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)

Oxidized nicotinamide adenine dinucleotide (NAD+) in cytosol may interact with renal brush-border membranes (BBM) and inhibit BBM phosphate transport. The possible mechanism of interaction was investigated in the present study. Incubation of BBM with [adenine-3H]NAD+ led to acid-stable binding of 3H to the BBM, in contrast there was no binding of 14C when [carbonyl-14C]NAD+ was used. The data are consistent with an ADP-ribosylation mechanism involving transfer of ADP-ribose from NAD+ to BBM. This was confirmed by using [adenylate-32P]NAD+ and by the release of bound 32P in the form of 5'-[32P]AMP when the BBM were treated with snake venom phosphodiesterase. After gradient centrifugation of BBM the ADP-ribosyltransferase was recovered at the same density as known BBM enzymes, indicating that ADP-ribosyltransferase is an intrinsic BBM component and not a contaminant. These findings indicate that cytosolic NAD+ may be used for ADP-ribosylation of BBM proteins and that this may be a mechanism for regulating the BBM phosphate transport system.
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PMID:NAD+-dependent ADP-ribosyltransferase in renal brush-border membranes. 631 20

Guanylhydrazones of p-nitrobenzaldehyde and methylglyoxal serve as acceptors of ADP-ribosyl groups for the reactions catalyzed by cholera toxin. The absorption spectrum of the ADP-ribosylated p-nitrobenzylidine aminoguanidine is similar to that of a 1:1 mixture of ADP-ribose and p-nitrobenzylidine aminoguanidine. Results from fast atom bombardment mass spectrometry prove that the product is mono-ADP-ribosylated. ADP-ribosylation lowers the pKa of the p-nitrobenzylidine aminoguanidine by 0.7-0.8 pH unit. Assay methods are developed for measuring the ADP-ribosyltransferase reaction by following the rate of disappearance of p-nitrobenzylidine aminoguanidine by high-performance liquid chromatography or spectrophotometrically by monitoring the absorbance increase at 370 nm accompanying ADP-ribosylation of p-nitrobenzylidine aminoguanidine. The high-performance liquid chromatographic system can be utilized to measure ADP-ribosyltransferase activity in animal tissues. By using this procedure, the presence and quantitation of an ADP-ribosyltransferase in a homogenate of rabbit skeletal muscle is reported.
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PMID:Assay of mono ADP-ribosyltransferase activity by using guanylhydrazones. 631 94

Islet-activating protein (IAP), pertussis toxin, is an oligomeric protein (Tamura, M., Nogimori, K., Murai, S., Yajima, M., Ito, K., Katada, T., Ui, M., and Ishii, S. (1982) Biochemistry 21, 5516-5522), the biggest subunit (Mr = 28,000, referred to as the A-protomer) of which catalyzes transfer of the ADP-ribose moiety of NAD to the membrane Mr = 41,000 protein. The pentamer, termed the B-oligomer, consisting of the residual subunits was the moiety of IAP that was responsible for binding to the cell surface, as revealed by competitive inhibition of the development of the IAP actions on intact rat C6 glioma cells and rat adipocytes. The binding of the B-oligomer to its receptor proteins was divalent via the constituent two dimers; it stimulated mitosis of lymphocytes and caused an insulin-like action to enhance glucose oxidation in adipocytes, just as did concanavalin A, presumably as a result of cross-linking or aggregation of the membrane proteins. The A-promoter displayed its biological action on adipocytes only when the B-oligomer had been bound to the cells. Thus, IAP is a typical A-B toxin in which the B-oligomer is first bound to the cell surface proteins to enable the A-protomer to reach to the site of its action within the cell. Diverse biological actions of pertussis toxin may be accounted for by the mitogenic action of the B-oligomer as well as ADP-ribosyltransferase activity of the A-promoter.
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PMID:A role of the B-oligomer moiety of islet-activating protein, pertussis toxin, in development of the biological effects on intact cells. 634 81

Poly(ADP-ribose) glycohydrolase has been purified about 12 300-fold from pig thymus with a recovery of 8.5%. The specific activity of the purified enzyme is 13.8 mumol min -1 mg protein -1. The molecular weight was estimated to be 59 000 by gel filtration through Sephadex G-100 in a non-denaturing solvent. Analysis of the final preparation by sodium dodecyl sulphate gel electrophoresis reveals two protein bands of molecular weight, 61 500 and 67 500. The Km value for poly(ADP-ribose) is estimated to be 1.8 microM monomer units. The enzyme preparation is free from phosphodiesterase, NADase and ADP-ribosyltransferase activities. The purified enzyme is inhibited by cyclic AMP, ADP-ribose, naphthylamine, histones H1, H2A, H2B, H3, polylysine, polyarginine, polyornithine and protamine. The inhibition by histone is relieved by an equal mass of DNA. Single-stranded DNA, poly(A), poly(I) and polyvinyl sulphate were inhibitory, but double-stranded DNA was not inhibitory.
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PMID:Isolation and purification of poly(ADP-ribose) glycohydrolase from pig thymus. 661 43

