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)

Guanine nucleotide-binding (G) proteins are involved in several transmembrane signaling systems. Choleragen (cholera toxin) activates adenylate cyclase by catalyzing the ADP-ribosylation of Gs alpha, the stimulatory G protein of the cyclase system. This reaction is enhanced by another guanine nucleotide-binding protein termed ADP-ribosylation factor or ARF that was purified from bovine brain membranes [R. A. Kahn and A. G. Gilman, Journal of Biological Chemistry (1986) 261, 7906-7911]. It was recently found that this ARF also increases the NAD:agmatine and NAD:protein ADP-ribosyltransferase, NAD glycohydrolase and auto-ADP-ribosylation activities of the toxin. We have purified and characterized two soluble proteins from bovine brain that act in a similar fashion to enhance choleragen activity in each of these reactions. The membrane and soluble factors are all proteins of approximately 19 kDa that require GTP or GTP analogues for activity and are ADP-ribosylated by the toxin. The ARF proteins apparently interact directly with choleragen in a GTP-dependent fashion to increase its catalytic activity and thus are part of a G protein cascade through which the toxin activates adenylate cyclase. The physiological function of the ARF proteins, as well as their possible relationships to the ras oncogene products and/or the family of G proteins that includes Gs alpha, remains to be determined.
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PMID:Participation of a guanine nucleotide-binding protein cascade in cholera toxin activation of adenylate cyclase. 249 82

The mechanism by which MgADP stimulates the activity of dinitrogenase reductase ADP-ribosyltransferase (DRAT) has been examined by using dinitrogenase reductases from Rhodospirillum rubrum, Klebsiella pneumoniae, and Azotobacter vinelandii as acceptor substrates. In the presence of 0.2 mM NAD, maximal rates of ADP-ribosylation of all three acceptors were observed at an ADP concentration of 150 microM; in the absence of added ADP, DRAT activity with the dinitrogenase reductases from R. rubrum and K. pneumoniae was less than 5% of the maximal rate, but the A. vinelandii protein was ADP-ribosylated at 40% of the maximal rate. Of eight dinucleotides tested, only ADP, 2'-deoxy-ADP, and ADP-beta S served as activators of the DRAT reaction; ADP, 2'-deoxy-ADP, and ADP-beta S were also the only dinucleotides found which inhibited acetylene reduction activity by dinitrogenase reductase. The dinucleotide specificities for both DRAT activation and acetylene reduction inhibition were the same for all three dinitrogenase reductases. In the DRAT reaction with the dinitrogenase reductases from K. pneumoniae and A. vinelandii, the Km for NAD was 30-fold higher in the absence of ADP than in its presence; the Km for NAD with the R. rubrum acceptor was not measurable. In the presence of saturating ADP, ADP-ribosylation of dinitrogenase reductase from R. rubrum was inhibited 63% by 1.5 mM ATP. It is concluded that MgADP stimulates DRAT activity by lowering the Km for NAD and that MgADP exerts its effect by binding to dinitrogenase reductase. MgATP inhibits DRAT activity by competing with MgADP for binding to dinitrogenase reductase.
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PMID:Effect of nucleotides on the activity of dinitrogenase reductase ADP-ribosyltransferase from Rhodospirillum rubrum. 250 83

The mechanism for "NH4+ switch-off/on" of nitrogenase activity in Azospirillum brasilense and A. lipoferum was investigated. A correlation was established between the in vivo regulation of nitrogenase activity by NH4Cl or glutamine and the reversible covalent modification of dinitrogenase reductase. Dinitrogenase reductase ADP-ribosyltransferase (DRAT) activity was detected in extracts of A. brasilense with NAD as the donor molecule. Dinitrogenase reductase-activating glycohydrolase (DRAG) activity was present in extracts of both A. brasilense and A. lipoferum. The DRAG activity in A. lipoferum was membrane associated, and it catalyzed the activation of inactive nitrogenase (by covalent modification of dinitrogenase reductase) from both A. lipoferum and Rhodospirillum rubrum. A region homologous to R. rubrum draT and draG was identified in the genomic DNA of A. brasilense as a 12-kilobase EcoRI fragment and in A. lipoferum as a 7-kilobase EcoRI fragment. It is concluded that a posttranslational regulatory system for nitrogenase activity is present in A. brasilense and A. lipoferum and that it operates via ADP-ribosylation of dinitrogenase reductase as it does in R. rubrum.
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PMID:Posttranslational regulatory system for nitrogenase activity in Azospirillum spp. 250 94

