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[PMID]:29343827
[Au] Autor:Page BDG; Valerie NCK; Wright RHG; Wallner O; Isaksson R; Carter M; Rudd SG; Loseva O; Jemth AS; Almlöf I; Font-Mateu J; Llona-Minguez S; Baranczewski P; Jeppsson F; Homan E; Almqvist H; Axelsson H; Regmi S; Gustavsson AL; Lundbäck T; Scobie M; Strömberg K; Stenmark P; Beato M; Helleday T
[Ad] Endereço:Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden. brent.page@scilifelab.se.
[Ti] Título:Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.
[So] Source:Nat Commun;9(1):250, 2018 01 17.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Progestinas/metabolismo
Pirofosfatases/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/metabolismo
Trifosfato de Adenosina/metabolismo
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Feminino
Células HL-60
Seres Humanos
Estrutura Molecular
Pirofosfatases/genética
Pirofosfatases/metabolismo
Interferência de RNA
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Progestins); 20762-30-5 (Adenosine Diphosphate Ribose); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.1.- (NUDT5 protein, human); EC 3.6.1.- (Pyrophosphatases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02293-7


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[PMID]:28837130
[Au] Autor:Bisceglie L; Bartolomei G; Hottiger MO
[Ad] Endereço:Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
[Ti] Título:ADP-ribose-specific chromatin-affinity purification for investigating genome-wide or locus-specific chromatin ADP-ribosylation.
[So] Source:Nat Protoc;12(9):1951-1961, 2017 Sep.
[Is] ISSN:1750-2799
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein ADP-ribosylation is a structurally heterogeneous post-translational modification (PTM) that influences the physicochemical and biological properties of the modified protein. ADP-ribosylation of chromatin changes its structural properties, thereby regulating important nuclear functions. A lack of suitable antibodies for chromatin immunoprecipitation (ChIP) has so far prevented a comprehensive analysis of DNA-associated protein ADP-ribosylation. To analyze chromatin ADP-ribosylation, we recently developed a novel ADP-ribose-specific chromatin-affinity purification (ADPr-ChAP) methodology that uses the recently identified ADP-ribose-binding domains RNF146 WWE and Af1521. In this protocol, we describe how to use this robust and versatile method for genome-wide and loci-specific localization of chromatin ADP-ribosylation. ADPr-ChAP enables bioinformatic comparisons of ADP-ribosylation with other chromatin modifications and is useful for understanding how ADP-ribosylation regulates biologically important cellular processes. ADPr-ChAP takes 1 week and requires standard skills in molecular biology and biochemistry. Although not covered in detail here, this technique can also be combined with conventional ChIP or DNA analysis to define the histone marks specifically associated with the ADP-ribosylated chromatin fractions and dissect the molecular mechanism and functional role of chromatin ADP-ribosylation.
[Mh] Termos MeSH primário: Adenosina Difosfato Ribose/metabolismo
Imunoprecipitação da Cromatina/métodos
Cromatina/isolamento & purificação
Cromatina/metabolismo
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/química
Animais
Linhagem Celular
Cromatina/química
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Chromatin); 20762-30-5 (Adenosine Diphosphate Ribose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170825
[St] Status:MEDLINE
[do] DOI:10.1038/nprot.2017.072


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[PMID]:28820960
[Ti] Título:Principles of Chemical Biology: Iron and CSCs, Histone Acylation sans Enzymes, Eliciting Silent Gene Clusters, and 2'-deoxy-ADPR as a Second Messenger.
[So] Source:Cell Chem Biol;24(8):919-920, 2017 Aug 17.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This month: Lysosomal iron linked to cell death in cancer stem cells, non-enzymatic catalyst SynCAc for histone acylation, cytotoxins ivermectin and etoposide bring new anti-fungals out of the crypt, and 2'-deoxy-ADPR as second messenger activating TRPM2.