An ADP-ribosyltransferase from turkey erythrocytes which utilizes proteins and low molecular weight guanidino compounds such as arginine and agmatine as ADP-ribose acceptors was stimulated by histones. The effect was specific in that choleragen, a bacterial mono(ADP-ribosyl)transferase that increased adenylate cyclase activity in animal cells, was not activated by histones. With the erythrocyte enzyme, histones decreased the apparent Km values for arginine methyl ester and agmatine and increased the stability of the transferase to thermal denaturation. Activation of the transferase by histones was rapid, with a minimal delay observed upon addition of histones to a histone-free assay. Activation by histones was reversed upon dilution of a sample containing histones into an assay mix free of histone. In the absence of histone, the transferase existed as a rapidly sedimenting species; in the presence of histone, the transferase sedimented as a protomer.
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PMID:Activation of an NAD:arginine ADP-ribosyltransferase by histone. 679 12

Cholera toxin catalyzed the ADP-ribosylation of a single plasma membrane protein (Mr 55 000) of both RL-PR-C rat hepatocytes and purified rat liver plasma membranes. Labeling of this protein from nicotinamide [2,8-3H]adenine dinucleotide was competitively inhibited by free arginine, but by no other amino acid tested, including lysine. The same protein was ADP-ribosylated from NAD+ endogenously, i.e., in the absence of toxin. This process was, however, not competitively inhibited by added arginine nor by any other amino acid tested lysine. Free ADP-ribose, even in 50-fold molar excess over the nicotinamide [2,8-3H]adenine dinucleotide substrate, did not reduce (by isotope dilution) the endogenous or cholera toxin-catalyzed labeling of the 55 000 dalton membrane protein. It is likely, therefore, that hepatocyte plasma membranes contain an ADP-ribosyltransferase, with a mechanism similar to that of the A subunit of cholera toxin, in that both transfer ADP-ribose to the same membrane protein and in that neither apparently produce free ADP-ribose as an intermediate. It is also clear that the acceptor residue in the 55 000 dalton protein is different for each process. Cholera toxin-catalyzed and endogenous transfer of ADP-ribose to the hepatocyte plasma membrane protein, in contrast to a pigeon erythrocyte system, required no cytosolic factors. The results indicate that ADP-ribosylation in cloned differentiated rat hepatocytes differs from that in pigeon erythrocytes in that the acceptor protein is larger (55 000 compared to 42 000 daltons), cytosolic factors are not required and transfer of ADP-ribose to the acceptor protein occurs endogenously.
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PMID:Endogenous and cholera toxin-catalyzed ADP-ribosylation of a plasma membrane protein by RL-PR-C cloned rat hepatocytes. 722 28

To investigate the origin of DNA repair in rat pleural mesothelial cells (RPMC) exposed to asbestos fibers, poly(ADP-ribose) polymerase (PARP) activity was measured in the asbestos-treated cells. As bleomycin has been shown to activate poly(ADP-ribose) synthesis in several cell systems, the response to bleomycin with regard to PARP assay was first investigated. Bleomycin produced a dose-dependent increase of poly(ADP-ribose) synthesis in RPMC. Likewise both chrysotile and crocidolite fibers produced a concentration-dependent PARP activation indicating that the formation of DNA strand breaks is one type of damage produced by asbestos in RPMC. Enhancement of DNA repair, assessed by the measurement of [3H] methylthymidine incorporation in growth arrested cells, was not detectable in the presence of 3-methoxybenzamide (3-MBA), a PARP inhibitor, confirming a relation between PARP activation and DNA repair. The participation of DNA breakage in asbestos toxicity on RPMC was determined by the colorimetric 3-4(5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. There was no relationship between DNA breakage and cytotoxicity since the use of PARP inhibitors did not change cell viability. These results indicate that asbestos produce DNA damage that is repaired in RPMC.
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PMID:Synthesis of poly(ADP-ribose) in asbestos treated rat pleural mesothelial cells in culture. 750 Sep 78

