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Pesquisa : D08.811.277.151.350 [Categoria DeCS]
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  1 / 223 MEDLINE  
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[PMID]:25644820
[Au] Autor:Morbini P; Capello GL; Alberizzi P; Benazzo M; Paglino C; Comoli P; Pedrazzoli P
[Ad] Endereço:Department of Molecular Medicine, Unit of Pathology, University of Pavia and Department of Pathology IRCCS Policlinico S. Matteo Foundation, Pavia, Italy. patrizia.morbini@unipv.it.
[Ti] Título:Markers of squamocolumnar junction cells in normal tonsils and oropharyngeal cancer with and without HPV infection.
[So] Source:Histol Histopathol;30(7):833-9, 2015 Jul.
[Is] ISSN:1699-5848
[Cp] País de publicação:Spain
[La] Idioma:eng
[Ab] Resumo:HPV infection has been identified recently as the causative agent of a subset of squamous cell carcinomas arising in oropharyngeal tonsils. Factors influencing the susceptibility of tonsillar epithelium to HPV-induced oncogenesis are far from being elucidated. A 5-protein signature including cytokeratin (CK)7, anterior gradient (AGR)2, cluster differentiation (CD)63, matrix metalloproteinase (MMP)7, and guanine deaminase (GDA) has recently been found to identify a residual embryonic cell population in the squamocolumnar (SC) junction of the cervix, susceptible to HPV infection, and cancers originating from these cells. The expression of SC junction markers was investigated with immunohistochemistry in normal tonsils and in oropharyngeal carcinomas (OPC) fully characterised for HPV. All markers were constantly expressed in the reticulated epithelial cells of the tonsillar crypts, with variable diffusion and intensity; in OPC, positivity was observed in 36,5%, 29,2%, 39%, 17%, and 25% of cases with respectively AGR2, CK7, GDA, CD63, and MMP7 antibodies. No OPC was positive for all markers; 6 were completely negative. AGR2 and CK7 showed significant association with tumor- and HPV-related parameters. AGR2 expression was associated with tumor origin in the tongue base (p=0.013); CK7 was associated with non-keratinising morphology (p=0.013). p16 tumor cell expression was associated with AGR2 (p=0.021); transcriptionally active HPV infection was associated with AGR2 and CK7 (p=0.024 and 0.043). Expression of SC junction markers in tonsillar crypt cells might be related to the embryological development of tonsillar structures; their partial association with HPV oncogenic infection could help to identify HPV-susceptible cells and related OPC.
[Mh] Termos MeSH primário: Carcinoma de Células Escamosas/etiologia
Carcinoma de Células Escamosas/metabolismo
Neoplasias Orofaríngeas/etiologia
Neoplasias Orofaríngeas/metabolismo
Tonsila Palatina/metabolismo
Infecções por Papillomavirus/complicações
Infecções por Papillomavirus/metabolismo
[Mh] Termos MeSH secundário: Biomarcadores/metabolismo
Carcinoma de Células Escamosas/patologia
Feminino
Guanina Desaminase/metabolismo
Seres Humanos
Imuno-Histoquímica
Queratina-7/metabolismo
Masculino
Metaloproteinase 7 da Matriz/metabolismo
Meia-Idade
Neoplasias Orofaríngeas/patologia
Tonsila Palatina/citologia
Papillomaviridae/patogenicidade
Infecções por Papillomavirus/patologia
Proteínas/metabolismo
Tetraspanina 30/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Biomarkers); 0 (CD63 protein, human); 0 (GDA protein, human); 0 (Keratin-7); 0 (Proteins); 0 (Tetraspanin 30); EC 3.4.24.23 (MMP7 protein, human); EC 3.4.24.23 (Matrix Metalloproteinase 7); EC 3.5.4.3 (Guanine Deaminase); EC 5.3.4.1 (AGR2 protein, human)
[Em] Mês de entrada:1604
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150204
[St] Status:MEDLINE
[do] DOI:10.14670/HH-11-590


  2 / 223 MEDLINE  
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[PMID]:24775806
[Au] Autor:Ribeiro JV; Cerqueira NM; Fernandes PA; Ramos MJ
[Ad] Endereço:REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre s/n, Porto, 4169-007, Portugal.