The ADP-ribosyl moiety of NAD was transferred to proteins with Mr values of 22,000 and 25,000 when bovine brain cytosol was incubated with a botulinum ADP-ribosyltransferase C3 (BT-C3) which was purified from the culture medium of a type C strain of Clostridium botulinum. Any protein fraction eluted from a chromatographic column to which the cytosol had been applied, however, was not significantly ADP-ribosylated by BT-C3, unless the reaction mixture was further supplemented with a small amount of the cytosol. Thus, substrate protein(s) could be partially purified based on their ability to be ADP-ribosylated by BT-C3 in the presence of the cytoplasmic activator(s). The rate of ADP-ribosylation of the substrates was extremely low by itself but was increased enormously and progressively when increasing amounts of cytosol were added, affording a reliable means for assay of the activator contained therein. The activator was separated from the substrate proteins and partially purified from the cytosol by sequential chromatography steps with an anion exchanger and a gel filtration column. The activity of the partially purified activator was heat-labile and protease-sensitive, suggesting that the activator was a protein or had a protein component necessary for activity. The action of the activator protein(s) was specific for BT-C3-catalyzed ADP-ribosylation; cholera toxin-catalyzed ADP-ribosylation of GTP-binding protein (Gs) was not supported by this activator. Thus, this is the first report to show that botulinum ADP-ribosyltransferase-catalyzed reaction can proceed significantly only in the presence of other protein factor(s), just as has been observed with an ADP-ribosylation factor required for cholera toxin-induced similar reaction.
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PMID:Activator protein supporting the botulinum ADP-ribosyltransferase reaction. 250 15

Human nuclear NAD+: protein ADP-ribosyltransferase(polymerizing) [pADPRT; poly(ADP-ribose)poly-merase; EC 2.4.2.30] is a DNA-dependent protein-modifying enzyme composed of several domains important for DNA binding, automodification, and NAD binding. We report that the human pADPRT gene is 43 kb in length and is split into 23 exons. All the intron-exon boundaries correspond to a canonical splice consensus sequence. Each of the four metal coordinating sites putatively forming the two zinc fingers of the DNA-binding domain is encoded separately. The automodification domain and the NAD-binding domain are coded for by 4 and 12 exons, respectively.
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PMID:Human nuclear NAD+ ADP-ribosyltransferase(polymerizing): organization of the gene. 251 74

Cholera toxin catalyzes the ADP-ribosylation that results in activation of the stimulatory guanine nucleotide-binding protein of the adenylyl cyclase system, known as Gs. The toxin also ADP-ribosylates other proteins and simple guanidino compounds and auto-ADP-ribosylates its AI protein (CTA1). All of the ADP-ribosyltransferase activities of CTAI are enhanced by 19-21-kDa guanine nucleotide-binding proteins known as ADP-ribosylation factors, or ARFs. CTAI contains a single cysteine located near the carboxy terminus. CTAI was immobilized through this cysteine by reaction with iodoacetyl-N-biotinyl-hexylenediamine and binding of the resulting biotinylated protein to avidin-agarose. Immobilized CTAI catalyzed the ARF-stimulated ADP-ribosylation of agmatine. The reaction was enhanced by detergents and phospholipid, but the fold stimulation by purified sARF-II from bovine brain was considerably less than that observed with free CTA. ADP-ribosylation of Gsa by immobilized CTAI, which was somewhat enhanced by sARF-II, was much less than predicted on the basis of the NAD:agmatine ADP-ribosyltransferase activity. Immobilized CTAI catalyzed its own auto-ADP-ribosylation as well as the ADP-ribosylation of the immobilized avidin and CTA2, with relatively little stimulation by sARF-II. ADP-ribosylation of CTA2 by free CTAI is minimal. These observations are consistent with the conclusion that the cysteine near the carboxy terminus of the toxin is not critical for ADP-ribosyltransferase activity or for its regulation by sARF-II. Biotinylation and immobilization of the toxin through this cysteine may, however, limit accessibility to Gsa or SARF-II, or perhaps otherwise reduce interaction with these proteins whether as substrates or activator.
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PMID:Activation of immobilized, biotinylated choleragen AI protein by a 19-kilodalton guanine nucleotide-binding protein. 251 98

In cultured human epidermal cells exposure to the vesicant sulfur mustard (HD) causes a decrease of the NAD+ content, which depends on the dose and the time period between exposure to HD and NAD+ measurement. Presumably, this NAD+ loss is due to activation of the enzyme NAD:protein ADP-ribosyltransferase (ADPRT) and may lead to glycolysis inhibition, disturbance of energy metabolism, and eventually cell death. Since prevention of this NAD+ depletion could lead to cell survival, HD-exposed cultures have been incubated with nicotinamide, a precursor of NAD+ and an inhibitor of ADPRT. Although a reduction in NAD+ levels of the cultures can be prevented, the uptake of glucose, which was taken as a measure for cellular viability, appears to be inhibited in cultures in which the NAD+ levels are at the 100% level at 4 hr after exposure. Therefore, prophylactic or therapeutic measures that are focused on maintenance of NAD+ levels in order to preserve energy supplies do not protect human epidermal cells in culture that have been exposed to HD. These experiments indicate that mechanisms other than NAD+ depletion may play an important role in HD-induced cell injury in human skin.
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PMID:NAD+ levels and glucose uptake of cultured human epidermal cells exposed to sulfur mustard. 252 91