[Mh] Termos MeSH primário: Histonas/metabolismo
Ferro/metabolismo
Sistemas do Segundo Mensageiro/fisiologia
[Mh] Termos MeSH secundário: Acilação
Adenosina Difosfato Ribose/análogos & derivados
Adenosina Difosfato Ribose/metabolismo
Seres Humanos
Família Multigênica
Células-Tronco Neoplásicas/citologia
Células-Tronco Neoplásicas/metabolismo
Canais de Cátion TRPM/química
Canais de Cátion TRPM/metabolismo
[Pt] Tipo de publicação:INTRODUCTORY JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histones); 0 (TRPM Cation Channels); 0 (TRPM2 protein, human); 20762-30-5 (Adenosine Diphosphate Ribose); E1UOL152H7 (Iron)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170819
[St] Status:MEDLINE


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[PMID]:28791810
[Au] Autor:Stepnik M; Spryszynska S; Gorzkiewicz A; Ferlinska M
[Ad] Endereço:Department of Toxicology and Carcinogenesis, Nofer Institute of Occupational Medicine, Lódz, Poland.
[Ti] Título:Cytotoxicity of anticancer drugs and PJ-34 (poly(ADP-ribose)polymerase-1 (PARP-1) inhibitor) on HL-60 and Jurkat cells.
[So] Source:Adv Clin Exp Med;26(3):379-385, 2017 May-Jun.
[Is] ISSN:1899-5276
[Cp] País de publicação:Poland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The majority of the clinical trials with poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors were conducted or are ongoing in patients with solid tumors, while trials with leukemia patients are less frequent. Surprisingly scarce data is available on the combinatory effects of PARP inhibitors with DNA damaging antitumor drugs in leukemic cells (primary cells or established lines). OBJECTIVES: The aim of the present study was to assess the effect of PJ-34 (PARP-1 inhibitor) on the cytotoxicity of different antileukemic drugs with different DNA damaging mechanisms and potency (doxorubicin, etoposide, cytarabine and chlorambucil) in human leukemic Jurkat and HL-60 cells. MATERIAL AND METHODS: Different exposure scenarios were applied: 1) 72 h simultaneous incubation with PJ-34 (2.5 or 5 µM for Jurkat and HL-60 cells, respectively) and a drug used at a wide concentration range; 2) preincubation of the cells with PJ-34 for 24 h and then with a combination of PJ-34 + drug for an additional 48 h; 3) preincubation of the cells with the drug for 24 h with a subsequent incubation with a combination of PJ-34 + drug for an additional 48 h. Cytotoxicity was assessed using a WST-1 reduction test. RESULTS: It was determined that PJ-34, when used in all 3 scenarios, did not induce any significant enhancement of cytotoxicity of the drugs either in Jurkat or in HL-60 cells. CONCLUSIONS: Although the results do not confirm the beneficial effects of PARP inhibition in combination treatment of the leukemic cells, we propose that future studies including an additional step with the inhibition of DNA repair by homologous recombination should provide promising results.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Células HL-60/efeitos dos fármacos
Células Jurkat/efeitos dos fármacos
Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores
Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose
Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Dano ao DNA/efeitos dos fármacos
Seres Humanos
Leucemia/tratamento farmacológico
Fenantrenos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride); 0 (Phenanthrenes); 0 (Poly(ADP-ribose) Polymerase Inhibitors); 20762-30-5 (Adenosine Diphosphate Ribose); EC 2.4.2.30 (Poly (ADP-Ribose) Polymerase-1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170810
[St] Status:MEDLINE
[do] DOI:10.17219/acem/60848


  5 / 3086 MEDLINE  
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[PMID]:28671679
[Au] Autor:Fliegert R; Bauche A; Wolf Pérez AM; Watt JM; Rozewitz MD; Winzer R; Janus M; Gu F; Rosche A; Harneit A; Flato M; Moreau C; Kirchberger T; Wolters V; Potter BVL; Guse AH
[Ad] Endereço:The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
[Ti] Título:2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
[So] Source:Nat Chem Biol;13(9):1036-1044, 2017 Sep.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca -permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca entry and, consequently, apoptosis. To date, adenosine 5'-diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2'-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10.4-fold higher whole-cell currents at saturation. Mechanistically, this increased activity was caused by a decreased rate of inactivation and higher average open probability. Using high-performance liquid chromatography (HPLC) and mass spectrometry, we detected endogenous 2'-deoxy-ADPR in Jurkat T lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed the synthesis of 2'-deoxy-ADPR from nicotinamide mononucleotide (NMN) and 2'-deoxy-ATP in vitro. Thus, 2'-deoxy-ADPR is an endogenous TRPM2 superagonist that may act as a cell signaling molecule.
