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[PMID]:29295983
[Au] Autor:Flett FJ; Ruksenaite E; Armstrong LA; Bharati S; Carloni R; Morris ER; Mackay CL; Interthal H; Richardson JM
[Ad] Endereço:Institute of Cell Biology, School of Biological Sciences, University of Edinburgh, The King's Buildings, Roger Land Building, Alexander Crum Brown Road, Edinburgh, EH9 3FF, UK.
[Ti] Título:Structural basis for DNA 3'-end processing by human tyrosyl-DNA phosphodiesterase 1.
[So] Source:Nat Commun;9(1):24, 2018 01 02.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tyrosyl-DNA phosphodiesterase (Tdp1) is a DNA 3'-end processing enzyme that repairs topoisomerase 1B-induced DNA damage. We use a new tool combining site-specific DNA-protein cross-linking with mass spectrometry to identify Tdp1 interactions with DNA. A conserved phenylalanine (F259) of Tdp1, required for efficient DNA processing in biochemical assays, cross-links to defined positions in DNA substrates. Crystal structures of Tdp1-DNA complexes capture the DNA repair machinery after 3'-end cleavage; these reveal how Tdp1 coordinates the 3'-phosphorylated product of nucleosidase activity and accommodates duplex DNA. A hydrophobic wedge splits the DNA ends, directing the scissile strand through a channel towards the active site. The F259 side-chain stacks against the -3 base pair, delimiting the junction of duplexed and melted DNA, and fixes the scissile strand in the channel. Our results explain why Tdp1 cleavage is non-processive and provide a molecular basis for DNA 3'-end processing by Tdp1.
[Mh] Termos MeSH primário: Dano ao DNA
Reparo do DNA
DNA/metabolismo
Diester Fosfórico Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Bases
Domínio Catalítico
Cristalografia por Raios X
DNA/química
DNA/genética
Seres Humanos
Modelos Moleculares
Conformação de Ácido Nucleico
Diester Fosfórico Hidrolases/química
Ligação Proteica
Domínios Proteicos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
9007-49-2 (DNA); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.- (tyrosyl-DNA phosphodiesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180104
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02530-z


  2 / 9237 MEDLINE  
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[PMID]:28460477
[Au] Autor:Park E; Kim D; Lee SM; Jun HS
[Ad] Endereço:Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.
[Ti] Título:Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice.
[So] Source:Oncotarget;8(16):27240-27251, 2017 Apr 18.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS.
[Mh] Termos MeSH primário: Receptores de Ácidos Lisofosfatídicos/antagonistas & inibidores
Receptores de Ácidos Lisofosfatídicos/metabolismo
Síndrome de Sjogren/metabolismo
[Mh] Termos MeSH secundário: Animais
Autoanticorpos/sangue
Autoanticorpos/imunologia
Citocinas/genética
Citocinas/metabolismo
Modelos Animais de Doenças
Feminino
Expressão Gênica
Imunoterapia Adotiva
Mediadores da Inflamação/metabolismo
Interleucina-17/sangue
Interleucina-17/metabolismo
Isoxazóis/farmacologia
Aparelho Lacrimal/imunologia
Aparelho Lacrimal/metabolismo
Aparelho Lacrimal/patologia
Masculino
Camundongos
Camundongos Endogâmicos NOD
Diester Fosfórico Hidrolases/genética
Diester Fosfórico Hidrolases/metabolismo
Propionatos/farmacologia
Receptores de Ácidos Lisofosfatídicos/genética
Saliva/metabolismo
Transdução de Sinais/efeitos dos fármacos
Síndrome de Sjogren/genética
Síndrome de Sjogren/imunologia
Síndrome de Sjogren/terapia
Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
Quinases Associadas a rho/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid); 0 (Autoantibodies); 0 (Cytokines); 0 (Inflammation Mediators); 0 (Interleukin-17); 0 (Isoxazoles); 0 (Propionates); 0 (Receptors, Lysophosphatidic Acid); EC 2.7.11.1 (Rock2 protein, mouse); EC 2.7.11.1 (rho-Associated Kinases); EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.15916


