid identity with a GPI-anchored rabbit muscle NAD:arginine ADP-ribosyltransferase, RT6.2 was expressed in rat mammary adenocarcinoma cells and the ability of the expressed protein to catalyze ADP-ribose transfer reactions was examined. Cells transformed with the RT6.2 gene expressed NAD glycohydrolase activity that was released from intact cells by phosphatidylinositol-specific phospholipase C, consistent with its presence on the cell surface. A similar activity was not detected with vector-transformed cells. RT6.2 did not ADP-ribosylate simple guanidino compounds. The molecular weight of the phosphatidylinositol-specific phospholipase C-released NAD glycohydrolase, determined by SDS-polyacrylamide gel electrophoresis, was 22,000-24,000, in good agreement with that of native RT6.2. These results strongly suggest that the rat T cell alloantigen RT6.2 is a GPI-anchored NAD glycohydrolase.
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PMID:Expression of NAD glycohydrolase activity by rat mammary adenocarcinoma cells transformed with rat T cell alloantigen RT6.2. 814 25

Exoenzyme S is an ADP-ribosyltransferase produced by Pseudomonas aeruginosa. Synthesis of exoenzyme S depends on an intact trans-regulatory locus encoding three protein products, ExsC, ExsB, and ExsA. To identify the phenotype of ExsC, -B, and -A mutants in exoenzyme S production, specific insertional mutations with the streptomycin resistance-encoding omega interposon were introduced into cloned DNA and returned to the chromosomes of P. aeruginosa PA103, PAO1, and PAK. Southern blot analysis was used to confirm insertion of omega and resolution of vector sequences. Exoenzyme S expression was measured in parental and mutant derivatives by Western blot (immunoblot) analysis and ADP-ribosyltransferase activity measurement. A complete set of mutations were obtained in strains PAK and PAO1, but in strain PA103, only an insertion in the exsA coding region was identified. Southern blot analysis demonstrated that extensive duplication and rearrangement of the PA103 chromosomal trans-regulatory locus occurred when exsC::omega or exsB::omega recombination events were attempted. Exoenzyme S antigen was not detectable in the supernatant or lysate fractions of mutant strains by Western blot analysis. ADP-ribosyltransferase activity was detected in the lysate but not in the supernatant fractions of mutant derivatives. The general secretion pathway appeared to function normally in mutant strains, as elastase, exotoxin A, and phospholipase C were measured in the supernatants of parental and mutant strains. Several differences were noted when the extracellular protein profiles of parental strains were compared with similar samples from the insertional mutant strains. Some of these differences appeared to be unrelated to exoenzyme S. These data suggest that insertional inactivation of the exoenzyme S trans-regulatory locus may affect a subset of other extracellular proteins.
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PMID:Construction and characterization of chromosomal insertional mutations of the Pseudomonas aeruginosa exoenzyme S trans-regulatory locus. 830 Feb 13

ADP-ribosylation of protein in heart membrane preparations has been shown to be present in adult tissue but absent from early neonate tissue [Piron and McMahon (1990) Biochem. J. 270, 591-597]. To further this observation, the cardiac membrane-bound form of arginine-specific mono-ADP-ribosyltransferase (EC 2.4.2.31) has been characterized. Apparent Km values of 330 and 470 microM were found in heart membrane preparations from rat and quail respectively. The Vmax. value depended greatly on the species of animal studied, and was 1.1 and 48 nmol/min per mg in rat and quail preparations respectively. The specific activity of the enzyme was lowest in pig, intermediate in rat, dog and rabbit, and highest in mouse and quail cardiac membranes. In the rat, the ADP-ribosylation of protein and enzyme activity were very low in heart preparations from 1-15-day-old animals. Thereafter the ADP-ribosylation and enzyme activity increased gradually to adulthood. Bacillus cereus phosphatidylinositol-specific phospholipase C, known to hydrolyse glycosylphosphatidylinositol anchors of proteins, released the mono-ADP-ribosyltransferase from membrane preparations of both rat and quail in a dose-dependent, Zn(2+)-inhibited manner. Thus it appears that a membrane-bound form of arginine-specific mono-ADP-ribosyltransferase is present in heart membranes from a variety of species and is not species-specific. The activity of this ADP-ribosyltransferase appears to be developmentally regulated and to be bound to the cardiac membranes by a glycosylphosphatidylinositol anchor.
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PMID:Developmental and biochemical characteristics of the cardiac membrane-bound arginine-specific mono-ADP-ribosyltransferase. 839 92