[Mh] Termos MeSH primário: Adenosina Difosfato Ribose/análogos & derivados
Clusterina/agonistas
[Mh] Termos MeSH secundário: ADP-Ribosil Ciclase 1/química
Adenosina Difosfato Ribose/química
Adenosina Difosfato Ribose/farmacologia
Cromatografia Líquida de Alta Pressão
Seres Humanos
Peróxido de Hidrogênio/química
Células Jurkat
Estrutura Molecular
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2'-deoxyadenosine diphosphate ribose); 0 (Clusterin); 20762-30-5 (Adenosine Diphosphate Ribose); BBX060AN9V (Hydrogen Peroxide); EC 3.2.2.6 (ADP-ribosyl Cyclase 1)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2415


  6 / 3086 MEDLINE  
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[PMID]:28652302
[Au] Autor:Hachisuka SI; Sato T; Atomi H
[Ad] Endereço:Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Kyoto, Japan.
[Ti] Título:Metabolism Dealing with Thermal Degradation of NAD in the Hyperthermophilic Archaeon Thermococcus kodakarensis.
[So] Source:J Bacteriol;199(19), 2017 Oct 01.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NAD is an important cofactor for enzymatic oxidation reactions in all living organisms, including (hyper)thermophiles. However, NAD is susceptible to thermal degradation at high temperatures. It can thus be expected that (hyper)thermophiles harbor mechanisms that maintain NAD concentrations and possibly remove and/or reuse undesirable degradation products of NAD Here we confirmed that at 85°C, thermal degradation of NAD results mostly in the generation of nicotinamide and ADP-ribose, the latter known to display toxicity by spontaneously linking to proteins. The hyperthermophilic archaeon possesses a putative ADP-ribose pyrophosphatase (ADPR-PPase) encoded by the TK2284 gene. ADPR-PPase hydrolyzes ADP-ribose to ribose 5-phosphate (R5P) and AMP. The purified recombinant TK2284 protein exhibited activity toward ADP-ribose as well as ADP-glucose. Kinetic analyses revealed a much higher catalytic efficiency toward ADP-ribose, suggesting that ADP-ribose was the physiological substrate. To gain insight into the physiological function of TK2284, a TK2284 gene disruption strain was constructed and examined. Incubation of NAD in the cell extract of the mutant strain at 85°C resulted in higher ADP-ribose accumulation and lower AMP production compared with those in experiments with the host strain cell extract. The mutant strain also exhibited lower cell yield and specific growth rates in a synthetic amino acid medium compared with those of the host strain. The results obtained here suggest that the ADPR-PPase in is responsible for the cleavage of ADP-ribose to R5P and AMP, providing a means to utilize the otherwise dead-end product of NAD breakdown. Hyperthermophilic microorganisms living under high temperature conditions should have mechanisms that deal with the degradation of thermolabile molecules. NAD is an important cofactor for enzymatic oxidation reactions and is susceptible to thermal degradation to ADP-ribose and nicotinamide. Here we show that an ADP-ribose pyrophosphatase homolog from the hyperthermophilic archaeon converts the detrimental ADP-ribose to ribose 5-phosphate and AMP, compounds that can be directed to central carbon metabolism. This physiological role for ADP-ribose pyrophosphatases might be universal in hyperthermophiles, as their homologs are widely distributed among both hyperthermophilic bacteria and archaea.