When isolated myelin membranes were ADP-ribosylated by [32P]NAD+ either in the absence of toxin (by the membrane ADP-ribosyltransferase) or in the presence of cholera toxin, the same proteins were ADP-ribosylated in both cases and myelin basic protein (MBP) was the major radioactive product. Therefore, cholera toxin was considered a good model for ADP-ribosylation of myelin proteins. Although purified human MBP migrates as a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis with a molecular mass of 20 kDa, the microheterogeneity that is masked under these conditions can be clearly demonstrated on alkaline-urea gels at pH 10.6. At this pH, MBP is resolved into several components that differ one from the other by a single charge (charge isomers). These charge isomers can be resolved on CM52 columns at pH 10.6, and several can be ADP-ribosylated. Component 1 (C-1), the most cationic charge isomer, incorporated 1.79 mol of ADP-ribose/mol of protein. C-2 and C-3 (which differ from C-1 by the loss of one and two positive charges, respectively) incorporated slightly less at 1.67 and 1.63 mol of ADP-ribose/mol of protein, respectively, whereas C-8, the least cationic, incorporated less than 0.11 mol/mol of protein. In the presence of neutral hydroxylamine, the ADP-ribosyl bond was shown to have a half-life of about 80 min, suggesting an N-glycosidic linkage between ADP-ribose and an arginyl residue of the protein.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:ADP-ribosylation of human myelin basic protein. 751 50

An NAD+:cysteine ADP-ribosyltransferase activity was purified from bovine erythrocytes on the assumption that, like pertussis toxin, the enzyme would exhibit a cysteine-dependent NAD+ glycohydrolase activity. A three-step purification procedure was developed involving (1) precipitation with 40% (NH4)2SO4, (2) binding to a cysteine-Sepharose affinity column, and (3) binding to an NAD+ affinity column. PAGE showed a single band of M(r) 45,000. The enzyme had been purified 47,000-fold and had a specific activity of 1900 nmol nicotinamide released/min per mg. A study of the kinetic properties of this enzyme showed saturation kinetics for cysteine (Km = 4.0 mM). The ability of this enzyme to ADP-ribosylate protein was investigated using re-sealed inverted bovine erythrocyte ghosts. Incubation of the purified enzyme with erythrocyte ghosts and [adenylate-32P]NAD+ led to the enhanced dose-dependent labelling of several proteins, a doublet of high M(r) and proteins of M(r) 60,000, 55,000 and 29,000, identified by autoradiography of separated proteins on SDS/PAGE. The enzyme-catalysed labelling of the major component at M(r) 55,000 was blocked by pre-treatment of the erythrocyte ghosts with N-ethymaleimide, a sulphydryl alkylating agent, and the label was released by mercuric ion, but not by hydroxylamine. These experiments suggested that a cysteine residue on the target protein had been mono-ADP-ribosylated. This supposition was further supported by identification of the mercf1p4ion-released radiolabelled product as ADP-ribose by HPLC, and the observation that free ADP-ribose was unable to modify the membrane target protein directly.
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PMID:The purification of a cysteine-dependent NAD+ glycohydrolase activity from bovine erythrocytes and evidence that it exhibits a novel ADP-ribosyltransferase activity. 757 29

To study biological functions of poly(ADP-ribose) polymerase (PARP), low-molecular-mass inhibitors have been used extensively, and the experimental results obtained led to the view that PARP plays a role in DNA repair as well as in other cellular processes, eg DNA replication, cell proliferation, and differentiation. Accumulating evidence that these inhibitors have side effects on other metabolic pathways prompted us to develop two molecular genetic systems for the modulation of poly(ADP-ribosyl)ation in living cells: i) the first approach is centered on the DNA-binding domain (DBD) of PARP, which recognizes DNA strand breaks through its zinc fingers, leading to enzyme activation. We have established stable cell culture systems for either constitutive or inducible overexpression of the DBD. In these cells we observe a drastic trans-dominant inhibition of poly(ADP-ribosyl)ation which is associated with sensitization of cells to gamma-irradiation; and ii) in an attempt to specifically increase the poly(ADP-ribose) formation capacity in living cells, the hamster cell line CO60 was stably transfected to obtain constitutive overexpression of full-length human PARP. These molecular genetic systems may be useful for the elucidation of the precise role of poly(ADP-ribosyl)ation in the biological response to DNA damage.
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PMID:Molecular genetic systems to study the role of poly(ADP-ribosyl)ation in the cellular response to DNA damage. 757 28


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