[Ti] Título:CHEM-PATH-TRACKER: An automated tool to analyze chemical motifs in molecular structures.
[So] Source:Chem Biol Drug Des;84(1):44-53, 2014 Jul.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In this article, we propose a method for locating functionally relevant chemical motifs in protein structures. The chemical motifs can be a small group of residues or structure protein fragments with highly conserved properties that have important biological functions. However, the detection of chemical motifs is rather difficult because they often consist of a set of amino acid residues separated by long, variable regions, and they only come together to form a functional group when the protein is folded into its three-dimensional structure. Furthermore, the assemblage of these residues is often dependent on non-covalent interactions among the constituent amino acids that are difficult to detect or visualize. To simplify the analysis of these chemical motifs and give access to a generalized use for all users, we developed chem-path-tracker. This software is a VMD plug-in that allows the user to highlight and reveal potential chemical motifs requiring only a few selections. The analysis is based on atoms/residues pair distances applying a modified version of Dijkstra's algorithm, and it makes possible to monitor the distances of a large pathway, even during a molecular dynamics simulation. This tool turned out to be very useful, fast, and user-friendly in the performed tests. The chem-path-tracker package is distributed as an independent platform and can be found at http://www.fc.up.pt/PortoBioComp/database/doku.php?id=chem-path-tracker.
[Mh] Termos MeSH primário: Algoritmos
Domínios e Motivos de Interação entre Proteínas
Proteínas/química
Software
[Mh] Termos MeSH secundário: Animais
Aquaporina 4/química
Guanina Desaminase/química
Seres Humanos
Transferases Intramoleculares/química
Modelos Moleculares
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Aquaporin 4); 0 (Proteins); EC 3.5.4.3 (Guanine Deaminase); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.7 (lanosterol synthase)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:140620
[Lr] Data última revisão:
140620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140430
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12349


  3 / 223 MEDLINE  
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[PMID]:24481069
[Au] Autor:Trautwein-Schult A; Jankowska D; Cordes A; Hoferichter P; Klein C; Matros A; Mock HP; Baronian K; Bode R; Kunze G
[Ad] Endereço:Leibniz Institute of Plant Genetics and Crop Plant Research (IPK), Gatersleben, Germany.
[Ti] Título:Arxula adeninivorans recombinant guanine deaminase and its application in the production of food with low purine content.
[So] Source:J Mol Microbiol Biotechnol;24(2):67-81, 2014.
[Is] ISSN:1660-2412
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Purines of exogenous and endogenous sources are degraded to uric acid in human beings. Concentrations >6.8 mg uric acid/dl serum cause hyperuricemia and its symptoms. Pharmaceuticals and the reduction of the intake of purine-rich food are used to control uric acid levels. A novel approach to the latter proposition is the enzymatic reduction of the purine content of food by purine-degrading enzymes. Here we describe the production of recombinant guanine deaminase by the yeast Arxula adeninivorans LS3 and its application in food. In media supplemented with nitrogen sources hypoxanthine or adenine, guanine deaminase (AGDA) gene expression is induced and intracellular accumulation of guanine deaminase (Agdap) protein occurs. The characteristics of the guanine deaminase isolated from wild-type strain LS3 and a transgenic strain expressing the AGDA gene under control of the strong constitutive TEF1 promoter were determined and compared. Both enzymes were dimeric and had temperature optima of 55°C with high substrate specificity for guanine and localisation in both the cytoplasm and vacuole of yeast. The enzyme was demonstrated to reduce levels of guanine in food. A mixture of guanine deaminase and other purine degradation enzymes will allow the reduction of purines in purine-rich foods.
