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Pesquisa : D08.811.464.259.400.300 [Categoria DeCS]
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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]: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]:27305780
[Au] Autor:Yang S; Guo L; Ban R; Xie X
[Ti] Título:[Effect of key-gene modification on uridine biosynthesis in Bacillus subtilis].
[So] Source:Wei Sheng Wu Xue Bao;56(1):56-67, 2016 Jan 04.
[Is] ISSN:0001-6209
[Cp] País de publicação:China
[La] Idioma:chi
[Ab] Resumo:OBJECTIVE: We studied several crucial factors influencing the uridine biosynthesis in Bacillus subtilis, including mutations of phosphoribosylpyrophosphate synthetase (PRPP synthetase) (prs) and carbamyl phosphate synthetase (pyrAA/pyrAB), and overexpression of heterologous 5'-nucleotidase (sdt1). METHODS: According to the inferred allosteric sites, we introduced point mutation into coding sequences of prs and pyrAB. The mutated prs gene was integratedly expressed in the xylR locus of the chromosome and the pyrAB gene was modified in-situ. The sdt1 gene was overexpressed in the saB locus of the chromosome. The effect of the genetic modification on uridine biosynthesis was characterized by the analysis of uridine, cytidine and uracil in the fermentation broth. RESULTS: The mutations of Asn120Ser, Leu135Ile, Glu52Gly or Val312Ala on PRPP synthase resulted in an increase of uridine production by 67% and 96%, respectively. The mutations of Ser948Phe, Thr977Ala and Lys993Ile on carbamyl phosphate synthase resulted in a 182% increase of uridine yield to 6.97 g/L. The overexpression of heterologous 5'-nucleotidase resulted in a 17% increase of uridine yield to 8.16 g/L. CONCLUSION: The activity and regulation mechanism of PRPP synthase and carbamyl phosphate synthase was an important factor to limit the excessive synthesis of uridine. Asn120Ser and Leu135Ile mutations of PRPP synthase and Ser948Phe, Thr977Ala and Lys993Ile mutations of carbamyl phosphate synthase will facilitate the biosynthesis of uridine. The additional Glu52Gly and Val312Ala mutations of PRPP synthase were beneficial for uridine biosynthesis. The reaction from UMP to uridine also limited the biosynthesis of uridine in B. subtilis.
[Mh] Termos MeSH primário: Bacillus subtilis/metabolismo
Proteínas de Bactérias/genética
Uridina/biossíntese
[Mh] Termos MeSH secundário: Bacillus subtilis/enzimologia
Bacillus subtilis/genética
Proteínas de Bactérias/metabolismo
Vias Biossintéticas
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo
Clonagem Molecular
Ribose-Fosfato Pirofosfoquinase/genética
Ribose-Fosfato Pirofosfoquinase/metabolismo
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); EC 2.7.6.1 (Ribose-Phosphate Pyrophosphokinase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)); WHI7HQ7H85 (Uridine)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160616
[Lr] Data última revisão:
160616
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160617
[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


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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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[PMID]:26446564
[Au] Autor:Huang YH; Huang CY
[Ti] Título:Creation of a putative third metal binding site in type II dihydroorotases significantly enhances enzyme activity.
[So] Source:Protein Pept Lett;22(12):1117-22, 2015.
[Is] ISSN:1875-5305
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Dihydroorotase (DHOase) is the third enzyme in the de novo biosynthesis pathway of pyrimidine nucleotides. DHOase is divided into two types (I and II). Type II DHOase generally contains a binuclear metal center in its active site. Recently, the crystal structure of DHOase domain in human CAD protein (huDHOase) has revealed three metal ions in the protein's active site. However, whether type II DHOase can have the critical third metal ion, as observed in huDHOase, remains unknown. In the present study, the putative third metal binding site in type II enzymes, such as the prokaryotic Salmonella enterica serovar Typhimurium LT2 DHOase (StDHOase) and the eukaryotic Saccharomyces cerevisiae DHOase (ScDHOase), was created and identified. StDHOase T198E and ScDHOase T208E mutants had higher activities compared with their wild-type enzymes. The need for a higher DHOase stability and activity may drive creation of the third metal ion binding site in huDHOase, which can be achieved by mutating a highly conserved position T in type II dihydroorotases to E, similar to that in huDHOase.
[Mh] Termos MeSH primário: Aspartato Carbamoiltransferase/química
Proteínas de Bactérias/química
Sítios de Ligação
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/química
Di-Hidro-Orotase/química
Proteínas Recombinantes/química
Proteínas de Saccharomyces cerevisiae/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Aspartato Carbamoiltransferase/genética
Aspartato Carbamoiltransferase/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo
Di-Hidro-Orotase/genética
Di-Hidro-Orotase/metabolismo
Seres Humanos
Modelos Moleculares
Dados de Sequência Molecular
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Proteínas de Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/metabolismo
Salmonella enterica/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (CAD trifunctional enzyme); 0 (Recombinant Proteins); 0 (Saccharomyces cerevisiae Proteins); 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:1608
[Cu] Atualização por classe:151105
[Lr] Data última revisão:
151105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151009
[St] Status:MEDLINE