[Mh] Termos MeSH primário: NAD/metabolismo
Pirofosfatases/metabolismo
Thermococcus/metabolismo
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/metabolismo
Carbono/metabolismo
Genes Bacterianos
Temperatura Alta
Cinética
Mutação
Niacinamida/metabolismo
Pirofosfatases/genética
Proteínas Recombinantes/isolamento & purificação
Proteínas Recombinantes/metabolismo
Thermococcus/enzimologia
Thermococcus/genética
Thermococcus/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); 0U46U6E8UK (NAD); 20762-30-5 (Adenosine Diphosphate Ribose); 25X51I8RD4 (Niacinamide); 7440-44-0 (Carbon); EC 3.6.1.- (Pyrophosphatases); EC 3.6.1.13 (ADPribose pyrophosphatase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE


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[PMID]:28640600
[Au] Autor:Plapp BV; Savarimuthu BR; Ferraro DJ; Rubach JK; Brown EN; Ramaswamy S
[Ad] Endereço:Department of Biochemistry, The University of Iowa , Iowa City, Iowa 52242, United States.
[Ti] Título:Horse Liver Alcohol Dehydrogenase: Zinc Coordination and Catalysis.
[So] Source:Biochemistry;56(28):3632-3646, 2017 Jul 18.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:During catalysis by liver alcohol dehydrogenase (ADH), a water bound to the catalytic zinc is replaced by the oxygen of the substrates. The mechanism might involve a pentacoordinated zinc or a double-displacement reaction with participation by a nearby glutamate residue, as suggested by studies of human ADH3, yeast ADH1, and some other tetrameric ADHs. Zinc coordination and participation of water in the enzyme mechanism were investigated by X-ray crystallography. The apoenzyme and its complex with adenosine 5'-diphosphoribose have an open protein conformation with the catalytic zinc in one position, tetracoordinated by Cys-46, His-67, Cys-174, and a water molecule. The bidentate chelators 2,2'-bipyridine and 1,10-phenanthroline displace the water and form a pentacoordinated zinc. The enzyme-NADH complex has a closed conformation similar to that of ternary complexes with coenzyme and substrate analogues; the coordination of the catalytic zinc is similar to that found in the apoenzyme, except that a minor, alternative position for the catalytic zinc is ∼1.3 Šfrom the major position and closer to Glu-68, which could form the alternative coordination to the catalytic zinc. Complexes with NADH and N-1-methylhexylformamide or N-benzylformamide (or with NAD and fluoro alcohols) have the classical tetracoordinated zinc, and no water is bound to the zinc or the nicotinamide rings. The major forms of the enzyme in the mechanism have a tetracoordinated zinc, where the carboxylate group of Glu-68 could participate in the exchange of water and substrates on the zinc. Hydride transfer in the Michaelis complexes does not involve a nearby water.
[Mh] Termos MeSH primário: Álcool Desidrogenase/metabolismo
Fígado/enzimologia
Zinco/metabolismo
[Mh] Termos MeSH secundário: 2,2'-Dipiridil/metabolismo
Adenosina Difosfato Ribose/metabolismo
Álcool Desidrogenase/química
Animais
Domínio Catalítico
Cristalografia por Raios X
Formamidas/metabolismo
Cavalos
Cinética
Fígado/metabolismo
Modelos Moleculares
NAD/metabolismo
Fenantrolinas/metabolismo
Ligação Proteica
Conformação Proteica
Água/química
Água/metabolismo
Zinco/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Formamides); 0 (N-benzylformamide); 0 (Phenanthrolines); 059QF0KO0R (Water); 0U46U6E8UK (NAD); 20762-30-5 (Adenosine Diphosphate Ribose); 551W113ZEP (2,2'-Dipyridyl); EC 1.1.1.1 (Alcohol Dehydrogenase); J41CSQ7QDS (Zinc); W4X6ZO7939 (1,10-phenanthroline)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170804
[Lr] Data última revisão:
170804
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170623
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00446


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[PMID]:28525742
[Au] Autor:Yang CS; Jividen K; Spencer A; Dworak N; Ni L; Oostdyk LT; Chatterjee M; Kusmider B; Reon B; Parlak M; Gorbunova V; Abbas T; Jeffery E; Sherman NE; Paschal BM
[Ad] Endereço:Center for Cell Signaling, University of Virginia, West Complex, 1335 Lee Street, Charlottesville, VA 22908, USA.