[Mh] Termos MeSH primário: Microbiologia de Alimentos
Guanina Desaminase/metabolismo
Purinas/análise
Saccharomycetales/enzimologia
[Mh] Termos MeSH secundário: Estabilidade Enzimática
Análise de Alimentos
Guanina Desaminase/química
Guanina Desaminase/genética
Multimerização Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Saccharomycetales/genética
Especificidade por Substrato
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Purines); 0 (Recombinant Proteins); EC 3.5.4.3 (Guanine Deaminase); W60KTZ3IZY (purine)
[Em] Mês de entrada:1501
[Cu] Atualização por classe:140606
[Lr] Data última revisão:
140606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140201
[St] Status:MEDLINE
[do] DOI:10.1159/000357674


  4 / 223 MEDLINE  
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[PMID]:24083949
[Au] Autor:Bitra A; Biswas A; Anand R
[Ad] Endereço:Department of Chemistry, Indian Institute of Technology , Mumbai 400076, India.
[Ti] Título:Structural basis of the substrate specificity of cytidine deaminase superfamily Guanine deaminase.
[So] Source:Biochemistry;52(45):8106-14, 2013 Nov 12.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Guanine deaminases (GDs) are important enzymes involved in purine metabolism as well as nucleotide anabolism pathways that exhibit a high degree of fidelity. Here, the structural basis of the substrate specificity of GDs was investigated by determining a series of X-ray structures of NE0047 (GD from Nitrosomonas europaea) with nucleobase analogues and nucleosides. The structures demonstrated that the interactions in the GD active site are tailor-made to accommodate only guanine and any substitutions in the purine ring or introduction of a pyrimidine ring results in rearrangement of the bases in a catalytically unfavorable orientation, away from the proton shuttling residue E143. In addition, X-ray structural studies performed on cytidine revealed that although it binds in an optimal conformation, its deamination does not occur because of the inability of the enzyme to orchestrate the closure of the catalytically important C-terminal loop (residues 181-189). Isothermal calorimetry measurements established that these nucleoside moieties also disrupt the sequential mode of ligand binding, thereby abrogating all intersubunit communication. Intriguingly, it was recently discovered that GDs can also serve as endogenous ammeline deaminases, although it is structurally nonhomologous with guanine. To understand the mechanism of dual-substrate specificity, the structure of NE0047 in complex with ammeline was determined to a resolution of 2.7 Å. The structure revealed that ammeline not only fits in the active site in a catalytically favorable orientation but also allows for closure of the C-terminal loop.
[Mh] Termos MeSH primário: Citidina Desaminase/química
Citidina Desaminase/metabolismo
Guanina Desaminase/química
Guanina Desaminase/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Catálise
Cristalografia por Raios X
Estrutura Molecular
Ligação Proteica
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 3.5.4.3 (Guanine Deaminase); EC 3.5.4.5 (Cytidine Deaminase)
[Em] Mês de entrada:1401
[Cu] Atualização por classe:131112
[Lr] Data última revisão:
131112
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131003
[St] Status:MEDLINE
[do] DOI:10.1021/bi400818e


  5 / 223 MEDLINE  
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[PMID]:23891230
[Au] Autor:Tantravedi S; Chakraborty S; Shah NH; Fishbein JC; Hosmane RS
[Ad] Endereço:Laboratory for Drug Design & Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
[Ti] Título:Analogs of iso-azepinomycin as potential transition-state analog inhibitors of guanase: synthesis, biochemical screening, and structure-activity correlations of various selectively substituted imidazo[4,5-e][1,4]diazepines.
