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[PMID]:28660315
[Au] Autor:Vitali J; Singh AK; Colaneri MJ
[Ad] Endereço:Department of Physics, Cleveland State University, Cleveland, OH, 44115, USA. j.vitali@csuohio.edu.
[Ti] Título:Characterization of the Dihydroorotase from Methanococcus jannaschii.
[So] Source:Protein J;36(4):361-373, 2017 Aug.
[Is] ISSN:1875-8355
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The gene that codes for the putative dihydroorotase in the hyperthermophilic archaeon Methanococcus jannaschii was subcloned in pET-21a and expressed in Escherichia coli. A purification protocol was devised. The purity of the protein was evaluated by SDS-PAGE and the protein was confirmed by sequencing using LC-MS. The calculated molecular mass is 48104 Da. SEC-LS suggested that the protein is a monomer in solution. ICP-MS showed that there are two Zn ions per monomer. Kinetic analysis of the recombinant protein gave hyperbolic kinetics with V = 12.2 µmol/min/mg and K = 0.14 mM at 25 °C. Furthermore the activity of the protein increased with temperature consistent with the hyperthermophilic nature of the organism. A homology model was constructed using the mesophilic Bacillus anthracis protein as the template. Residues known to be critical for Zn and substrate binding were conserved. The activity of the enzyme at 85 and 90 °C was found to be relatively constant over 160 min and this correlates with the temperature of optimal growth of the organism of 85 °C. The amino acid sequences and structures of the two proteins were compared and this gave insight into some of the factors that may confer thermostability-more Lys and Ile, fewer Ala, Thr, Gln and Gly residues, and shorter N- and C-termini. Additional and better insight into the thermostabilization strategies adopted by this enzyme will be provided when its crystal structure is determined.
[Mh] Termos MeSH primário: Proteínas Arqueais/química
Di-Hidro-Orotase/química
Methanocaldococcus/química
Zinco/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas Arqueais/genética
Proteínas Arqueais/metabolismo
Bacillus anthracis/química
Bacillus anthracis/enzimologia
Sítios de Ligação
Clonagem Molecular
Sequência Conservada
Di-Hidro-Orotase/genética
Di-Hidro-Orotase/metabolismo
Estabilidade Enzimática
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Cinética
Methanocaldococcus/enzimologia
Peso Molecular
Fases de Leitura Aberta
Plasmídeos/química
Plasmídeos/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Relação Estrutura-Atividade
Especificidade por Substrato
Termodinâmica
Transformação Bacteriana
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Archaeal Proteins); 0 (Recombinant Proteins); EC 3.5.2.3 (Dihydroorotase); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170630
[St] Status:MEDLINE
[do] DOI:10.1007/s10930-017-9729-7


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[PMID]:28007989
[Au] Autor:Koch J; Mayr JA; Alhaddad B; Rauscher C; Bierau J; Kovacs-Nagy R; Coene KL; Bader I; Holzhacker M; Prokisch H; Venselaar H; Wevers RA; Distelmaier F; Polster T; Leiz S; Betzler C; Strom TM; Sperl W; Meitinger T; Wortmann SB; Haack TB
[Ad] Endereço:Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
[Ti] Título:CAD mutations and uridine-responsive epileptic encephalopathy.
[So] Source:Brain;140(2):279-286, 2017 02.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Unexplained global developmental delay and epilepsy in childhood pose a major socioeconomic burden. Progress in defining the molecular bases does not often translate into effective treatment. Notable exceptions include certain inborn errors of metabolism amenable to dietary intervention. CAD encodes a multifunctional enzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidines can be recycled from uridine. Exome sequencing in three families identified biallelic CAD mutations in four children with global developmental delay, epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4 and 5 years after a neurodegenerative disease course. Supplementation of the two surviving children with oral uridine led to immediate cessation of seizures in both. A 4-year-old female, previously in a minimally conscious state, began to communicate and walk with assistance after 9 weeks of treatment. A 3-year-old female likewise showed developmental progress. Blood smears normalized and anaemia resolved. We establish CAD as a gene confidently implicated in this neurometabolic disorder, characterized by co-occurrence of global developmental delay, dyserythropoietic anaemia and seizures. While the natural disease course can be lethal in early childhood, our findings support the efficacy of uridine supplementation, rendering CAD deficiency a treatable neurometabolic disorder and therefore a potential condition for future (genetic) newborn screening.
