scholarly journals 3′-5′ Phosphoadenosine phosphate is an inhibitor of PARP-1 and a potential mediator of the lithium-dependent inhibition of PARP-1 in vivo

2012 ◽  
Vol 443 (2) ◽  
pp. 485-490 ◽  
Author(s):  
Elie Toledano ◽  
Vasily Ogryzko ◽  
Antoine Danchin ◽  
Daniel Ladant ◽  
Undine Mechold
Keyword(s):  
Potent Inhibitor ◽  
Strand Breaks ◽  
Potential Mediator ◽  
Single Strand Breaks ◽  
Physiological Regulator ◽  
Dependent Inhibition ◽  
Key Enzyme ◽  
Parp 1

pAp (3′-5′ phosphoadenosine phosphate) is a by-product of sulfur and lipid metabolism and has been shown to have strong inhibitory properties on RNA catabolism. In the present paper we report a new target of pAp, PARP-1 [poly(ADP-ribose) polymerase 1], a key enzyme in the detection of DNA single-strand breaks. We show that pAp can interact with PARP-1 and inhibit its poly(ADP-ribosyl)ation activity. In vitro, inhibition of PARP-1 was detectable at micromolar concentrations of pAp and altered both PARP-1 automodification and heteromodification of histones. Analysis of the kinetic parameters revealed that pAp acted as a mixed inhibitor that modulated both the Km and the Vmax of PARP-1. In addition, we showed that upon treatment with lithium, a very potent inhibitor of the enzyme responsible for pAp recycling, HeLa cells exhibited a reduced level of poly(ADP-ribosyl)ation in response to oxidative stress. From these results, we propose that pAp might be a physiological regulator of PARP-1 activity.

Possible Mode of Action of Ticlopidine: A Novel Inhibitor of Platelet Aggregation

1979 ◽  
Author(s):  
H. Johnson ◽  
J. B. Heywood
Keyword(s):  
Platelet Aggregation ◽  
Mode Of Action ◽  
Potent Inhibitor ◽  
Platelet Reactivity ◽  
Inhibitory Effect ◽  
Thromboxane Synthetase ◽  
Sustained Effect ◽  
Dependent Inhibition

Ticlopidine (T) is weakly active in vitro, but is a potent inhibitor of platelet aggregation induced by ADP, collagen, thrombin, adrenaline, arachidonic acid, prostaglandin (PG) endoperoxide and thromboxane A2 with a sustained effect, when administered to a variety of animal species, including man. Platelets from treated animals were normal in ultrastructure and 14C-ADP binding was not modified by T. Basal PG synthesis was unaffected, whereas aspirin (A) had a marked inhibitory effect. Platelet cyclo-oxygenase and thromboxane synthetase activities were 90.6±12.9 and 96.1±5.3% of control following T treatment. In contrast to A, T had no effect on vascularprostacyclin (PGI2) synthesis, this being 1.4±0.1, 0.5±0.1 and 1.3±0. 3ng/mg wet weight aorta in T and A-treated and control animals respectively. Platelets from T-treated rats were significantly more responsive to inhibition by exogenous PGI2 (0.2-4 ng/ml) and PGE1 (4- 20 ng/ml). when compared with controls. T administration (30-300 mg/kg) resulted in a dose-dependent inhibition of ADP-induced platelet aggregation (26.0- 87. 5%) and enhancement of platelet reactivity to PGI2 (37.0-159.8%). There was a good correlation between these parameters (r=+0.994). T is a potent inhibitor of platelet aggregati on with a novel mode of action. It is not aspirin-like, but may act to potentiate endogenous PGI2 in vivo, possibly through an effect on platelet adenylate cyclase.

Compounds of the Cysteine-cysteamine Group and their Influence on Infectivity, Strand Breaks and Base Damage in Gamma-irradiated DNA of Coliphage ΦX-174

1973 ◽  
Vol 28 (7-8) ◽  
pp. 466-470 ◽  
Author(s):  
Günther Stephan ◽  
Gerhart Hotz
Keyword(s):  
Protective Effect ◽  
Sucrose Gradient ◽  
Base Damage ◽  
Rf System ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Radiation Induced ◽  
Gamma Irradiated

Single- and double-stranded (RF) DNA of page ΦX-174 were 60Co-gamma irradiated. Dependence of radiosensitivity on the concentration of cysteamine and cystamine was measured. Radioresistance of DNA in vivo (phage particles) as well as of DNA in vitro (infectious DNA) increase between 10-4 and 10-1 ᴍ of superprotective agents. The same relationship is observed when the DNA is in the dry and in the wet state. By fractionating radiation damaged RFI and radiation induced RFII by means of sucrose gradient sedimentation it was possible to measure the protective effect of cysteamine on lesions other than strand-breaks. A pronounced radioprotective effect of cysteamine on the production of single-strand breaks in RF -DNA was found (DRF 20). The convenience of the RF system for studying effects of radioprotective agents on the occurrence of different radiation induced lesions is discussed.