[So] Source:Bioorg Med Chem;21(17):4893-903, 2013 Sep 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Guanase is an important enzyme of the purine salvage pathway of nucleic acid metabolism and its inhibition has beneficial implications in viral, bacterial, and cancer therapy. The work described herein is based on a hypothesis that azepinomycin, a heterocyclic natural product and a purported transition state analog inhibitor of guanase, does not represent the true transition state of the enzyme-catalyzed reaction as closely as does iso-azepinomycin, wherein the 6-hydroxy group of azepinomycin has been translocated to the 5-position. Based on this hypothesis, and assuming that iso-azepinomycin would bind to guanase at the same active site as azepinomycin, several analogs of iso-azepinomycin were designed and successfully synthesized in order to gain a preliminary understanding of the hydrophobic and hydrophilic sites surrounding the guanase binding site of the ligand. Specifically, the analogs were designed to explore the hydrophobic pockets, if any, in the vicinity of N1, N3, and N4 nitrogen atoms as well as O(5) oxygen atom of iso-azepinomycin. Biochemical inhibition studies of these analogs were performed using a mammalian guanase. Our results indicate that (1) increasing the hydrophobicity near O(5) results in a negative effect, (2) translocating the hydrophobicity from N3 to N1 also results in decreased inhibition, (3) increasing the hydrophobicity near N3 or N4 produces significant enhancement of inhibition, (4) increasing the hydrophobicity at either N3 or N4 with a simultaneous increase in hydrophobicity at O(5) considerably diminishes any gain in inhibition made by solely enhancing hydrophobicity at N3 or N4, and (5) finally, increasing the hydrophilic character near N3 has also a deleterious effect on inhibition. The most potent compound in the series has a Ki value of 8.0±1.5µM against rabbit liver guanase.
[Mh] Termos MeSH primário: Azepinas/química
Inibidores Enzimáticos/síntese química
Guanina Desaminase/antagonistas & inibidores
Imidazóis/química
[Mh] Termos MeSH secundário: Animais
Azepinas/síntese química
Azepinas/metabolismo
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Guanina Desaminase/metabolismo
Isomerismo
Cinética
Fígado/enzimologia
Ligação Proteica
Coelhos
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Azepines); 0 (Enzyme Inhibitors); 0 (Imidazoles); 7GBN705NH1 (imidazole); 89354-15-4 (azepinomycin); EC 3.5.4.3 (Guanine Deaminase)
[Em] Mês de entrada:1403
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130730
[St] Status:MEDLINE


  6 / 223 MEDLINE  
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[PMID]:23838888
[Au] Autor:Braunschweig D; Krakowiak P; Duncanson P; Boyce R; Hansen RL; Ashwood P; Hertz-Picciotto I; Pessah IN; Van de Water J
[Ad] Endereço:Department of Internal Medicine, University of California at Davis, Davis, CA, USA.
[Ti] Título:Autism-specific maternal autoantibodies recognize critical proteins in developing brain.
[So] Source:Transl Psychiatry;3:e277, 2013 Jul 09.
[Is] ISSN:2158-3188
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Autism spectrum disorders (ASDs) are neurodevelopmental in origin, affecting an estimated 1 in 88 children in the United States. We previously described ASD-specific maternal autoantibodies that recognize fetal brain antigens. Herein, we demonstrate that lactate dehydrogenase A and B (LDH), cypin, stress-induced phosphoprotein 1 (STIP1), collapsin response mediator proteins 1 and 2 (CRMP1, CRMP2) and Y-box-binding protein to comprise the seven primary antigens of maternal autoantibody-related (MAR) autism. Exclusive reactivity to specific antigen combinations was noted in 23% of mothers of ASD children and only 1% of controls. ASD children from mothers with specific reactivity to LDH, STIP1 and CRMP1 and/or cypin (7% vs 0% in controls; P<0.0002; odds ratios of 24.2 (95% confidence interval: 1.45-405)) had elevated stereotypical behaviors compared with ASD children from mothers lacking these antibodies. We describe the first panel of clinically significant biomarkers with over 99% specificity for autism risk thereby advancing our understanding of the etiologic mechanisms and therapeutic possibilities for MAR autism.