Many cell surface proteins are anchored into the cell membrane by glycosylphosphatidylinositol (GPI), among those a recently discovered arginine-specific mono-ADP-ribosyltransferase on cytotoxic T cells (CTL). This enzyme transfers ADP-ribose to cell surface proteins resulting in inhibition of cytotoxic and proliferative activity. Here we report that ADP-ribosyltransferase is released in active forms by crosslinking CD3, exposure to Il-2 or PMA stimulation. Release of transferase is specific, as another GPI-anchored protein, Thy-1 is not released. Transferase molecules released by cell activation are indistinguishable in size from molecules released by phospholipase C, suggesting that the release mechanism acts close to or within the GPI anchor. Protease inhibitors fail to inhibit transferase release with exception of 1,10-phenanthroline and its 4,7-diphenyl derivative. This suggests that the release mechanism acts on the cell surface but does not discriminate between action of a metalloprotease or phospholipase D. Release of transferase is shown to be rapid, it is not suppressed by monensin or brefeldin A and independent of serum phospholipase D, consistent with a mechanism acting on the cell surface. Transferase expression is shown to be dependent on the cell activation stage. In CTL clones, the transferase is demonstrable as a phospholipase C releasable molecule at early but not later stages of Ag specific activation.
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PMID:Release of a glycosylphosphatidylinositol-anchored ADP-ribosyltransferase from cytotoxic T cells upon activation. 859 99

1. The effect of mastoparan on phosphatidylcholine hydrolysis was examined in 1321N1 human astrocytoma cells. Mastoparan (3-30 microM) caused an accumulation of diacylglycerol (DG) and phosphatidic acd (PA) accompanied by choline release in a concentration- and time-dependent manner. 2. In the presence of 2% n-butanol, mastoparan (3-100 microM) induced phosphatidylbutanol (PBut) accumulation in a concentration- and time-dependent manner, suggesting that mastoparan activates phospholipase D (PLD). Propranolol (30-300 microM), a phosphatidate phosphohydrolase inhibitor, inhibited DG accumulation induced by mastoparan, supporting this idea. 3. Depletion of extracellular free calcium ion did not alter the effect of mastoparan on PLD activity. 4. A protein kinase C (PKC) inhibitor, calphostin C (1 microM), did not inhibit mastoparan-induce PLD activation but the ability of mastoparan to stimulate phospholipase D activity was decreased in the PKC down regulated cells. 5. PLD activity stimulated by mastoparan was not prevented by pretreatment of the cells with pertussis toxin (PT) or C3 ADP-ribosyltransferase. Furthermore, guanine nucleotides did not affect PLD activity stimulation by mastoparan in membrane preparations. 6. Mastoparan stimulated PLD in several cell lines such as RBL-2H3, RBL-1, HL-60, P388, endothelial cells, as well as 1321N1 human astrocytoma cells. 7. These results suggest that mastoparan induces phosphatidylcholine (PC) hydrolysis by activation of PLD, not by activation of phosphatidylcholine-specific phospholipase C (PC-PLC); mastoparan-induced PLD activation is not mediated by G proteins.
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PMID:Mastoparan-induced phosphatidylcholine hydrolysis by phospholipase D activation in human astrocytoma cells. 864 Mar 50

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

Post-translational modifications are important in regulating the functions of signal proteins. This is well established for intracellular proteins, but little is known in the case of extracellular domains of cell surface molecules. We recently described a cell surface protein, mono-ADP-ribosyltransferase (ADPRT), on cytotoxic T cells and showed that it mediates attachment of ADP-ribose to cell surface proteins. Concomitantly, cytolytic activity and cell proliferation are inhibited. Here we report that one of the principal proteins modified by this enzyme is lymphocyte function-associated molecule-1 (LFA-1). While both chains are ADP-ribosylated on the extracellular domain of the molecule, persistence of the modification differs between the chains. Label is released from the beta-chain by 1 h, yet remains for at least 6 h on the alpha-chain. Loss of label is suppressed by phosphodiesterase inhibitors such as ADP-ribose and p-nitrophenylthymidine 5'-monophosphate, pointing to the involvement of this class of enzyme. Modification of LFA-1 requires expression of the cell surface ADPRT and causes the loss of epitopes recognized by alpha- and beta-chain-specific Abs. Concomitantly, the generation of inositol phosphates induced by Ab cross-linking of LFA-1 is significantly inhibited. Consistent with this effect, anti-LFA-1-induced homotypic cell adhesion is also inhibited. These effects are not seen in cells from which the ADPRT was removed by phospholipase C. Moreover, cells lacking the cell surface ADPRT are not inhibited by NAD in the cell adhesion assay, but gain this property upon transfection with the ADPRT gene. It is concluded that the cell surface protein mono-ADPRT regulates LFA-1 functions.
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PMID:Cell surface ADP-ribosyltransferase regulates lymphocyte function-associated molecule-1 (LFA-1) function in T cells. 887 30


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