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)

Highly purified, polymyxin-released, low molecular weight Escherichia coli heat-labile enterotoxin (LT) catalyzed the hydrolysis of NAD to ADP-ribose and nicotinamide. This NAD glycohydrolase activity was stimulated by dithiothreitol and was independent of cellular components. Nicotinamide formation was enhanced by arginine methyl ester > d-arginine congruent with l-arginine congruent with guanidine. A 20-fold increase in activity was noted with arginine methyl ester, and maximal activity again required dithiothreitol. When the reaction was initiated with toxin, a delay was observed before a constant rate was established. The reaction products found after incubation of [adenine-U-(14)C]NAD and l-[(3)H]arginine or unlabeled arginine methyl ester with the enterotoxin had mobilities on thin-layer chromatograms similar to the reaction products obtained after incubation of choleragen with these substrates and are consistent with the formation of ADP-ribose-l-arginine and ADP-ribose-l-arginine methyl ester, respectively. Both toxins, which catalyze the NAD-dependent activation of adenylate cyclase, thus appear to possess NAD glycohydrolase and ADP-ribosyltransferase activities. Although the activities of both toxins are dependent on dithiothreitol, Escherichia coli enterotoxin exhibited optimal activity in Tris (Cl(-)) (pH 7.5) and was inhibited by high concentrations of potassium phosphate (pH 7.0) or low pH (sodium acetate, pH 6.2). It appears that the optimal assay conditions as well as the kinetic constants for the reactants differ from those previously noted with choleragen. It is probable therefore that although the two toxins catalyze similar reactions, they differ in primary structure. The presence of transferase and glycohydrolase activities in structurally distinct toxins that activate adenylate cyclase strengthens our hypothesis that the ADP-ribosylation of arginine is a model for the NAD-dependent activation of adenylate cyclase; activation may result from ADP-ribosylation of the cyclase itself or of a protein that regulates its activity.
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PMID:Activation of adenylate cyclase by heat-labile Escherichia coli enterotoxin. Evidence for ADP-ribosyltransferase activity similar to that of choleragen. 20 60

An ADP-ribosyltransferase was purified approximately 500-fold from the supernatant fraction of turkey erythrocytes. The enzyme hydrolyzed [carbonyl-(14)C]NAD to ADP-ribose and [carbonyl-(14)C]nicotinamide at a low rate. Nicotinamide formation from NAD was enhanced by arginine methyl ester > D-arginine approximately L-arginine > guanidine; lysine, histidine, and citrulline were ineffective. Incubation of [adenine-U-(14)C]NAD and arginine methyl ester or arginine with the purified enzyme resulted in the formation of new compounds that contained (14)C, reacted with ninhydrin, and quenched background fluorescence of thin-layer plates viewed in ultraviolet light. Their mobilities on thin-layer chromatograms were indistinguishable from those of ADP-ribosylarginine methyl ester and ADP-ribosylarginine formed during incubation of choleragen with NAD and arginine methyl ester or arginine, respectively [Moss, J. & Vaughan, M. (1977) J. Biol. Chem. 252, 2455-2457]. The purified transferase also catalyzed the incorporation of label from [adenine-(14)C]-NAD into lysozyme, histones and polyarginine. When the (14)C-labeled lysozyme was incubated with snake venom phosphodiesterase, the radioactivity was released and, on thin-layer chromatograms, exhibited a mobility indistinguishable from that of 5'-AMP, as would be expected of an ADP-ribosylated protein, but not of a poly(ADP-ribosylated) product. The purified transferase activated rat brain adenylate cyclase and, as is the case with choleragen, activation was absolutely dependent on NAD. The presence in the avian erythrocyte of a protein that, like choleragen and Escherichia coli heat-labile enterotoxin, apparently activates adenylate cyclase and possesses ADP-ribosyl transferase activity is consistent with the view that the mechanisms through which the bacterial toxins produce pathology are not entirely foreign to vertebrate cells, at least some of which may possess and employ an analogous mechanism for activation of adenylate cyclase.
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PMID:Isolation of an avian erythrocyte protein possessing ADP-ribosyltransferase activity and capable of activating adenylate cyclase. 21 2

We have identified a guanidine group specific ADP-ribosyltransferase activity, capable of transferring an ADP-ribose group from NAD to a low molecular weight guanidine compound [p-(nitrobenzylidine)amino]guanidine and proteins such as histone and poly-L-arginine, in a variety of murine cell lines. The enzyme activity appears to be associated with an integral membrane protein of apparent molecular weight 30-33 kDa. Incubation of the viable cells in isotonic phosphate buffered saline with [32P]NAD results in the incorporation of label into cellular proteins. Dimethyl sulfoxide treatment of the cells downregulates the transferase activity as well as the ADP-ribosylation of cell proteins with extracellular NAD.
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PMID:Guanidine group specific ADP-ribosyltransferase in murine cells. 190 5