[Mh] Termos MeSH primário: Transtorno Autístico/imunologia
Autoanticorpos/imunologia
Encéfalo/crescimento & desenvolvimento
Proteínas do Tecido Nervoso/imunologia
[Mh] Termos MeSH secundário: Especificidade de Anticorpos/imunologia
Western Blotting
Encéfalo/imunologia
Criança
Eletroforese em Gel Bidimensional
Feminino
Guanina Desaminase/imunologia
Seres Humanos
Peptídeos e Proteínas de Sinalização Intercelular/imunologia
Isoenzimas/imunologia
L-Lactato Desidrogenase/imunologia
Troca Materno-Fetal/imunologia
Gravidez
Comportamento Estereotipado
Proteína 1 de Ligação a Y-Box/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Autoantibodies); 0 (CRMP1 protein, human); 0 (GDA protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (Isoenzymes); 0 (Nerve Tissue Proteins); 0 (Y-Box-Binding Protein 1); 0 (YBX1 protein, human); 0 (collapsin response mediator protein-2); EC 1.1.1.27 (L-Lactate Dehydrogenase); EC 1.1.1.27.- (lactate dehydrogenase 1); EC 1.1.1.27.- (lactate dehydrogenase 5); EC 3.5.4.3 (Guanine Deaminase)
[Em] Mês de entrada:1312
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130711
[St] Status:MEDLINE
[do] DOI:10.1038/tp.2013.50


  7 / 223 MEDLINE  
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[PMID]:23557066
[Au] Autor:Bitra A; Hussain B; Tanwar AS; Anand R
[Ad] Endereço:Department of Chemistry, IIT Bombay , Mumbai, India 400076.
[Ti] Título:Identification of function and mechanistic insights of guanine deaminase from Nitrosomonas europaea: role of the C-terminal loop in catalysis.
[So] Source:Biochemistry;52(20):3512-22, 2013 May 21.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:NE0047 from Nitrosomonas europaea has been annotated as a zinc-dependent deaminase; however, the substrate specificity is unknown because of the low level of structural similarity and sequence identity compared to other family members. In this study, the function of NE0047 was established as a guanine deaminase (catalytic efficiency of 1.2 × 10(5) M(-1) s(-1)), exhibiting secondary activity towards ammeline. The structure of NE0047 in the presence of the substrate analogue 8-azaguanine was also determined to a resolution of 1.9 Å. NE0047 crystallized as a homodimer in an asymmetric unit. It was found that the extreme nine-amino acid C-terminal loop forms an active site flap; in one monomer, the flap is in the closed conformation and in the other in the open conformation with this loop region exposed to the solvent. Calorimetric data obtained using the full-length version of the enzyme fit to a sequential binding model, thus supporting a cooperative mode of ligand occupancy. In contrast, the mutant form of the enzyme (ΔC) with the deletion of the extreme nine amino acids follows an independent model of ligand occupancy. In addition, the ΔC mutant also does not exhibit any enzyme activity. Therefore, we propose that the progress of the reaction is communicated via changes in the conformation of the C-terminal flap and the closed form of the enzyme is the catalytically active form, while the open form allows for product release. The catalytic mechanism of deamination was also investigated, and we found that the mutagenesis of the highly conserved active site residues Glu79 and Glu143 resulted in a complete loss of activity and concluded that they facilitate the reaction by serving as proton shuttles.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Guanina Desaminase/química
Nitrosomonas europaea/enzimologia
[Mh] Termos MeSH secundário: Proteínas de Bactérias/metabolismo
Catálise
Domínio Catalítico
Guanina Desaminase/metabolismo
Ligantes
Modelos Moleculares
Nitrosomonas europaea/metabolismo
Conformação Proteica
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Ligands); EC 3.5.4.3 (Guanine Deaminase)
[Em] Mês de entrada:1402
[Cu] Atualização por classe:131205
[Lr] Data última revisão:
131205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130406
[St] Status:MEDLINE
[do] DOI:10.1021/bi400068g


  8 / 223 MEDLINE  
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[PMID]:23084905
[Au] Autor:Chakraborty S; Shah NH; Fishbein JC; Hosmane RS
[Ad] Endereço:Laboratory for Drug Design and Synthesis, Department of Chemistry & Biochemistry, University of Maryland, Baltimore County, 1000 Hilltop Circle, Baltimore, Maryland 21250, USA.