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[PMID]:29273417
[Au] Autor:Cherukupalli S; Hampannavar GA; Chinnam S; Chandrasekaran B; Sayyad N; Kayamba F; Reddy Aleti R; Karpoormath R
[Ad] Endereço:Department of Pharmaceutical Chemistry, College of Health Sciences, University of KwaZulu-Natal, Durban 4000, South Africa.
[Ti] Título:An appraisal on synthetic and pharmaceutical perspectives of pyrazolo[4,3-d]pyrimidine scaffold.
[So] Source:Bioorg Med Chem;26(2):309-339, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Pyrazolo[4,3-d]pyrimidine, a fused heterocycle bearing pyrazole and pyrimidine portions has gained a significant attention in the field of bioorganic and medicinal chemistry. Pyrazolo[4,3-d]pyrimidine derivatives have demonstrated numerous pharmacological activities particularly, anti-cancer, anti-infectious, phosphodiesterase inhibitors, adenosine antagonists and cytokinin antagonists etc. This review extensively unveils the synthetic and pharmacological diversity with special emphasis on structural variations around pyrazolo[4,3-d]pyrimidine scaffold. This endeavour has thus uncovered the medicinal worthiness of pyrazolo[4,3-d]pyrimidine framework. To the best of our knowledge this review is the first compilation on synthetic, medicinal and structure activity relationship (SAR) aspects of pyrazolo[4,3-d]pyrimidines since 1956.
[Mh] Termos MeSH primário: Anti-Infecciosos/farmacologia
Antineoplásicos/farmacologia
Inibidores Enzimáticos/farmacologia
Neoplasias/tratamento farmacológico
Pirazóis/farmacologia
Pirimidinas/farmacologia
[Mh] Termos MeSH secundário: Adenosina/antagonistas & inibidores
Adenosina/metabolismo
Anti-Infecciosos/síntese química
Anti-Infecciosos/química
Antineoplásicos/síntese química
Antineoplásicos/química
Citocininas/antagonistas & inibidores
Citocininas/metabolismo
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Estrutura Molecular
Diester Fosfórico Hidrolases/metabolismo
Pirazóis/síntese química
Pirazóis/química
Pirimidinas/síntese química
Pirimidinas/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Antineoplastic Agents); 0 (Cytokinins); 0 (Enzyme Inhibitors); 0 (Pyrazoles); 0 (Pyrimidines); 271-80-7 (pyrazolo(3,4-d)pyrimidine); EC 3.1.4.- (Phosphoric Diester Hydrolases); K72T3FS567 (Adenosine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171224
[St] Status:MEDLINE


  4 / 9237 MEDLINE  
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[PMID]:29289611
[Au] Autor:Kazemi N; Estiar MA; Fazilaty H; Sakhinia E
[Ad] Endereço:Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Division of Medical Genetics, Department of Clinical Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
[Ti] Título:Variants in GNPTAB, GNPTG and NAGPA genes are associated with stutterers.
[So] Source:Gene;647:93-100, 2018 Mar 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Non-syndromic stuttering is a neurodevelopmental disorder characterized by disruptions in normal flow of speech in the form of repetition, prolongation and involuntary halts. Previously, mutations with more severe effects on GNPTAB and GNPTG have been reported to cause Mucolipidosisll (ML-ll) and Mucolipidosislll (ML-lll), two lysosomal storage disorders with multiple pathologies. We used homozygosity mapping and Sanger sequencing to investigate variants of the three genes in 25 Iranian families with at least two first degree related non-syndromic stutterers. Bioinformatic evaluation and Segregation analysis of the found variants helped us define probable consequences. We also compared our findings with those related to Mucolipidosis. 14 variations were found in the three genes 3 of which, including a novel variant within intronic region of GNPTG and a heterozygous 2-bp deletion in coding region of GNPTAB, co-segregated with stuttering in the families they were found. Bioinformatics analysis predicted all three variants causing deleterious effects on gene functioning. Our findings support the role of these three variants in non-syndromic stuttering. This finding may challenge the current belief that variations causing stuttering are at different sites and have less severe consequences than genetic changes that cause ML-ll and ML-lll.
[Mh] Termos MeSH primário: Predisposição Genética para Doença/genética
Mutação/genética
Diester Fosfórico Hidrolases/genética
Gagueira/genética
Transferases (Outros Grupos de Fosfato Substituídos)/genética
[Mh] Termos MeSH secundário: Criança
Pré-Escolar
Feminino
Heterozigoto
Homozigoto
Seres Humanos
Íntrons/genética
Masculino
Mucolipidoses/genética
Fenótipo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.8.- (Transferases (Other Substituted Phosphate Groups)); EC 2.7.8.15 (GNPTAB protein, human); EC 2.7.8.17 (GNPTG protein, human); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.45 (N-acetylglucosamine-1-phosphodiester alpha-N-acetylglucosaminidase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180101
[St] Status:MEDLINE


