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)

We have studied the automodification reaction of poly(ADP-ribose)polymerase (PARP) (EC 2.4.2.30). The individual reactions of initiation, elongation, and branching catalyzed by this enzyme have been dissected out by manipulating the concentration of beta NAD, the ADP-ribosylation substrate. While PARP-mono(ADP-ribose) conjugates were the predominant products of automodification at 200 nM NAD (initiation), highly branched and complex polymers were synthesized at 200 microM NAD (polymerization). Initial rates of automodification increased with second order kinetics as a function of the enzyme concentration at both 200 nM and 200 microM NAD. These results are consistent with the conclusion that two molecules of PARP are required for ADP-ribose polymer synthesis during enzyme automodification. Thus, the auto-poly(ADP-ribosyl)ation reaction of PARP is intermolecular. In agreement with this notion, we observed that initial rates of the initiation reaction with 3'-deoxyNAD as a substrate also increased with the square of the enzyme concentration. In addition, the auto-poly(ADP-ribosyl)ation reaction of PARP increased with second order kinetics as a function of the NAD concentration at nanomolar levels (0.2-106 microM). Therefore, the dimeric structure of PARP also requires two molecules of bound NAD for efficient ADP-ribose polymerization.
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PMID:Dissection of ADP-ribose polymer synthesis into individual steps of initiation, elongation, and branching. 757 22

Poly(ADP-ribose) polymerase (PARP) plays an important role in a number of cellular processes including DNA repair. Since poly(ADP-ribosyl)ation occurs in response to radiation- or drug-induced DNA damage, inhibitors of the enzyme may enhance the antitumour activity of radiotherapy or cytotoxic drug treatment. In this review the development of PARP inhibitors is discussed, and structure-activity relationships amongst inhibitors of the enzyme are presented. Studies to date regarding the in vitro and in vivo activity of PARP inhibitors, as resistance modifying agents in cancer therapy, are also overviewed.
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PMID:The role of inhibitors of poly(ADP-ribose) polymerase as resistance-modifying agents in cancer therapy. 757 23

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

Dissection of the human poly(ADP-ribose) polymerase (PARP) molecule in terms of its structure-function relationship has proved to be an essential step towards understanding the biological role of poly(ADP-ribosylation) as a cellular response to DNA damage in eukaryotes. Current approaches aimed at elucidating the implication of this multifunctional enzyme in the maintenance of the genomic integrity will be presented.
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PMID:Poly(ADP-ribose) polymerase: structure-function relationship. 757 29

A nuclear poly(ADP-ribose) polymerase (PARP) is activated by gamma-irradiation and consequently synthesizes poly(ADP-ribose) by binding to DNA strand-breaks. This property suggests that PARP is a DNA strand-break-signal generator. Meanwhile, the cell-cycle arrest occurs in G1 and G2 phases following gamma-irradiation. We found that PARP inhibitors including 3-aminobenzamide (3-AB) suppressed G1 arrest and enhanced G2 arrest following gamma-irradiation. These observations suggested that PARP is critical for the induction of G1 arrest and is also involved in the regulation of G2 arrest. Furthermore, the effects of 3-AB on the G1-arrest signal-transduction pathway were also studied. We found that p53 stabilization following gamma-irradiation was not inhibited but the p53-responsive transient increases of WAF1/CIP1/p21 and MDM-2 mRNA were suppressed by 3-AB. Therefore, it is suggested that PARP participates in G1-arrest signal-transduction pathway through the modulation of WAF1/CIP1/p21 and MDM-2 mRNA expression.
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PMID:Role of poly(ADP-ribose) polymerase in cell-cycle checkpoint mechanisms following gamma-irradiation. 757 30

Despite extensive research, the pathogenesis of inflammatory bowel disease (IBD) is still unclear. Immunological disorders have been described in patients with both Crohn's disease (CD) and ulcerative colitis (UC). In this work serum samples collected from 58 patients with CD and 55 patients with UC were tested in ELISA against a panel of nuclear and cytoplasmic proteins and peptides in order to determine whether specific autoantibodies are produced in these patients. Low levels of IgG antibodies to histones H1, H2A, H2B, H3, and H4, to Hsp-70 and ubiquitin stress proteins, Ro/SSA and La/SSB proteins and myosin were detected in some of these sera. In contrast, the following antibodies of IgG isotype could be much more frequently demonstrated: antibodies to ubiquitinated H2A (U-H2A) peptide T4 (51.7% in CD; 18.2% in UC), antibodies to the zinc-finger peptide F2 of poly-(ADP-ribose polymer)ase (PARP) involved in DNA repair (58.6% in CD; 25.5% in UC) and actin antibodies (43.1% in CD; 7.3% in UC). In a follow-up study of 12 patients with CD and UC (75 additional samples), we found IgG antibodies to several histone peptides occurring essentially in the serum of patients with CD. Although we found no obvious correlation between the presence or level of these various antibodies and C-reactive protein, or the location of the disease, in a number (but not all) of patients, we observed a strikingly good relationship between antibodies to histone peptides, U-H2A peptide T4, and PARP peptide F2 and the Crohn's disease activity index. The mechanism of induction of these antibodies still remains obscure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Distinct production of autoantibodies to nuclear components in ulcerative colitis and in Crohn's disease. 758 46

