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

---

Query: EC:2.4.2.30 (PARP)
13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamine synthetase from the photosynthetic bacterium Rhodospirillum rubrum is the target of both ATP- and NAD-dependent modification. Incubation of R. rubrum cell supernatant with [alpha-32P]NAD results in the labeling of glutamine synthetase and two other unidentified proteins. Dinitrogenase reductase ADP-ribosyltransferase does not appear to be responsible for the modification of glutamine synthetase or the unidentified proteins. The [alpha-32P]ATP- and [alpha-32P] NAD-dependent modifications of R. rubrum glutamine synthetase appear to be exclusive and the two forms of modified glutamine synthetase are separable on two-dimensional gels. Loss of enzymatic activity by glutamine synthetase did not correlate with [alpha-32P]NAD labeling. This is in contrast to inactivation by nonphysiological ADP-ribosylation of other glutamine synthetases by an NAD:arginine ADP-ribosyltransferase from turkey erythrocytes (Moss, J., Watkins, P.A., Stanley, S.J., Purnell, M.R., and Kidwell, W.R. (1984) J. Biol. Chem. 259, 5100-5104). A 32P-labeled protein spot comigrates with the NAD-treated glutamine synthetase spot when glutamine synthetase purified from H3 32PO4-grown cells is analyzed on two-dimensional gels. The adenylylation site of R. rubrum glutamine synthetase has been determined to be Leu-(Asp)-Tyr-Leu-Pro-Pro-Glu-Glu-Leu-Met; the tyrosine residue is the site of modification.
...
PMID:ATP-dependent and NAD-dependent modification of glutamine synthetase from Rhodospirillum rubrum in vitro. 197 53

Hepatic poly(ADP ribose) polymerase (EC 2.4.2.30) activity as an indicator of DNA damage was measured in rats fed a low methionine, choline-devoid diet (MCD) for a 3-wk period. Additional groups of rats were either injected intraperitoneally (i.p.) with large doses of nicotinamide (NAM) or saline or fed the MCD diet without folic acid (MCFD). As a positive control, some rats were fed the MCD diet supplemented with methionine and choline (MCD + Met). In all groups of methyl donor-deficient rats and associated with increases in hepatic lipid levels, hepatic malondialdehyde concentrations were found to be increased. This observation is evidence for the occurrence of lipid peroxidation in methyl donor deficiency. Methyl donor deficiency was also associated with a significantly elevated hepatic poly(ADP ribose) polymerase activity in all groups of rats as compared to the positive control, suggesting a stimulation of DNA repair processes. The highest enzyme activity was observed in the MCD-NAM i.p. group.
...
PMID:Hepatic poly(ADP ribose) polymerase activity in methyl donor-deficient rats. 253 Dec 22

Exocytosis is a common phenomenon in neutrophil functions. We earlier reported the co-localization of arginine-specific ADP-ribosyltransferase [EC 2.4.2.31] and its target protein p33 (mim-1 protein) in cytoplasmic granules in chicken polymorphonuclear leukocytes (so-called heterophils) [Mishima, K., Terashima, M., Obara, S., Yamada, K., Imai, K., and Shimoyama, M. (1991) J. Biochem. 110, 388-394]. In the present study, we obtained evidence that the transferase and p33 were released into the extracellular space by the stimulus of calcium ionophore A23187 or serum-opsonized zymosan, but scarcely by phorbol myristate acetate (PMA) or N-formyl-Met-Leu-Phe (fMLP), thereby indicating the co-localization of the transferase and p33 in the azurophilic granules, and not in specific granules. [32P]ADP-ribosylation of p33 occurred in the extracellular space, induced by the stimulus of A23187 or opsonized zymosan in the presence of [32P]NAD. Our findings are interpreted to mean that heterophil transferase and p33 may be involved in neutrophil functions during processes of inflammation.
...
PMID:Exocytosis of arginine-specific ADP-ribosyltransferase and p33 induced by A23187 and calcium or serum-opsonized zymosan in chicken polymorphonuclear leukocytes. 901 Jul 72

mRNA from human polymorphonuclear neutrophil leucocytes (PMNs) was probed with cDNA encoding human skeletal muscle arginine-specific ADP-ribosyltransferase (ART1). A single 2.6-kb transcript was identified, which was similar in size to that observed in human skeletal muscle RNA. An 872-bp cDNA fragment, corresponding to the amino acid sequence of the processed human skeletal muscle enzyme, was generated by reverse transcription-PCR amplification of RNA from human PMNs, and was found to be identical to the ART1 cDNA derived from human skeletal muscle. ART1 was expressed as a fusion protein with glutathione S-transferase (GST) in insect cells, and antibodies were raised against the fusion protein in a rabbit. Following removal of GST immunoreactivity by immunoprecipitation, these antibodies were used to measure the abundance of immunoreactive ART1 on the surface of PMNs. Exposure of PMNs to formyl-Met-Leu-Phe (FMLP) was followed by a rapid increase in the abundance of cell surface ART1 (T1/2 = 1.9 min), and the concentration of FMLP for half-maximum response was 28.6 nM. Similar responses were observed after exposure of the cells to platelet-activating factor or interleukin-8, and we conclude that some of the effects of these chemotaxins are mediated by translocation of an intracellular pool of ART1 to its site of catalytic activity on the outer aspect of the plasma membrane.
...
PMID:Chemotaxin-dependent translocation of immunoreactive ADP-ribosyltransferase-1 to the surface of human neutrophil polymorphs. 1009 75