  5 / 9237 MEDLINE  
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[PMID]:29286727
[Au] Autor:Segota I; Franck C
[Ad] Endereço:Laboratory of Atomic and Solid State Physics, Cornell University, Ithaca 14853, USA.
[Ti] Título:Extracellular Processing of Molecular Gradients by Eukaryotic Cells Can Improve Gradient Detection Accuracy.
[So] Source:Phys Rev Lett;119(24):248101, 2017 Dec 15.
[Is] ISSN:1079-7114
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic cells sense molecular gradients by measuring spatial concentration variation through the difference in the number of occupied receptors to which molecules can bind. They also secrete enzymes that degrade these molecules, and it is presently not well understood how this affects the local gradient perceived by cells. Numerical and analytical results show that these enzymes can substantially increase the signal-to-noise ratio of the receptor difference and allow cells to respond to a much broader range of molecular concentrations and gradients than they would without these enzymes.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Células Eucarióticas/metabolismo
Modelos Biológicos
Diester Fosfórico Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Ácido Aspártico Endopeptidases/metabolismo
Quimiotaxia
Dictyostelium/enzimologia
Dictyostelium/metabolismo
Difusão
Células Eucarióticas/citologia
Células Eucarióticas/enzimologia
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Saccharomyces cerevisiae Proteins); E0399OZS9N (Cyclic AMP); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.4.23.- (Aspartic Acid Endopeptidases); EC 3.4.23.- (BAR1 protein, S cerevisiae)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171230
[St] Status:MEDLINE
[do] DOI:10.1103/PhysRevLett.119.248101


  6 / 9237 MEDLINE  
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[PMID]:28462841
[Au] Autor:Chen L; Chen D; Tang L; Ren J; Chen J; Zhen X; Liu YC; Zhang C; Luo H; Shen J; Xiong B
[Ad] Endereço:School of PharmaceuticalSciences, Nanchang University, Nanchang 330006, China; Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
[Ti] Título:Design and optimization of purine derivatives as in vivo active PDE10A inhibitors.
[So] Source:Bioorg Med Chem;25(13):3315-3329, 2017 07 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Phosphodiesterases are important enzymes regulating signal transduction mediated by second messenger molecules cAMP or cGMP. PDE10A is a unique member in the PDE family because of its selective expression in medium spiny neurons. It is recognized as anti-psychotic drug target. Based on the structural similarity between our previous chemistry work on 8-aminoimidazo[1,2-a]pyrazines and the PDE10A inhibitors reported by Bartolome-Nebreda et al., we initialized a project for developing PDE10A inhibitors. After several rounds of optimization, we were able to obtain a few compounds with good PDE10A enzymatic activity. And after further PDE enzymatic selectivity study, metabolic stability assay and in vivo pharmacological tests we identified two inhibitors as interesting lead compounds with the potential for further PDE10A lead optimizatioin.
[Mh] Termos MeSH primário: Desenho de Drogas
Diester Fosfórico Hidrolases/metabolismo
Purinas/farmacologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Seres Humanos
Locomoção/efeitos dos fármacos
Masculino
Camundongos
Microssomos/química
Microssomos/metabolismo
Estrutura Molecular
Inibição Pré-Pulso/efeitos dos fármacos
Purinas/síntese química
Purinas/química
Ratos
Ratos Sprague-Dawley
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Purines); EC 3.1.4.- (PDE10A protein, human); EC 3.1.4.- (Phosphoric Diester Hydrolases); W60KTZ3IZY (purine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171208
[Lr] Data última revisão:
171208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


  7 / 9237 MEDLINE  
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[PMID]:28743508
[Au] Autor:Balupuri A; Lee DY; Lee MH; Chae S; Jung E; Kim Y; Ryu J; Kang NS
[Ad] Endereço:Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon 305-764, Republic of Korea.
[Ti] Título:Design, synthesis, docking and biological evaluation of 4-phenyl-thiazole derivatives as autotaxin (ATX) inhibitors.
[So] Source:Bioorg Med Chem Lett;27(17):4156-4164, 2017 09 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The autotaxin-lysophophatidic acid (ATX-LPA) signaling pathway is involved in several human diseases such as cancer, autoimmune diseases, inflammatory diseases neurodegenerative diseases and fibrotic diseases. Herein, a series of 4-phenyl-thiazole based compounds was designed and synthesized. Compounds were evaluated for their ATX inhibitory activity using FS-3 and human plasma assays. In the FS-3 assay, compounds 20 and 21 significantly inhibited the ATX at low nanomolar level (IC =2.99 and 2.19nM, respectively). Inhibitory activity of 21 was found to be slightly better than PF-8380 (IC =2.80nM), which is one of the most potent ATX inhibitors reported till date. Furthermore, 21 displayed higher potency (IC =14.99nM) than the first clinical ATX inhibitor, GLPG1690 (IC =242.00nM) in the human plasma assay. Molecular docking studies were carried out to explore the binding pattern of newly synthesized compounds within active site of ATX. Docking studies suggested the putative binding mode of the novel compounds. Good ATX inhibitory activity of 21 was attributed to the hydrogen bonding interactions with Asn230, Trp275 and active site water molecules; electrostatic interaction with catalytic zinc ion and hydrophobic interactions with amino acids of the hydrophobic pocket.
[Mh] Termos MeSH primário: Desenho de Drogas
Simulação de Acoplamento Molecular
Diester Fosfórico Hidrolases/metabolismo
Tiazóis/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Seres Humanos
Estrutura Molecular
Relação Estrutura-Atividade
Tiazóis/síntese química
Tiazóis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Thiazoles); EC 3.1.4.- (Phosphoric Diester Hydrolases); EC 3.1.4.39 (alkylglycerophosphoethanolamine phosphodiesterase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE


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[PMID]:29073277
[Au] Autor:Luo Z; Fan Y; Li Q; Han B; Liu Y; Li S; Qiu H; Pang Z
[Ad] Endereço:College of Light Industry and Food Engineering, Guangxi University, Nanning, China.
[Ti] Título:Isolation, purification and characterization of 5'-phosphodiesterase from Aspergillus fumigatus.
[So] Source:PLoS One;12(10):e0186011, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:5'-Phosphodiesterase (5'-PDE) catalyzes the hydrolysis of ribonucleic acid to obtain a mixture of ribonucleotides, such as 5'-guanosine monophosphate and 5'-adenosine monophosphate. In this study, a 5'-PDE was newly isolated and purified from Aspergillus fumigatus. Following purification, this enzyme exhibited a specific activity of 1036.76 U/mg protein, a molecular weight of 9.5 kDa, and an optimal temperature and pH for enzyme activity of 60°C and 5.0, respectively. However, its activity was partially inhibited by Fe3+, Cu2+, and Zn2+, but slightly improved by the presence of K+ and Na+. Additionally, chemical-modification experiments were also applied to investigate the structural information of 5'-PDE, in which the residues containing carboxyl and imidazole groups were essential for enzyme activity based on their localization in the 5'-PDE active site. Furthermore, purified 5'-PDE could specifically catalyze the synthesis of ribonucleotides with a Vmax 0.71 mmol/mg·min and a KM of 13.60 mg/mL.
[Mh] Termos MeSH primário: Aspergillus fumigatus/enzimologia
Diester Fosfórico Hidrolases/isolamento & purificação
[Mh] Termos MeSH secundário: Catálise
Hidrólise
Peso Molecular
Diester Fosfórico Hidrolases/química
Diester Fosfórico Hidrolases/metabolismo
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.4.- (Phosphoric Diester Hydrolases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171027
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186011