[Mh] Termos MeSH primário: Aspartato Carbamoiltransferase/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Di-Hidro-Orotase/genética
Mutação/genética
Espasmos Infantis/tratamento farmacológico
Espasmos Infantis/genética
Uridina/uso terapêutico
[Mh] Termos MeSH secundário: Anemia/complicações
Anemia/tratamento farmacológico
Anemia/genética
Encéfalo/diagnóstico por imagem
Criança
Pré-Escolar
Análise Mutacional de DNA
Deficiências do Desenvolvimento/complicações
Deficiências do Desenvolvimento/genética
Feminino
Seres Humanos
Lactente
Imagem por Ressonância Magnética
Masculino
Espasmos Infantis/complicações
Espasmos Infantis/diagnóstico por imagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CAD trifunctional enzyme); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)); WHI7HQ7H85 (Uridine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161224
[St] Status:MEDLINE
[do] DOI:10.1093/brain/aww300


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[PMID]:27746403
[Au] Autor:Hervé G; Evans HG; Fernado R; Patel C; Hachem F; Evans DR
[Ad] Endereço:From the Laboratoire BIOSIPE, Sorbonne Universités, Institut de Biologie Paris Seine, CNRS, Université Pierre et Marie Curie, 75005 Paris, France, guy.herve@upmc.fr.
[Ti] Título:Activation of Latent Dihydroorotase from Aquifex aeolicus by Pressure.
[So] Source:J Biol Chem;292(2):629-637, 2017 Jan 13.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Elevated hydrostatic pressure was used to probe conformational changes of Aquifex aeolicus dihydroorotase (DHO), which catalyzes the third step in de novo pyrimidine biosynthesis. The isolated protein, a 45-kDa monomer, lacks catalytic activity but becomes active upon formation of a dodecameric complex with aspartate transcarbamoylase (ATC). X-ray crystallographic studies of the isolated DHO and of the complex showed that association induces several major conformational changes in the DHO structure. In the isolated DHO, a flexible loop occludes the active site blocking the access of substrates. The loop is mostly disordered but is tethered to the active site region by several electrostatic and hydrogen bonds. This loop becomes ordered and is displaced from the active site upon formation of DHO-ATC complex. The application of pressure to the complex causes its time-dependent dissociation and the loss of both DHO and ATC activities. Pressure induced irreversible dissociation of the obligate ATC trimer, and as a consequence the DHO is also inactivated. However, moderate hydrostatic pressure applied to the isolated DHO subunit mimics the complex formation and reversibly activates the isolated subunit in the absence of ATC, suggesting that the loop has been displaced from the active site. This effect of pressure is explained by the negative volume change associated with the disruption of ionic interactions and exposure of ionized amino acids to the solvent (electrostriction). The interpretation that the loop is relocated by pressure was validated by site-directed mutagenesis and by inhibition by small peptides that mimic the loop residues.
[Mh] Termos MeSH primário: Aspartato Carbamoiltransferase/metabolismo
Bactérias/enzimologia
Proteínas de Bactérias/metabolismo
Di-Hidro-Orotase/metabolismo
Multimerização Proteica/fisiologia
[Mh] Termos MeSH secundário: Aspartato Carbamoiltransferase/química
Aspartato Carbamoiltransferase/genética
Bactérias/genética
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Domínio Catalítico/fisiologia
Di-Hidro-Orotase/química
Di-Hidro-Orotase/genética
Ativação Enzimática/fisiologia
Pressão Hidrostática
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.2.3 (Dihydroorotase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161018
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.739862


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[PMID]:27829037
[Au] Autor:von Beeren C; Maruyama M; Kronauer DJ
[Ad] Endereço:Laboratory of Social Evolution and Behavior, The Rockefeller University, New York, NY, 10065, United States of America.
[Ti] Título:Community Sampling and Integrative Taxonomy Reveal New Species and Host Specificity in the Army Ant-Associated Beetle Genus Tetradonia (Coleoptera, Staphylinidae, Aleocharinae).