The cabbage butterfly, Pieris rapae, produces an ADP-ribosylating cytotoxic protein, pierisin-1. Unlike other ADP-ribosylating toxins, the acceptor site for ADP-ribosylation by pierisin-1 is the N-2 position of guanine bases in DNA. The present study was designed to characterize this novel guanine-specific ADP-ribosyltransferase, pierisin-1. The N-terminal polypeptide from Met-1 to Arg-233, but not the C-terminal Ser-234-Met-850 polypeptide, was found to exhibit guanine ADP-ribosyltransferase activity. Trypsin-treated pierisin-1, which is considered to be a "nicked" full-length form composed of associated N- and C-terminal fragments, also demonstrated such activity. Optimum conditions for the N-terminal polypeptide of pierisin-1 were pH 8-10, 37-40 degrees C, in the presence of 100-200 mM NaCl or KCl. Other metal ions such as Ca(2+) or Mg(2+) were not required. Kinetic studies demonstrated potent ADP-ribosyltransferase activity with a K(M) value for NAD of 0.17 mM and k(cat) of 55 per second. Under these optimum conditions, the specific activity of trypsin-treated pierisin-1 was about half (k(cat) = 25 per second). When the conditions were changed to pH 5-7 or 10-20 degrees C, some activity (6-55% or 5-20%, respectively, of that under optimal conditions) of the N-terminal polypeptide was still evident; however, almost all of the trypsin-treated enzyme activity disappeared. This implies the inhibition of the N-terminal enzyme domain by the associated C-terminal fragment. Long-term reactions indicated that a single molecule of pierisin-1 has the capacity to generate more than 10(6) ADP-ribosylated DNA adducts, which could cause the death of a mammalian cell.
...
PMID:Enzymatic properties of pierisin-1 and its N-terminal domain, a guanine-specific ADP-ribosyltransferase from the cabbage butterfly. 1511 71

In order to clarify the role of the 1-substituent of quinazoline derivatives in their inhibitory activity against poly(ADP-ribose) polymerase (PARP), two novel inhibitors, 1 [8-hydroxy-1-(3-morpholinopropyl)-quinazoline-2,4(1H,3H)-dione] and 2 [8-hydroxy-1-(3-phenoxypropyl)-quinazoline-2,4(1H,3H)-dione], were synthesized and subjected to X-ray crystal analysis in complex with the PARP C-terminal catalytic domain (PARP-CD), which requires NAD+ coenzyme for biological function. The nicotinamide-mimicking part of the quinazoline skeleton of 1 and 2 were both located at the nicotinamide subsite of the NAD+-binding pocket in the same manner as previously reported inhibitors: three hydrogen bonds [(Gly-863)NH-O12, (Gly-863)O-HN3 and (Ser-904)O(gamma)-O12] and stacking interaction between the Tyr-907 phenol and the quinazoline ring. On the other hand, the N-morpholinoprop-3-yl moiety introduced at the 1-position of the quinazoline ring in 1 bridged the large gap between the donor site and the acceptor site through a (Met-890)NH-O20(morpholine) hydrogen bond, where the donor and the acceptor sites are classified as the binding sites of NAD+ and the ADP moiety of the poly(ADP-ribose) chain, respectively. In contrast, the N-phenoxyprop-3-yl moiety in 2 formed hydrophobic interactions close to the adenosine-binding site of NAD+, unlike the hydrogen bond such as in 1. As the inhibitory activities of 1 and 2 for PARP were much more potent than those of the unsubstituted nicotinamide analogues, these results suggest that the occupation of the proximal region of the ADP phosphate-and adenosine-binding subsite of the donor site or that of the gap between the donor and the acceptor site by the 1-substituent of quinazoline may increase the inhibitory activity considerably. The nearly equal inhibitory activities of 1 and 2, despite of their different binding modes at the active site, indicate that this 1-substituent is promising in improving the bioavailability of the inhibitor without compromising its inhibitory activity.
...
PMID:Binding mode of novel 1-substituted quinazoline derivatives to poly(ADP-ribose) polymerase-catalytic domain, revealed by X-ray crystal structure analysis of complexes. 1663 19