1. The effects of racemic thalidomide (D[+]/L[-] alpha-phthalimido-glutarimide) on acetaminophen (AAP)-induced hepatitis were tested in male NMRI mice (n = 133) and quantified as serum activities of glutamate-oxaloacetate transaminase (GOT) and glutamate-pyruvate transaminase (GPT). 2. A 2.1-fold increase of GOT and a 1.9-fold increase of GPT activities (P < 0.001) were observed in mice treated perorally with 500 mg/kg of AAP plus 150 mg/kg of thalidomide (Thal). In the absence of AAP, Thal did not display any detectable hepatotoxic effects. 3. The Thal-induced exacerbation of AAP hepatotoxicity was completely inhibited by nicotinic acid amide, a selective inhibitor of poly(ADP-ribose) polymerase (PARP) (P < 0.0001), suggesting a possible influence of Thal on the hepatic metabolism of NAD-adenoribosylation. 4. We see the main application of nicotinic acid amide as for the combinational use in pharmaceutical preparations of AAP in order to avoid hepatic damage in patients treated with AAP and Thal.
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PMID:Exacerbation of acetaminophen hepatotoxicity by thalidomide and protection by nicotinic acid amide. 759 Jan 13

Administration of hepatocarcinogens aflataxin B1 (AFB1) and N-nitrosodimethylamine (NDMA) to rats caused single-strand breaks in hepatic nuclear DNA. The damage was found to be maximum at 4 hours following AFB1 administration and at 2 hours following NDMA administration. These damages were repaired after 17 and 4 hours, respectively in cases of AFB1 and NDMA. The activity of poly(ADP-ribose)polymerase (PARP), an enzyme known to use single-strand breaks of DNA as cofactor, was observed to increase with increasing damage to DNA and decrease as and when this damage got repaired. DNA polymerase beta and DNA ligase activities were also seen to increase and decline in a way analogous to PARP. In contrast, DNA topoisomerase activity declined corresponding to an increase in PARP activity. These observations suggest a possible role of PARP in coordinating the activities of other enzymes involved in DNA repair. It is also envisaged that these parameters can be utilized to devise strategies to counteract the deleterious effects of chemical carcinogens.
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PMID:Activity of some nuclear enzymes associated with DNA repair following hepatocarcinogen administration to rats. 759 30

In order to examine the structure-function relationship of the poly (ADP-ribose) polymerase (PARP) catalytic domain, potential active-site residues in the catalytic domain have previously been described. Here, we have used mutagenesis with hydroxylamine to generate a random library of PARP mutants. The identification, overproduction in insect cells, purification and characterization of a gain-of-function mutant (L713F) is described. We show that the kcat of this mutant is increased over nine times compared to the wild-type enzyme; the Km for NAD+ is unchanged. The size and the branching structure of the ADP-ribose polymers are similar in both the wild-type and the mutant enzyme. This mutation may have an allosteric effect on the catalytic site and could be useful in analyzing the consequences of poly ADP-ribose overproduction in vivo on cell survival following DNA damage.
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PMID:Characterisation of a gain-of-function mutant of poly(ADP-ribose) polymerase. 762 44

Poly(ADPR) polymerase (PARP; EC 2.4.2.30) is a nuclear enzyme, which, when activated by oxygen- and nitrogen-radical-induced DNA strand breaks, transfers ADP ribose units to nuclear proteins and initiates apoptosis by depletion of cellular NAD and ATP pools. The present study investigates whether the oxidative stress-dependent activation of PARP plays a role in the etiopathogenesis of arthritis. The antiarthritic reactivity of the biogenic PARP inhibitor nicotinamide was tested in DBA/1 x B10A(4R) mice suffering from potassium peroxochromate-induced arthritis. Daily doses of 4 mmol/kg of NA suppressed the arthritis by 35% and inhibited the phagocytic generation of reactive oxygen species, which increases sixfold during the development of arthritis. The onset, progression, and remission of arthritis correlated positively to the phorbolester-activated respiratory burst of neutrophils and monocytes, and a dose-dependent inhibition of NADPH oxidase activity was determined with human phagocytes. Our data support the hypothesis that oxidative stress-induced alterations in cellular signal transduction pathways play a pivotal role in the development of arthritis, which can be suppressed by the simultaneous inhibition of poly(ADPR) polymerase and NADPH oxidase.
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PMID:Modulation of inflammatory arthritis by inhibition of poly(ADP ribose) polymerase. 762 65


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