[So] Source:PLoS One;11(11):e0165056, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Army ant colonies host a diverse community of arthropod symbionts. Among the best-studied symbiont communities are those of Neotropical army ants of the genus Eciton. It is clear, however, that even in these comparatively well studied systems, a large proportion of symbiont biodiversity remains unknown. Even more striking is our lack of knowledge regarding the nature and specificity of these host-symbiont interactions. Here we surveyed the diversity and host specificity of rove beetles of the genus Tetradonia Wasmann, 1894 (Staphylinidae: Aleocharinae). Systematic community sampling of 58 colonies of the six local Eciton species at La Selva Biological Station, Costa Rica, combined with an integrative taxonomic approach, allowed us to uncover species diversity, host specificity, and co-occurrence patterns of symbionts in unprecedented detail. We used an integrative taxonomic approach combining morphological and genetic analyses, to delineate species boundaries. Mitochondrial DNA barcodes were analyzed for 362 Tetradonia specimens, and additional nuclear markers for a subset of 88 specimens. All analyses supported the presence of five Tetradonia species, including two species new to science. Host specificity is highly variable across species, ranging from generalists such as T. laticeps, which parasitizes all six local Eciton species, to specialists such as T. lizonae, which primarily parasitizes a single species, E. hamatum. Here we provide a dichotomous key along with diagnostic molecular characters for identification of Tetradonia species at La Selva Biological Station. By reliably assessing biodiversity and providing tools for species identification, we hope to set the baseline for future studies of the ecological and evolutionary dynamics in these species-rich host-symbiont networks.
[Mh] Termos MeSH primário: Formigas/parasitologia
Biodiversidade
Coleópteros/fisiologia
Simbiose
[Mh] Termos MeSH secundário: Animais
Formigas/classificação
Aspartato Carbamoiltransferase/classificação
Aspartato Carbamoiltransferase/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/classificação
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Coleópteros/classificação
Coleópteros/genética
Costa Rica
Código de Barras de DNA Taxonômico/métodos
DNA Mitocondrial/química
DNA Mitocondrial/genética
Di-Hidro-Orotase/classificação
Di-Hidro-Orotase/genética
Complexo IV da Cadeia de Transporte de Elétrons/classificação
Complexo IV da Cadeia de Transporte de Elétrons/genética
Especificidade de Hospedeiro
Proteínas de Insetos/classificação
Proteínas de Insetos/genética
Filogenia
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CAD trifunctional enzyme); 0 (DNA, Mitochondrial); 0 (Insect Proteins); EC 1.9.3.1 (Electron Transport Complex IV); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing))
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161110
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0165056


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[PMID]:27650727
[Au] Autor:Tiwari K; Kumar R; Dubey VK
[Ad] Endereço:Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Assam 781039, India.
[Ti] Título:Biochemical characterization of dihydroorotase of Leishmania donovani: Understanding pyrimidine metabolism through its inhibition.
[So] Source:Biochimie;131:45-53, 2016 Dec.
[Is] ISSN:1638-6183
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:De novo pyrimidine biosynthesis pathway is well developed and functional in protozoan parasite Leishmania donovani. The dihydroorotase (LdDHOase) is third enzyme of the pathway. The enzyme was cloned, expressed in E. coli BL21 (DE3), purified to homogeneity and biochemically characterized. The estimated kcat for the forward reaction and reverse reactions were 2.1 ± 0.1 s and 1.1 ± 0.15 s , respectively. Homology modeling and docking studies were done to find out potential inhibitors for LdDHOase. Biotin sulfone and Kaempferol were found to be potential inhibitors of LdDHOase based on docking studies. These inhibitors were verified using recombinant LdDHOase and their anti-leishmanial effect was evaluated. Moreover, alterations in expressions of de novo as well as salvage pathways enzymes, after treatment of L. donovani with dihydroorotase inhibitor(s) were evaluated and discussed as survival mechanism of the pathogen. Further, effect of inhibition of cytidine deaminase, a key enzyme of salvage pathway of pyrimidine biosynthesis, was also evaluated on parasitic survival and alteration in gene expression of enzymes of both pathways. Further, effect of both pathways inhibition was also evaluated. The data suggests that the inhibition of single pathway can be overcome by increased expression of enzyme(s) of alternate pathway and both pathways seem to be equally important in the pathogen. When both pathways are simultaneously inhibited, parasite shows significant DNA damage and parasitic death.