Manganese-induced single strand breaks of mitochondrial DNA in vitro and in vivo

2008 ◽  
Vol 26 (2) ◽  
pp. 123-127 ◽  
Author(s):  
Jian Jiao ◽  
Yanmin Qi ◽  
Juanling Fu ◽  
Zongcan Zhou
Keyword(s):  
Mitochondrial Dna ◽  
Single Strand ◽  
Strand Breaks ◽  
Single Strand Breaks

scholarly journals Physical and Functional Interaction between DNA Ligase IIIα and Poly(ADP-Ribose) Polymerase 1 in DNA Single-Strand Break Repair

2003 ◽  
Vol 23 (16) ◽  
pp. 5919-5927 ◽  
Author(s):  
John B. Leppard ◽  
Zhiwan Dong ◽  
Zachary B. Mackey ◽  
Alan E. Tomkinson
Keyword(s):  
Dna Repair ◽  
Zinc Finger ◽  
Strand Break ◽  
Single Strand ◽  
Dna Ligase ◽  
Strand Breaks ◽  
Single Strand Breaks ◽  
Parp 1 ◽  
Dna Ligase Iii

ABSTRACT The repair of DNA single-strand breaks in mammalian cells is mediated by poly(ADP-ribose) polymerase 1 (PARP-1), DNA ligase IIIα, and XRCC1. Since these proteins are not found in lower eukaryotes, this DNA repair pathway plays a unique role in maintaining genome stability in more complex organisms. XRCC1 not only forms a stable complex with DNA ligase IIIα but also interacts with several other DNA repair factors. Here we have used affinity chromatography to identify proteins that associate with DNA ligase III. PARP-1 binds directly to an N-terminal region of DNA ligase III immediately adjacent to its zinc finger. In further studies, we have shown that DNA ligase III also binds directly to poly(ADP-ribose) and preferentially associates with poly(ADP-ribosyl)ated PARP-1 in vitro and in vivo. Our biochemical studies have revealed that the zinc finger of DNA ligase III increases DNA joining in the presence of either poly(ADP-ribosyl)ated PARP-1 or poly(ADP-ribose). This provides a mechanism for the recruitment of the DNA ligase IIIα-XRCC1 complex to in vivo DNA single-strand breaks and suggests that the zinc finger of DNA ligase III enables this complex and associated repair factors to locate the strand break in the presence of the negatively charged poly(ADP-ribose) polymer.

scholarly journals Targeting Penicillium expansum GMC Oxidoreductase with High Affinity Small Molecules for Reducing Patulin Production

Biology ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 21
Author(s):  
Vincenzo Tragni ◽  
Pietro Cotugno ◽  
Anna De Grassi ◽  
Maria Maddalena Cavalluzzi ◽  
Annamaria Mincuzzi ◽  
...  
Keyword(s):  
Ring Closure ◽  
Penicillium Expansum ◽  
In Vitro Assays ◽  
High Affinity ◽  
Dependent Inhibition ◽  
Key Enzyme ◽  
Gmc Oxidoreductase ◽  
Comparative Model

Flavine adenine dinucleotide (FAD) dependent glucose methanol choline oxidoreductase (GMC oxidoreductase) is the terminal key enzyme of the patulin biosynthetic pathway. GMC oxidoreductase catalyzes the oxidative ring closure of (E)-ascladiol to patulin. Currently, no protein involved in the patulin biosynthesis in Penicillium expansum has been experimentally characterized or solved by X-ray diffraction. Consequently, nothing is known about P. expansum GMC oxidoreductase substrate-binding site and mode of action. In the present investigation, a 3D comparative model for P. expansum GMC oxidoreductase has been described. Furthermore, a multistep computational approach was used to identify P. expansum GMC oxidoreductase residues involved in the FAD binding and in substrate recognition. Notably, the obtained 3D comparative model of P. expansum GMC oxidoreductase was used for performing a virtual screening of a chemical/drug library, which allowed to predict new GMC oxidoreductase high affinity ligands to be tested in in vitro/in vivo assays. In vitro assays performed in presence of 6-hydroxycoumarin and meticrane, among the highly affinity predicted binders, confirmed a dose-dependent inhibition (17–81%) of patulin production by 6-hydroxycoumarin (10 µM–1 mM concentration range), whereas the approved drug meticrane inhibited patulin production by 43% already at 10 µM. Furthermore, 6-hydroxycoumarin and meticrane caused a 60 and 41% reduction of patulin production, respectively, in vivo on apples at 100 µg/wound.

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