To analyze a possible involvement of ADP-ribosylation reactions in 3T3-L1 pre-adipocyte differentiation. ADP-ribosyltransferase activities is permeabilized cells as well as endogenous amounts of protein-bound mono- and poly(ADP-ribose) residues were determined. Also, in vivo labeling with [3H]adenosine of ADP-ribose residues linked to high-mobility-group (HMG) proteins was performed. As an additional probe, the effects of ADP-ribosylation inhibitors and non-inhibitory analogs were studied. Basal and total poly(ADP-ribose) polymerase activities markedly increased prior to the appearance of the differentiation marker glycerol-3-phosphate dehydrogenase. Despite these apparent changes in activity, however, neither protein-bound poly(ADP-ribose) residue nor mono(ADP-ribosyl) groups in histones, nor the NAD content, changed significantly under these conditions. Furthermore, although HMG protein-associated [3H]ADP-ribose was reduced in differentiating [3H]adenosine-labeled cells, the data suggest altered precursor pool labeling rather than a specific decrease in ADP-ribosylated HMG proteins. Non-participation of ADP-ribosylation reactions in 3T3-L1 differentiation is further supported by experiments with inhibitors and non-inhibitory analogs. Benzamide at 0.3-3 mM per se without effect on differentiation, was able to induce specific gene expression when combined with insulin (10(-12)-10(-7) M). Similar effects were seen with benzoate as well as with nicotinamide, 3-aminobenzamide and their corresponding acids. The data indicate that benzamide and analogs have profound effects on chromatin functions that are not mediated by ADP-ribosylation reactions.
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PMID:Differentiation of 3T3-L1 pre-adipocytes induced by inhibitors of poly(ADP-ribose) polymerase and by related noninhibitory acids. 252 99

Treatment of fragment A chain of diphtheria toxin (DT-A) with diethylpyrocarbonate modifies His-21, the single histidine residue present in the chain, without alteration of other residues. Parallel to histidine modification, NAD+ binding and the NAD-glycohydrolase and ADP-ribosyltransferase activities of DT-A are lost. Both NAD+ and adenosine are very effective in protecting DT-A from histidine modification and in preserving its biological properties, while adenine is ineffective. Reversal of histidine modification with hydroxylamine restores both NAD+ binding and enzymatic activities of the toxin. The possible role of His-21 in the activity of diphtheria toxin is discussed in relation to the available three-dimensional structure of the related toxin produced by Pseudomonas aeruginosa.
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PMID:Histidine 21 is at the NAD+ binding site of diphtheria toxin. 252 25

The structural gene of the S-1 subunit of pertussis toxin (rS-1) and the catalytic C180 peptide of the S-1 subunit (C180 peptide) were independently subcloned downstream of the tac promoter in Escherichia coli. Both constructions included DNA encoding for the predicted leader sequence of the S-1 subunit which was inserted between the tac promoter and the structural gene. E. coli containing the plasmids encoding for rS-1 and C180 peptide produced a peptide that reacted with anti-pertussis toxin antibody and had a molecular weight corresponding to that of the cloned gene; some degradation of rS-1 was observed. Extracts of E. coli containing plasmids encoding for rS-1 and the C180 peptide possessed ADP-ribosyltransferase activity. Subcellular fractionation showed that both rS-1 and the C180 peptide were present in the periplasm, indicating that E. coli recognized the pertussis toxin peptide leader sequence. The protein sequence of the amino terminus of the C180 peptide was identical to that of authentic S-1 subunit produced by Bordetella pertussis, which showed that E. coli leader peptidase correctly processed the pertussis toxin peptide leader sequence. Two single amino acid substitutions at residue 26 (C180I-26) and residue 139 (C180S-139) which were previously shown to reduce ADP-ribosyltransferase activity were introduced into the C180 peptide. C180I-26 possessed approximately 1% of the NAD-glycohydrolase activity of the C180 peptide, suggesting that tryptophan 26 functions in the interaction of NAD with the C180 peptide. In contrast, C180S-139 possessed essentially the same level of NAD-glycohydrolase activity as the C180 peptide, suggesting that glutamic acid 139 does not function in the interaction of NAD but plays a role in a later step in the ADP-ribosyltransferase reaction.
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PMID:Expression and secretion of the S-1 subunit and C180 peptide of pertussis toxin in Escherichia coli. 254 19


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