[Mh] Termos MeSH primário: Di-Hidro-Orotase/metabolismo
Leishmania donovani/metabolismo
Proteínas de Protozoários/metabolismo
Pirimidinas/metabolismo
[Mh] Termos MeSH secundário: Biotina/análogos & derivados
Biotina/química
Biotina/farmacologia
Citidina Desaminase/antagonistas & inibidores
Citidina Desaminase/genética
Citidina Desaminase/metabolismo
Di-Hidro-Orotase/antagonistas & inibidores
Di-Hidro-Orotase/genética
Eletroforese em Gel de Poliacrilamida
Escherichia coli/genética
Regulação Enzimológica da Expressão Gênica
Quempferóis/química
Quempferóis/farmacologia
Cinética
Leishmania donovani/efeitos dos fármacos
Leishmania donovani/genética
Simulação de Acoplamento Molecular
Estrutura Molecular
Ácido Orótico/análogos & derivados
Ácido Orótico/química
Ácido Orótico/metabolismo
Domínios Proteicos
Proteínas de Protozoários/antagonistas & inibidores
Proteínas de Protozoários/genética
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Especificidade por Substrato
Sulfonas/química
Sulfonas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Kaempferols); 0 (Protozoan Proteins); 0 (Pyrimidines); 0 (Recombinant Proteins); 0 (Sulfones); 155-54-4 (4,5-dihydroorotic acid); 22451MYQ9X (biotin sulfone); 61H4T033E5 (Orotic Acid); 6SO6U10H04 (Biotin); 731P2LE49E (kaempferol); EC 3.5.2.3 (Dihydroorotase); EC 3.5.4.5 (Cytidine Deaminase); K8CXK5Q32L (pyrimidine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160922
[St] Status:MEDLINE


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[PMID]:27499369
[Au] Autor:Rice AJ; Lei H; Santarsiero BD; Lee H; Johnson ME
[Ad] Endereço:Center for Biomolecular Sciences and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 900 S, Ashland, IL 60607, USA.
[Ti] Título:Ca-asp bound X-ray structure and inhibition of Bacillus anthracis dihydroorotase (DHOase).
[So] Source:Bioorg Med Chem;24(19):4536-4543, 2016 Oct 01.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dihydroorotase (DHOase) is the third enzyme in the de novo pyrimidine synthesis pathway and is responsible for the reversible cyclization of carbamyl-aspartate (Ca-asp) to dihydroorotate (DHO). DHOase is further divided into two classes based on several structural characteristics, one of which is the length of the flexible catalytic loop that interacts with the substrate, Ca-asp, regulating the enzyme activity. Here, we present the crystal structure of Class I Bacillus anthracis DHOase with Ca-asp in the active site, which shows the peptide backbone of glycine in the shorter loop forming the necessary hydrogen bonds with the substrate, in place of the two threonines found in Class II DHOases. Despite the differences in the catalytic loop, the structure confirms that the key interactions between the substrate and active site residues are similar between Class I and Class II DHOase enzymes, which we further validated by mutagenesis studies. B. anthracis DHOase is also a potential antibacterial drug target. In order to identify prospective inhibitors, we performed high-throughput screening against several libraries using a colorimetric enzymatic assay and an orthogonal fluorescence thermal binding assay. Surface plasmon resonance was used for determining binding affinity (KD) and competition analysis with Ca-asp. Our results highlight that the primary difference between Class I and Class II DHOase is the catalytic loop. We also identify several compounds that can potentially be further optimized as potential B. anthracis inhibitors.
[Mh] Termos MeSH primário: Bacillus anthracis/enzimologia
Di-Hidro-Orotase/antagonistas & inibidores
Di-Hidro-Orotase/química
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
[Mh] Termos MeSH secundário: Antraz/tratamento farmacológico
Antibacterianos/química
Antibacterianos/farmacologia
Bacillus anthracis/química
Bacillus anthracis/metabolismo
Cristalografia por Raios X
Di-Hidro-Orotase/metabolismo
Seres Humanos
Modelos Moleculares
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Enzyme Inhibitors); EC 3.5.2.3 (Dihydroorotase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171001
[Lr] Data última revisão:
171001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160809
[St] Status:MEDLINE


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[PMID]:26792711
[Au] Autor:Naranjo-Díaz N; Conn JE; Correa MM
[Ad] Endereço:Grupo de Microbiología Molecular, Escuela de Microbiología, Universidad de Antioquia, Medellín, Colombia. Electronic address: jezzid4@gmail.com.
[Ti] Título:Behavior and population structure of Anopheles darlingi in Colombia.
[So] Source:Infect Genet Evol;39:64-73, 2016 Apr.