[Ti] Título:Investigations into specificity of azepinomycin for inhibition of guanase: discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues.
[So] Source:Bioorg Med Chem Lett;22(23):7214-8, 2012 Dec 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In our long and broad program to explore structure-activity relationships of the natural product azepinomycin and its analogues for inhibition of guanase, an important enzyme of purine salvage pathway of nucleic acid metabolism, it became necessary to investigate if the nucleoside analogues of the heterocycle azepinomycin, which are likely to be formed in vivo, would be more or less potent than the parent heterocycle. To this end, we have resynthesized both azepinomycin (1) and its two diastereomeric nucleoside analogues (2 and 3), employing a modified, more efficient procedure, and have biochemically screened all three compounds against a mammalian guanase. Our results indicate that the natural product is at least 200 times more potent toward inhibition of guanase as compared with its nucleoside analogues, with the observed K(i) of azepinomycin (1) against the rabbit liver guanase=2.5 (±0.6)×10(-6) M, while K(i) of Compound 2=1.19 (±0.02)×10(-4) M and that of Compound 3=1.29 (±0.03)×10(-4) M. It is also to be noted that while IC(50) value of azepinomycin against guanase in cell culture has long been reported, no inhibition studies nor K(i) against a pure mammalian enzyme have ever been documented. In addition, we have, for the first time, determined the absolute stereochemistry of the 6-OH group of 2 and 3 using conformational analysis coupled with 2-D (1)H NMR NOESY.
[Mh] Termos MeSH primário: Azepinas/química
Inibidores Enzimáticos/síntese química
Guanina Desaminase/antagonistas & inibidores
Compostos Heterocíclicos/química
Nucleosídeos/síntese química
[Mh] Termos MeSH secundário: Animais
Azepinas/síntese química
Azepinas/isolamento & purificação
Cromatografia Líquida de Alta Pressão
Inibidores Enzimáticos/química
Inibidores Enzimáticos/isolamento & purificação
Guanina Desaminase/metabolismo
Compostos Heterocíclicos/síntese química
Compostos Heterocíclicos/isolamento & purificação
Cinética
Fígado/enzimologia
Espectroscopia de Ressonância Magnética
Conformação Molecular
Nucleosídeos/química
Nucleosídeos/isolamento & purificação
Coelhos
Estereoisomerismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Azepines); 0 (Enzyme Inhibitors); 0 (Heterocyclic Compounds); 0 (Nucleosides); 89354-15-4 (azepinomycin); EC 3.5.4.3 (Guanine Deaminase)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:121023
[St] Status:MEDLINE


  9 / 223 MEDLINE  
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[PMID]:22662200
[Au] Autor:Egeblad L; Welin M; Flodin S; Gräslund S; Wang L; Balzarini J; Eriksson S; Nordlund P
[Ad] Endereço:Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden.
[Ti] Título:Pan-pathway based interaction profiling of FDA-approved nucleoside and nucleobase analogs with enzymes of the human nucleotide metabolism.
[So] Source:PLoS One;7(5):e37724, 2012.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To identify interactions a nucleoside analog library (NAL) consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of "off target effects." However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA) and uridine phosphorylase 1 (UPP1). An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔT(agg) around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.
[Mh] Termos MeSH primário: Nucleosídeos/metabolismo
Nucleotídeos/metabolismo
[Mh] Termos MeSH secundário: Desenho de Drogas
Ensaios Enzimáticos/métodos
Enzimas/metabolismo
Guanina Desaminase/química
Guanina Desaminase/metabolismo
Seres Humanos
Cinética
Redes e Vias Metabólicas
Nucleosídeos/química
Nucleotídeos/química
Ribonucleotídeo Redutases/química
Ribonucleotídeo Redutases/metabolismo
Uridina Fosforilase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzymes); 0 (Nucleosides); 0 (Nucleotides); EC 1.17.4.- (Ribonucleotide Reductases); EC 2.4.2.3 (Uridine Phosphorylase); EC 3.5.4.3 (Guanine Deaminase)
[Em] Mês de entrada:1212
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120605
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0037724


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[PMID]:22031893
[Au] Autor:Tseng CY; Firestein BL
[Ad] Endereço:Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8082, USA.