Membranes purified from cells of Streptomyces griseus strain 52-1 possess an ADP-ribosyltransferase activity. The enzyme transfers the ADP-ribose moiety of NAD to one major membrane protein of Mr 32,000 and 2-3 minor proteins of larger molecular weights. The effects of inhibitors on the ADP-ribosyltransferase activity proves that the reaction is enzymatic and suggests that the enzyme ADP-ribosylates the guanidine group of arginine. The kinetics of liberation of ADP-ribose during alkaline hydrolysis of the modified proteins is consistent with the arginine-ADP-ribose bond. This is the first report of ADP-ribosylation of proteins in a Gram-positive bacterium.
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PMID:ADP-ribosylation of membrane proteins of Streptomyces griseus strain 52-1. 212 Jan 8

Clostridium spiroforme iotalike toxin produced time- and concentration-dependent incorporation of ADP-ribose into homo-poly-L-arginine. Polyasparagine, polyglutamic acid, polylysine, and agmatine were poor substrates. Enzyme activity was associated with the light-chain polypeptide of the toxin. The heavy chain did not possess ADP-ribosyltransferase activity, nor did it enhance or inhibit activity of the light chain. In broken-cell assays, the toxin acted mainly on G-actin, rather than F-actin. A single ADP-ribose group was transferred to each substrate molecule (G-actin). The enzyme was heat sensitive, had a pH optimum in the range of 7 to 8, was inhibited by high concentrations of nicotinamide, and was reversibly denatured by urea and guanidine. Physiological levels of nucleotides (AMP, ADP, ATP, and ADP-ribose) and cations (Na+, K+, Ca2+, and Mg2+) were not very active as enzyme inhibitors. The toxin was structurally and functionally similar to Clostridium botulinum type C2 toxin and Clostridium perfringens iota toxin. When combined with previous findings, the data suggest that a new class of mono(ADP-ribosyl)ating toxins has been found and that these agents belong to a related and possibly homologous series of binary toxins.
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PMID:Production by Clostridium spiroforme of an iotalike toxin that possesses mono(ADP-ribosyl)transferase activity: identification of a novel class of ADP-ribosyltransferases. 252 Dec 14

An NAD- and guanidine-dependent ADP-ribosyltransferase has been purified more than 500,000-fold from turkey erythrocytes with an 18% yield. The enzyme in the 100,000 X g supernatant fraction was bound to phenyl-Sepharose, eluted with 50% propylene glycol, and further purified by sequential chromatographic steps on carboxymethylcellulose, NAD-agarose and concanavalin A-agarose. The transferase was specifically eluted from concanavalin A-agarose with alpha-methylmannoside. The enzymatic activity was extremely labile following the first purification step. Both propylene glycol and NaCl stabilized the transferase; significant increases in enzyme recovery were obtained by conducting the NAD- and concanavalin A-agarose chromatography in buffer containing propylene glycol. The purified protein exhibits one predominant protein band on SDS-polyacrylamide gels with an estimated molecular weight of 28,300. On Ultrogel AcA54 chromatography, single coincident peaks of ADP-ribosyltransferase activity and protein were observed. Enzyme activity was independent of DNA; the highly purified transferase was inhibited by thymidine, nicotinamide, and theophylline. The specific activity of the purified enzyme (350 mumol of ADP-ribose transferred from NAD to arginine methyl estermin-1mg-1) is comparable to that reported for purified NAD glycohydrolases and poly(ADP-ribosyl)transferases.
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PMID:Isolation and properties of an NAD- and guanidine-dependent ADP-ribosyltransferase from turkey erythrocytes. 624 48

A partially purified protein preparation from rat liver catalyzed the ADP-ribosylation of low molecular weight guanidino compounds and proteins. Agmatine and arginine, previously shown to be effective acceptors for the guanidine-dependent erythrocyte ADP-ribosyltransferase, were used as acceptors by the rat liver enzyme; lysine, histidine, and serine were inactive. The product of the reaction between [adenine-U-14C]NAD and agmatine catalyzed by the rat liver enzyme co-chromatographed with [adenine-U-14C]ADP-ribose-agmatine which was synthesized by the erythrocyte transferase; in parallel assays, formation of this product was associated with stoichiometric release of [carbonyl-14C]nicotinamide from [carbonyl-14C]NAD. In the presence of histones or other proteins and [adenine-U-14C]NAD or [32P]NAD, the rat liver enzyme catalyzed the formation of a radioactive product which was precipitable by trichloroacetic acid. Digestion of the [adenine-U-14C]-labeled precipitate with snake venom phosphodiesterase released a labeled compound identified as 5'-AMP. These data are consistent with the conclusion that a mono-(ADP-ribosyltransferase) is present in rat liver which utilizes guanidino compounds such as arginine as ADP-ribose acceptors. The ADP-ribose-glutamate bond has been shown to exist in rat liver. Since the catalytic sites of each transferase can accommodate and thus ADP-ribosylate only one specific amino acid, a family of site-specific transferases must be present. The availability of multiple site-specific transferases permits the cell to exert further control over ADP-ribosylation.
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PMID:Amino acid-specific ADP-ribosylation. Identification of an arginine-dependent ADP-ribosyltransferase in rat liver. 626 27