[Is] ISSN:1567-7257
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Anopheles darlingi is a widely distributed and important malaria vector in Colombia. Biogeographical and ecological heterogeneity across the Colombian distribution led to the hypothesis of behavioral and genetic differentiation among A. darlingi populations. A total of 2017 A. darlingi specimens were collected during 222 h of sampling. This vector was the most abundant anopheline species in most of the localities sampled. Subdivision between samples collected west and east of the Andes was indicated by 1) mitochondrial COI and nuclear CAD sequences from NW-W and CE-S populations (COI ΦST=0.48761-0.81974, CAD FST=0.11319-0.21321), 2) a COI haplotype network, and 3) SAMOVA. Endo- and exophagy were detected in populations west of the Andes, whereas exophagy was evident in PTG, a locality east of the Andes. Isolation by resistance was significant for COI and explained 26% of the genetic differentiation. We suggest that at a macrogeographic scale, the Andes influence the differentiation of A. darlingi in Colombia and may drive divergence, and, at a microgeographic scale, ecological differences have a significant impact on structure. These data could constitute a baseline for the design of effective vector interventions, locality-specific for the east and similar for panmictic populations west of the Andes.
[Mh] Termos MeSH primário: Anopheles/classificação
Anopheles/genética
Aspartato Carbamoiltransferase/genética
Evolução Biológica
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Di-Hidro-Orotase/genética
Complexo IV da Cadeia de Transporte de Elétrons/genética
[Mh] Termos MeSH secundário: Animais
Anopheles/fisiologia
Colômbia
Deriva Genética
Variação Genética
Haplótipos
Proteínas de Insetos/genética
Filogeografia
Densidade Demográfica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CAD trifunctional enzyme); 0 (Insect Proteins); EC 1.9.3.1 (Electron Transport Complex IV); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing))
[Em] Mês de entrada:1612
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160122
[St] Status:MEDLINE


  8 / 403 MEDLINE  
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[PMID]:26657846
[Au] Autor:Matsunaga R; Nishino T; Yokoyama A; Nakashima A; Kikkawa U; Konishi H
[Ad] Endereço:Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
[Ti] Título:Versatile function of the circadian protein CIPC as a regulator of Erk activation.
[So] Source:Biochem Biophys Res Commun;469(3):377-83, 2016 Jan 15.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The CLOCK-interacting protein, Circadian (CIPC), has been identified as an additional negative-feedback regulator of the circadian clock. However, recent study on CIPC knockout mice has shown that CIPC is not critically required for basic circadian clock function, suggesting other unknown biological roles for CIPC. In this study, we focused on the cell cycle dependent nuclear-cytoplasmic shuttling function of CIPC and on identifying its binding proteins. Lys186 and 187 were identified as the essential amino acid residues within the nuclear localization signal (NLS) of CIPC. We identified CIPC-binding proteins such as the multifunctional enzyme CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase), which is a key enzyme for de novo pyrimidine synthesis. Compared to control cells, HEK293 cells overexpressing wild-type CIPC showed suppressed cell proliferation and retardation of cell cycle. We also found that PMA-induced Erk activation was inhibited with expression of wild-type CIPC. In contrast, the NLS mutant of CIPC, which reduced the ability of CIPC to translocate into the nucleus, did not exhibit these biological effects. Since CAD and Erk have significant roles in cell proliferation and cell cycle, CIPC may work as a cell cycle regulator by interacting with these binding proteins.
[Mh] Termos MeSH primário: Aspartato Carbamoiltransferase/metabolismo
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo
Proteínas de Transporte/metabolismo
Ritmo Circadiano/fisiologia
Di-Hidro-Orotase/metabolismo
MAP Quinases Reguladas por Sinal Extracelular/metabolismo
Regulação da Expressão Gênica/fisiologia
[Mh] Termos MeSH secundário: Animais
Células COS
Cercopithecus aethiops
Ativação Enzimática
Retroalimentação Fisiológica/fisiologia
Células HEK293
Células HeLa
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CAD trifunctional enzyme); 0 (CIPC protein, mouse); 0 (Carrier Proteins); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing))
[Em] Mês de entrada:1605
[Cu] Atualização por classe:160117
[Lr] Data última revisão:
160117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151215
[St] Status:MEDLINE


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[PMID]:26633560
[Au] Autor:Amatu A; Somaschini A; Cerea G; Bosotti R; Valtorta E; Buonandi P; Marrapese G; Veronese S; Luo D; Hornby Z; Multani P; Murphy D; Shoemaker R; Lauricella C; Giannetta L; Maiolani M; Vanzulli A; Ardini E; Galvani A; Isacchi A; Sartore-Bianchi A; Siena S
[Ad] Endereço:Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.
[Ti] Título:Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.