[Ti] Título:The role of PSD-95 and cypin in morphological changes in dendrites following sublethal NMDA exposure.
[So] Source:J Neurosci;31(43):15468-80, 2011 Oct 26.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Focal swelling or varicosity formation in dendrites and loss of dendritic spines are the earliest indications of glutamate-induced excitotoxicity. Although it is known that microtubule dynamics play a role in varicosity formation, very little is known about the proteins that directly impact microtubules during focal swelling and dendritic spine loss. Our laboratory has recently reported that the postsynaptic protein PSD-95 and its cytosolic interactor (cypin) regulate the patterning of dendrites in hippocampal neurons. Cypin promotes microtubule assembly, and PSD-95 disrupts microtubule organization. Thus, we hypothesized that cypin and PSD-95 may play a role in altering dendrite morphology and spine number in response to sublethal NMDA-induced excitotoxicity. Using an in vitro model of glutamate-induced toxicity in rat hippocampal cultures, we found that cypin overexpression or PSD-95 knockdown increases the percentage of neurons with varicosities and the number of varicosities along dendrites, decreases the size of varicosities after sublethal NMDA exposure, and protects neurons from NMDA-induced death. In contrast, cypin knockdown or PSD-95 overexpression results in opposite effects. We further show that cypin regulates the density of spines/filopodia: cypin overexpression decreases the number of protrusions per micrometer of dendrite while cypin knockdown results in an opposite effect. Cypin overexpression and PSD-95 knockdown attenuate NMDA-promoted decreases in protrusion density. Thus, we have identified a novel pathway by which the microtubule cytoskeleton is regulated during sublethal changes to dendrites.
[Mh] Termos MeSH primário: Proteínas de Transporte/metabolismo
Dendritos/efeitos dos fármacos
Agonistas de Aminoácidos Excitatórios/farmacologia
Guanina Desaminase/metabolismo
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Proteínas de Membrana/metabolismo
N-Metilaspartato/farmacologia
Neurônios/citologia
[Mh] Termos MeSH secundário: Análise de Variância
Animais
Proteínas de Transporte/genética
Proteína 4 Homóloga a Disks-Large
Embrião de Mamíferos
Regulação da Expressão Gênica/efeitos dos fármacos
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Guanina Desaminase/genética
Hipocampo/citologia
Indóis
Peptídeos e Proteínas de Sinalização Intracelular/genética
Proteínas de Membrana/genética
Proteínas Associadas aos Microtúbulos/metabolismo
Neurônios/efeitos dos fármacos
Nocodazol/farmacologia
Paclitaxel/farmacologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Ratos
Proteínas Ribossômicas/metabolismo
Fatores de Tempo
Transfecção/métodos
Tubulina (Proteína)/genética
Tubulina (Proteína)/metabolismo
Moduladores de Tubulina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Carrier Proteins); 0 (Disks Large Homolog 4 Protein); 0 (Dlg4 protein, rat); 0 (Excitatory Amino Acid Agonists); 0 (Gda protein, rat); 0 (Indoles); 0 (Intracellular Signaling Peptides and Proteins); 0 (Membrane Proteins); 0 (Microtubule-Associated Proteins); 0 (Mtap2 protein, rat); 0 (RNA, Small Interfering); 0 (Ribosomal Proteins); 0 (Tubulin); 0 (Tubulin Modulators); 0 (ribosomal protein L9); 147336-22-9 (Green Fluorescent Proteins); 47165-04-8 (DAPI); 6384-92-5 (N-Methylaspartate); EC 3.5.4.3 (Guanine Deaminase); P88XT4IS4D (Paclitaxel); SH1WY3R615 (Nocodazole)
[Em] Mês de entrada:1112
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:111028
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.2442-11.2011



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