The sarcoplasmic reticulum and glycogen pellet derived from rabbit skeletal muscle and the sarcolemma and sarcoplasmic reticulum from pig skeletal muscle contains NAD:dependent mono ADP-ribosyltransferase activity toward the guanidine analog, P- nitrobenzylidine aminoguanidine. No or little activity could be found in the sarcolemma or sarcoplasmic reticulum derived from canine cardiac muscle. Seventy percent of activity extracted from rabbit skeletal muscle is localized in the sarcoplasmic reticulum. The enzyme has a pH optimum of 7.4, and KM of 0.5 mM and 0.35 mM for NAD and p-nitro benzylidine aminoguanidine, respectively. Inorganic phosphate, KCl, and guanidine derivatives inhibit the reaction. Incubation of the sarcoplasmic reticulum or glycogen pellet with (adenylate-32P) NAD or [adenosine-14C(U)]-labeled NAD results in the incorporation of radioactivity into proteins. A large number of proteins are labeled in the sarcoplasmic reticulum fraction. The major labeled band in the glycogen pellet corresponds to a protein of molecular weight of 83 K.
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PMID:NAD: guanidino group specific mono ADP-ribosyltransferase activity in skeletal muscle. 632 92

Carbonyl compounds with diverse carbon skeletons may be differentially related to the pathogenesis of vascular diseases. In this study, we compared intracellular signals delivered into cultured human umbilical vein endothelial cells (HUVECs) by glyoxal (GO) and methylglyoxal (MGO), which differ only by a methyl group. Depending on their concentrations, GO and MGO promoted phosphorylations of ERK1 and ERK2, which were blocked by the protein-tyrosine kinase (PTK) inhibitors herbimycin A and staurosporine, thereby being PTK-dependent. GO and MGO also induced phosphorylations of JNK, p38 MAPK, and c-Jun, either PTK-dependently (GO) or -independently (MGO). Next, we found that MGO, but not GO, induced degradation of poly(ADP-ribose) polymerase (PARP) as the intracellular substrate of caspase-3. Curcumin and SB203580, which inhibit JNK and p38 MAPK signaling pathways, but not herbimycin A/staurosporine, prevented the MGO-induced PARP degradation. We then found that MGO, but not GO, reduced the intracellular glutathione level, and that cysteine, but not cystine, inhibited the MGO-mediated activation of ERK, JNK, p38 MAPK, or c-Jun more extensively than did lysine or arginine. In addition, all the signals triggered by GO and MGO were blocked by amino guanidine (AG), which traps carbonyls. These results demonstrated that GO and MGO triggered two distinct signal cascades, one for PTK-dependent control of ERK and another for PTK-independent redox-linked activation of JNK/p38 MAPK and caspases in HUVECs, depending on the structure of the carbon skeleton of the chemicals.
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PMID:Glyoxal and methylglyoxal trigger distinct signals for map family kinases and caspase activation in human endothelial cells. 1142 86

Poly (ADP-ribose) synthase or polymerase (PARS and PARP, respectively) is a cytotoxic enzyme which causes cellular damage. Nicotinamide, a compound of vitamin B complex, has been reported to exert an inhibitory effect on PARS or PARP. The present study tests the effects of nicotinamide on acute lung injury and associated alterations following ischaemia/reperfusion (I/R) of the isolated perfused rat's lung. I/R increased the lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, pulmonary arterial pressure and capillary permeability. The insult also increased nitrate/nitrite, methyl guanidine, tumour necrosis factor-alpha and interleukin-1beta in lung perfusate, while it decreased adenosine triphosphate content with an increase in PARP activity in lung tissue. Most of the I/R-induced changes were abrogated by post-treatment (30 min after I/R) with nicotinamide (100 mg.kg(-1) body weight). However, the increase in pulmonary arterial pressure was enhanced by nicotinamide post-treatment. Following I/R, the inducible nitric oxide synthase (iNOS) mRNA expression was enhanced. Nicotinamide reduced the iNOS expression. The results suggest that nicotinamide exerted a protective effect on the acute lung injury caused by ischaemia/reperfusion. The mechanisms may be mediated through the inhibition on the poly (adenosine diphosphate-ribose) polymerase activity, inducible nitric oxide synthase expression and the subsequent suppression of nitric oxide, free radicals and pro-inflammatory cytokines with restoration of adenosine triphosphate.
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PMID:Nicotinamide abrogates acute lung injury caused by ischaemia/reperfusion. 1750 97


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