[So] Source:Br J Cancer;113(12):1730-4, 2015 Dec 22.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. METHODS: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. RESULTS: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. CONCLUSIONS: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Aspartato Carbamoiltransferase/genética
Benzamidas/uso terapêutico
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Neoplasias Colorretais/tratamento farmacológico
Di-Hidro-Orotase/genética
Rearranjo Gênico
Indazóis/uso terapêutico
Receptores Proteína Tirosina Quinases/genética
[Mh] Termos MeSH secundário: Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Feminino
Seres Humanos
Meia-Idade
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Benzamides); 0 (CAD trifunctional enzyme); 0 (Indazoles); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases); EC 2.7.10.1 (anaplastic lymphoma kinase); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)); L5ORF0AN1I (entrectinib)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151204
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2015.401


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[PMID]:26560030
[Au] Autor:Rabinovich S; Adler L; Yizhak K; Sarver A; Silberman A; Agron S; Stettner N; Sun Q; Brandis A; Helbling D; Korman S; Itzkovitz S; Dimmock D; Ulitsky I; Nagamani SC; Ruppin E; Erez A
[Ad] Endereço:Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
[Ti] Título:Diversion of aspartate in ASS1-deficient tumours fosters de novo pyrimidine synthesis.
[So] Source:Nature;527(7578):379-383, 2015 Nov 19.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cancer cells hijack and remodel existing metabolic pathways for their benefit. Argininosuccinate synthase (ASS1) is a urea cycle enzyme that is essential in the conversion of nitrogen from ammonia and aspartate to urea. A decrease in nitrogen flux through ASS1 in the liver causes the urea cycle disorder citrullinaemia. In contrast to the well-studied consequences of loss of ASS1 activity on ureagenesis, the purpose of its somatic silencing in multiple cancers is largely unknown. Here we show that decreased activity of ASS1 in cancers supports proliferation by facilitating pyrimidine synthesis via CAD (carbamoyl-phosphate synthase 2, aspartate transcarbamylase, and dihydroorotase complex) activation. Our studies were initiated by delineating the consequences of loss of ASS1 activity in humans with two types of citrullinaemia. We find that in citrullinaemia type I (CTLN I), which is caused by deficiency of ASS1, there is increased pyrimidine synthesis and proliferation compared with citrullinaemia type II (CTLN II), in which there is decreased substrate availability for ASS1 caused by deficiency of the aspartate transporter citrin. Building on these results, we demonstrate that ASS1 deficiency in cancer increases cytosolic aspartate levels, which increases CAD activation by upregulating its substrate availability and by increasing its phosphorylation by S6K1 through the mammalian target of rapamycin (mTOR) pathway. Decreasing CAD activity by blocking citrin, the mTOR signalling, or pyrimidine synthesis decreases proliferation and thus may serve as a therapeutic strategy in multiple cancers where ASS1 is downregulated. Our results demonstrate that ASS1 downregulation is a novel mechanism supporting cancerous proliferation, and they provide a metabolic link between the urea cycle enzymes and pyrimidine synthesis.
[Mh] Termos MeSH primário: Argininossuccinato Sintase/deficiência
Ácido Aspártico/metabolismo
Neoplasias/metabolismo
Pirimidinas/biossíntese
[Mh] Termos MeSH secundário: Animais
Argininossuccinato Sintase/metabolismo
Aspartato Carbamoiltransferase/metabolismo
Proteínas de Ligação ao Cálcio/antagonistas & inibidores
Proteínas de Ligação ao Cálcio/metabolismo
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo
Linhagem Celular Tumoral
Proliferação Celular
Citrulinemia/metabolismo
Citosol/metabolismo
Di-Hidro-Orotase/metabolismo
Regulação para Baixo
Ativação Enzimática
Seres Humanos
Masculino
Camundongos
Camundongos SCID
Neoplasias/enzimologia
Neoplasias/patologia
Transportadores de Ânions Orgânicos/antagonistas & inibidores
Transportadores de Ânions Orgânicos/metabolismo
Fosforilação
Serina-Treonina Quinases TOR/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Calcium-Binding Proteins); 0 (Organic Anion Transporters); 0 (Pyrimidines); 1340-08-5 (citrin); 30KYC7MIAI (Aspartic Acid); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 3.5.2.3 (Dihydroorotase); EC 6.3.4.5 (Argininosuccinate Synthase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)); K8CXK5Q32L (pyrimidine)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151113
[St] Status:MEDLINE
[do] DOI:10.1038/nature15529



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