  9 / 9237 MEDLINE  
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[PMID]:29045455
[Au] Autor:Wotanis CK; Brennan WP; Angotti AD; Villa EA; Zayner JP; Mozina AN; Rutkovsky AC; Sobe RC; Bond WG; Karatan E
[Ad] Endereço:Department of Biology, Appalachian State University, Boone, North Carolina, United States of America.
[Ti] Título:Relative contributions of norspermidine synthesis and signaling pathways to the regulation of Vibrio cholerae biofilm formation.
[So] Source:PLoS One;12(10):e0186291, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The polyamine norspermidine is one of the major polyamines synthesized by Vibrionales and has also been found in various aquatic organisms. Norspermidine is among the environmental signals that positively regulate Vibrio cholerae biofilm formation. The NspS/MbaA signaling complex detects extracellular norspermidine and mediates the response to this polyamine. Norspermidine binding to the NspS periplasmic binding protein is thought to inhibit the phosphodiesterase activity of MbaA, increasing levels of the biofilm-promoting second messenger cyclic diguanylate monophosphate, thus enhancing biofilm formation. V. cholerae can also synthesize norspermidine using the enzyme NspC as well as import it from the environment. Deletion of the nspC gene was shown to reduce accumulation of bacteria in biofilms, leading to the conclusion that intracellular norspermidine is also a positive regulator of biofilm formation. Because V. cholerae uses norspermidine to synthesize the siderophore vibriobactin it is possible that intracellular norspermidine is required to obtain sufficient amounts of iron, which is also necessary for robust biofilm formation. The objective of this study was to assess the relative contributions of intracellular and extracellular norspermidine to the regulation of biofilm formation in V. cholerae. We show the biofilm defect of norspermidine synthesis mutants does not result from an inability to produce vibriobactin as vibriobactin synthesis mutants do not have diminished biofilm forming abilities. Furthermore, our work shows that extracellular, but not intracellular norspermidine, is mainly responsible for promoting biofilm formation. We establish that the NspS/MbaA signaling complex is the dominant mediator of biofilm formation in response to extracellular norspermidine, rather than norspermidine synthesized by NspC or imported into the cell.
[Mh] Termos MeSH primário: Biofilmes/crescimento & desenvolvimento
Espermidina/análogos & derivados
Vibrio cholerae/genética
[Mh] Termos MeSH secundário: Catecóis/metabolismo
GMP Cíclico/análogos & derivados
GMP Cíclico/metabolismo
Ferro/metabolismo
Oxazóis/metabolismo
Proteínas Periplásmicas de Ligação/genética
Proteínas Periplásmicas de Ligação/metabolismo
Diester Fosfórico Hidrolases/genética
Diester Fosfórico Hidrolases/metabolismo
Transdução de Sinais
Espermidina/biossíntese
Espermidina/metabolismo
Vibrio cholerae/crescimento & desenvolvimento
Vibrio cholerae/patogenicidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Catechols); 0 (Oxazoles); 0 (Periplasmic Binding Proteins); 56-18-8 (norspermidine); 61093-23-0 (bis(3',5')-cyclic diguanylic acid); 88217-23-6 (vibriobactin); E1UOL152H7 (Iron); EC 3.1.4.- (Phosphoric Diester Hydrolases); H2D2X058MU (Cyclic GMP); U87FK77H25 (Spermidine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171019
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186291


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[PMID]:28976747
[Au] Autor:Lamarche LB; Kumar RP; Trieu MM; Devine EL; Cohen-Abeles LE; Theobald DL; Oprian DD
[Ad] Endereço:Department of Biochemistry, Brandeis University , Waltham, Massachusetts 02454, United States.
[Ti] Título:Purification and Characterization of RhoPDE, a Retinylidene/Phosphodiesterase Fusion Protein and Potential Optogenetic Tool from the Choanoflagellate Salpingoeca rosetta.
[So] Source:Biochemistry;56(43):5812-5822, 2017 Oct 31.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RhoPDE is a type I rhodopsin/phosphodiesterase gene fusion product from the choanoflagellate Salpingoeca rosetta. The gene was discovered around the time that a similar type I rhodopsin/guanylyl cyclase fusion protein, RhoGC, was shown to control phototaxis of an aquatic fungus through a cGMP signaling pathway. RhoPDE has potential as an optogenetic tool catalyzing the hydrolysis of cyclic nucleotides. Here we provide an expression and purification system for RhoPDE, as well as a crystal structure of the C-terminal phosphodiesterase catalytic domain. We show that RhoPDE contains an even number of transmembrane segments, with N- and C-termini both located on the cytoplasmic surface of the cell membrane. The purified protein exhibits an absorption maximum at 490 nm in the dark state, which shifts to 380 nm upon exposure to light. The protein acts as a cGMP-selective phosphodiesterase. However, the activity does not appear to be modulated by light. The protein is also active with cAMP as a substrate, but with a roughly 5-7-fold lower k . A truncation consisting solely of the phosphodiesterase domain is also active with a k for cGMP roughly 6-9-fold lower than that of the full-length protein. The isolated PDE domain was crystallized, and the X-ray structure showed the protein to be a dimer similar to human PDE9. We anticipate that the purification system introduced here will enable further structural and biochemical experiments to improve our understanding of the function and mechanism of this unique fusion protein.
[Mh] Termos MeSH primário: Coanoflagelados/enzimologia
Diester Fosfórico Hidrolases
Proteínas de Protozoários
[Mh] Termos MeSH secundário: Coanoflagelados/genética
Cristalografia por Raios X
Expressão Gênica
Seres Humanos
Diester Fosfórico Hidrolases/biossíntese
Diester Fosfórico Hidrolases/química
Diester Fosfórico Hidrolases/genética
Diester Fosfórico Hidrolases/isolamento & purificação
Domínios Proteicos
Proteínas de Protozoários/biossíntese
Proteínas de Protozoários/química
Proteínas de Protozoários/genética
Proteínas de Protozoários/isolamento & purificação
Proteínas Recombinantes de Fusão/biossíntese
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Protozoan Proteins); 0 (Recombinant Fusion Proteins); EC 3.1.4.- (Phosphoric Diester Hydrolases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00519



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