[Ti] Título:Ubiquitin Modification by the E3 Ligase/ADP-Ribosyltransferase Dtx3L/Parp9.
[So] Source:Mol Cell;66(4):503-516.e5, 2017 May 18.
[Is] ISSN:1097-4164
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ADP-ribosylation of proteins is emerging as an important regulatory mechanism. Depending on the family member, ADP-ribosyltransferases either conjugate a single ADP-ribose to a target or generate ADP-ribose chains. Here we characterize Parp9, a mono-ADP-ribosyltransferase reported to be enzymatically inactive. Parp9 undergoes heterodimerization with Dtx3L, a histone E3 ligase involved in DNA damage repair. We show that the Dtx3L/Parp9 heterodimer mediates NAD -dependent mono-ADP-ribosylation of ubiquitin, exclusively in the context of ubiquitin processing by E1 and E2 enzymes. Dtx3L/Parp9 ADP-ribosylates the carboxyl group of Ub Gly76. Because Gly76 is normally used for Ub conjugation to substrates, ADP-ribosylation of the Ub carboxyl terminus precludes ubiquitylation. Parp9 ADP-ribosylation activity therefore restrains the E3 function of Dtx3L. Mutation of the NAD binding site in Parp9 increases the DNA repair activity of the heterodimer. Moreover, poly(ADP-ribose) binding to the Parp9 macrodomains increases E3 activity. Dtx3L heterodimerization with Parp9 enables NAD and poly(ADP-ribose) regulation of E3 activity.
[Mh] Termos MeSH primário: Adenosina Difosfato Ribose/metabolismo
Proteínas de Neoplasias/metabolismo
Neoplasias/enzimologia
Poli(ADP-Ribose) Polimerases/metabolismo
Ubiquitina-Proteína Ligases/metabolismo
Ubiquitina/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Reparo do DNA
Células HEK293
Seres Humanos
Mutação
NAD/metabolismo
Proteínas de Neoplasias/genética
Neoplasias/genética
Neoplasias/patologia
Poli(ADP-Ribose) Polimerases/genética
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Interferência de RNA
Fatores de Tempo
Transfecção
Ubiquitina-Proteína Ligases/genética
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Neoplasm Proteins); 0 (PARP9 protein, human); 0 (Ubiquitin); 0U46U6E8UK (NAD); 20762-30-5 (Adenosine Diphosphate Ribose); EC 2.3.2.27 (DTX3L protein, human); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.4.2.30 (Poly(ADP-ribose) Polymerases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE


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[PMID]:28520971
[Au] Autor:Bonfiglio JJ; Colby T; Matic I
[Ad] Endereço:Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse 9b, Cologne 50931, Germany.
[Ti] Título:Mass spectrometry for serine ADP-ribosylation? Think o-glycosylation!
[So] Source:Nucleic Acids Res;45(11):6259-6264, 2017 Jun 20.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein ADP-ribosylation (ADPr), a biologically and clinically important post-translational modification, exerts its functions by targeting a variety of different amino acids. Its repertoire recently expanded to include serine ADPr, which is emerging as an important and widespread signal in the DNA damage response. Chemically, serine ADPr (and more generally o-glycosidic ADPr) is a form of o-glycosylation, and its extreme lability renders it practically invisible to standard mass spectrometry approaches, often leading to erroneous localizations. The knowledge from the mature field of o-glycosation and our own initial difficulties with mass spectrometric analyzes of serine ADPr suggest how to avoid these misidentifications and fully explore the scope of o-glycosidic ADPr in DNA damage response and beyond.