Osteosarcoma (OSA), the most common malignant bone tumor in dogs and children, exhibits a similar clinical presentation and molecular biology in both species. Unfortunately, 30-40% of children and 90% of dogs still die of disease despite aggressive therapy. The purpose of this study was to test the biologic activity of a novel heat shock protein 90 (HSP90) inhibitor, STA-1474, against OSA. Canine and human OSA cell lines and normal canine osteoblasts were treated with STA-1474 and evaluated for effects on proliferation (CyQuant), apoptosis (Annexin V, PARP cleavage, caspase 3/7 activation) and known HSP90 client proteins. HSP90 was immunoprecipitated from normal and malignant osteoblasts and Western blotting for co-chaperones was performed. Mice bearing canine OSA xenografts were treated with STA-1474, and tumors samples were evaluated for caspase-3 activation and loss of p-Akt/Akt. Treatment with STA-1474 promoted loss of cell viability, inhibition of cell proliferation and induction of apoptosis in OSA cell lines. STA-1474 and its active metabolite STA-9090 also demonstrated increased potency compared to 17-AAG. STA-1474 exhibited selectivity for OSA cells versus normal canine osteoblasts, and HSP90 co-precipitated with co-chaperones p23 and Hop in canine OSA cells but not in normal canine osteoblasts. Furthermore, STA-1474 downregulated the expression of p-Met/Met, p-Akt/Akt and p-STAT3. Finally, STA-1474 induced tumor regression, caspase-3 activation and downregulation of p-Met/Met and p-Akt/Akt in OSA xenografts. Together, these data suggest that HSP90 represents a relevant target for therapeutic intervention in OSA.
...
PMID:The novel HSP90 inhibitor STA-1474 exhibits biologic activity against osteosarcoma cell lines. 1954 63

The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models. TA in a dose dependent manner inhibited proliferation and cell viability of two different lung cancer cells, A549 and CRL5803. TA treatment for 48 h significantly decreased the expression of Sp1, Sp3 and Sp4. The hepatocyte growth factor receptor, c-Met is overexpressed in a variety of cancers including lung cancer and Sp proteins mediate the regulation of c-Met. TA diminished the expression of c-Met protein and modulates its downstream signaling pathway. Furthermore, TA treatment significantly increased the number of apoptotic cells and pro-apoptotic markers c-PARP and Bax confirming the activation of apoptotic pathways. In vivo studies using the orthotopic mice model for lung cancer showed that TA (25 mg/kg/2 days and 50 mg/kg/2 days) resulted in a dose dependent decrease in tumor formation. The immunohistochemical staining of lung tissue showed high expression of Sp1, Sp3, Sp4, c-Met and phospho Met in control group and a dose dependent decrease in TA treated groups. The crucial findings of this study support that targeting c-Met with a potent inhibitor of Sp proteins is a robust strategy for the implications in lung cancer treatment and TA can serve as a therapeutic agent for this devastating disease.
...
PMID:Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice. 1985 11

Since several years, the perception of lung cancer has considerably evolved. Indeed, we have proceeded from a simple classification based on histology to a molecular dismemberment, with a lot of subtypes of tumors according to there molecular alteration profile. Mutations of the EGFR receptor define so a group of cancers particularly sensitive to EGFR tyrosine kinase inhibitors (TKI). Gefitinib has shown its efficacy in term of response and survival in first line treatment of NSCLC arboring EGFR mutations. Recently, the ALK-AML4 translocation has been found in approximately 5% of NSCLC, accessible to a specified targeted therapy (crizotinib) with response rate around 60%. NSCLC with HER2 mutation or amplification could be treated with trastuzumab, whereas treatments targeting Met pathway are currently in development. At last, several drugs active in case of DNA repair dysfunction, like PARP inhibitors, have already shown there efficacy in particular types of NSCLC. In a very near future, molecular screening of these molecular alterations should be systematic from the diagnostic, to allow a personalized treatment according to the mutation profile.
...
PMID:[Biomarkers and targeted therapies in non-small cell lung cancer: present and future treatments]. 2177 66

Cadmium is an established human and animal carcinogen. Most evidence is available for elevated risk for lung cancer after occupational exposure; however, associations between cadmium exposure and tumors at other locations including kidney, breast, and prostate may be relevant as well. Furthermore, enhanced cancer risk may not be restricted to comparatively high occupational exposure, but may also occur via environmental exposure, for example in areas in close proximity to zinc smelters. The underlying mechanisms are still a matter of manifold research activities. While direct interactions with DNA appear to be of minor importance, elevated levels of reactive oxygen species (ROS) have been detected in diverse experimental systems, presumably due to an inactivation of detoxifying enzymes. Also, the interference with proteins involved in the cellular response to DNA damage, the deregulation of cell growth as well as resistance to apoptosis appears to be involved in cadmium-induced carcinogenicity. Within this context, cadmium has been shown to disturb nucleotide excision repair, base excision repair, and mismatch repair. Particularly sensitive targets appear to be proteins with zinc-binding structures, present in DNA repair proteins such as XPA, PARP-1 as well as in the tumor suppressor protein p53. Whether or not these interactions are due to displacement of zinc or due to reactions with thiol groups involved in zinc complexation or in other critical positions under realistic exposure conditions remains to be elucidated. Further potential mechanisms relate to the interference with cellular redox regulation, either by enhanced generation of ROS or by reaction with thiol groups involved in the regulation of signaling pathways. Particularly the combination of these multiple mechanisms may give rise to a high degree of genomic instability evident in cadmium-adapted cells, relevant not only for tumor initiation, but also for later steps in tumor development.
Met Ions Life Sci 2013
PMID:Cadmium and cancer. 2343 Jul 82


1 2 Next >>

---