[Mh] Termos MeSH primário: Espectrometria de Massas/métodos
Processamento de Proteína Pós-Traducional
Serina/química
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/química
Sequência de Aminoácidos
Dano ao DNA
Reações Falso-Negativas
Glicosilação
Seres Humanos
Análise de Sequência de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
20762-30-5 (Adenosine Diphosphate Ribose); 452VLY9402 (Serine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx446


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[PMID]:28515263
[Au] Autor:Fliegert R; Watt JM; Schöbel A; Rozewitz MD; Moreau C; Kirchberger T; Thomas MP; Sick W; Araujo AC; Harneit A; Potter BVL; Guse AH
[Ad] Endereço:The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
[Ti] Título:Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349.
[So] Source:Biochem J;474(13):2159-2175, 2017 Jun 16.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:TRPM2 (transient receptor potential channel, subfamily melastatin, member 2) is a Ca -permeable non-selective cation channel activated by the binding of adenosine 5'-diphosphoribose (ADPR) to its cytoplasmic NUDT9H domain (NUDT9 homology domain). Activation of TRPM2 by ADPR downstream of oxidative stress has been implicated in the pathogenesis of many human diseases, rendering TRPM2 an attractive novel target for pharmacological intervention. However, the structural basis underlying this activation is largely unknown. Since ADP (adenosine 5'-diphosphate) alone did not activate or antagonize the channel, we used a chemical biology approach employing synthetic analogues to focus on the role of the ADPR terminal ribose. All novel ADPR derivatives modified in the terminal ribose, including that with the seemingly minor change of methylating the anomeric-OH, abolished agonist activity at TRPM2. Antagonist activity improved as the terminal substituent increasingly resembled the natural ribose, indicating that gating by ADPR might require specific interactions between hydroxyl groups of the terminal ribose and the NUDT9H domain. By mutating amino acid residues of the NUDT9H domain, predicted by modelling and docking to interact with the terminal ribose, we demonstrate that abrogating hydrogen bonding of the amino acids Arg1433 and Tyr1349 interferes with activation of the channel by ADPR. Taken together, using the complementary experimental approaches of chemical modification of the ligand and site-directed mutagenesis of TRPM2, we demonstrate that channel activation critically depends on hydrogen bonding of Arg1433 and Tyr1349 with the terminal ribose. Our findings allow for a more rational design of novel TRPM2 antagonists that may ultimately lead to compounds of therapeutic potential.
[Mh] Termos MeSH primário: Adenosina Difosfato Ribose/metabolismo
Arginina/metabolismo
Canais de Cátion TRPM/metabolismo
Tirosina/metabolismo
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/química
Adenosina Difosfato Ribose/genética
Sequência de Aminoácidos
Arginina/química
Arginina/genética
Cálcio/metabolismo
Sinalização do Cálcio
Células HEK293
Seres Humanos
Ativação do Canal Iônico
Mutagênese Sítio-Dirigida
Mutação/genética
Técnicas de Patch-Clamp
Ligação Proteica
Conformação Proteica
Pirofosfatases/metabolismo
Homologia de Sequência de Aminoácidos
Canais de Cátion TRPM/química
Canais de Cátion TRPM/genética
Tirosina/química
Tirosina/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (TRPM Cation Channels); 0 (TRPM2 protein, human); 20762-30-5 (Adenosine Diphosphate Ribose); 42HK56048U (Tyrosine); 94ZLA3W45F (Arginine); EC 3.6.1.- (NUDT9); EC 3.6.1.- (Pyrophosphatases); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20170091



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