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[PMID]:25941824
[Au] Autor:Lada AG; Kliver SF; Dhar A; Polev DE; Masharsky AE; Rogozin IB; Pavlov YI
[Ad] Endereço:Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
[Ti] Título:Disruption of Transcriptional Coactivator Sub1 Leads to Genome-Wide Re-distribution of Clustered Mutations Induced by APOBEC in Active Yeast Genes.
[So] Source:PLoS Genet;11(5):e1005217, 2015 May.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in genomes of species are frequently distributed non-randomly, resulting in mutation clusters, including recently discovered kataegis in tumors. DNA editing deaminases play the prominent role in the etiology of these mutations. To gain insight into the enigmatic mechanisms of localized hypermutagenesis that lead to cluster formation, we analyzed the mutational single nucleotide variations (SNV) data obtained by whole-genome sequencing of drug-resistant mutants induced in yeast diploids by AID/APOBEC deaminase and base analog 6-HAP. Deaminase from sea lamprey, PmCDA1, induced robust clusters, while 6-HAP induced a few weak ones. We found that PmCDA1, AID, and APOBEC1 deaminases preferentially mutate the beginning of the actively transcribed genes. Inactivation of transcription initiation factor Sub1 strongly reduced deaminase-induced can1 mutation frequency, but, surprisingly, did not decrease the total SNV load in genomes. However, the SNVs in the genomes of the sub1 clones were re-distributed, and the effect of mutation clustering in the regions of transcription initiation was even more pronounced. At the same time, the mutation density in the protein-coding regions was reduced, resulting in the decrease of phenotypically detected mutants. We propose that the induction of clustered mutations by deaminases involves: a) the exposure of ssDNA strands during transcription and loss of protection of ssDNA due to the depletion of ssDNA-binding proteins, such as Sub1, and b) attainment of conditions favorable for APOBEC action in subpopulation of cells, leading to enzymatic deamination within the currently expressed genes. This model is applicable to both the initial and the later stages of oncogenic transformation and explains variations in the distribution of mutations and kataegis events in different tumor cells.
[Mh] Termos MeSH primário: Proteínas de Ligação a DNA/genética
Regulação Fúngica da Expressão Gênica
Proteínas de Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/genética
Fatores de Transcrição/genética
Ativação Transcricional
[Mh] Termos MeSH secundário: Desaminase APOBEC-1
Alelos
Sistemas de Transporte de Aminoácidos Básicos/genética
Sistemas de Transporte de Aminoácidos Básicos/metabolismo
Aspartato Carbamoiltransferase/genética
Aspartato Carbamoiltransferase/metabolismo
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/metabolismo
Proteínas de Transporte de Cátions/genética
Proteínas de Transporte de Cátions/metabolismo
Citidina Desaminase/genética
Citidina Desaminase/metabolismo
DNA de Cadeia Simples
Proteínas de Ligação a DNA/metabolismo
Genes Reporter
Estudos de Associação Genética
Sequenciamento de Nucleotídeos em Larga Escala
Mutação
Taxa de Mutação
Polimorfismo de Nucleotídeo Único
Regiões Promotoras Genéticas
Proteínas de Saccharomyces cerevisiae/metabolismo
Análise de Sequência de DNA
Fatores de Transcrição/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Amino Acid Transport Systems, Basic); 0 (CAN1 protein, S cerevisiae); 0 (Cation Transport Proteins); 0 (DNA, Single-Stranded); 0 (DNA-Binding Proteins); 0 (SUB1 protein, S cerevisiae); 0 (Saccharomyces cerevisiae Proteins); 0 (Transcription Factors); 0 (URA2 protein, S cerevisiae); 136956-54-2 (TRK1 protein, S cerevisiae); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.4.36 (APOBEC-1 Deaminase); EC 3.5.4.5 (Cytidine Deaminase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing))
[Em] Mês de entrada:1604
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150506
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1005217


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[PMID]:25678555
[Au] Autor:Ng BG; Wolfe LA; Ichikawa M; Markello T; He M; Tifft CJ; Gahl WA; Freeze HH
[Ad] Endereço:Human Genetics Program, Sanford - Burnham Medical Research Institute, 10901 N. Torrey Pines Rd, La Jolla, CA 92037, USA.
[Ti] Título:Biallelic mutations in CAD, impair de novo pyrimidine biosynthesis and decrease glycosylation precursors.
[So] Source:Hum Mol Genet;24(11):3050-7, 2015 Jun 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In mitochondria, carbamoyl-phosphate synthetase 1 activity produces carbamoyl phosphate for urea synthesis, and deficiency results in hyperammonemia. Cytoplasmic carbamoyl-phosphate synthetase 2, however, is part of a tri-functional enzyme encoded by CAD; no human disease has been attributed to this gene. The tri-functional enzyme contains carbamoyl-phosphate synthetase 2 (CPS2), aspartate transcarbamylase (ATCase) and dihydroorotase (DHOase) activities, which comprise the first three of six reactions required for de novo pyrimidine biosynthesis. Here we characterize an individual who is compound heterozygous for mutations in different domains of CAD. One mutation, c.1843-1G>A, results in an in-frame deletion of exon 13. The other, c.6071G>A, causes a missense mutation (p.Arg2024Gln) in a highly conserved residue that is essential for carbamoyl-phosphate binding. Metabolic flux studies showed impaired aspartate incorporation into RNA and DNA through the de novo synthesis pathway. In addition, CTP, UTP and nearly all UDP-activated sugars that serve as donors for glycosylation were decreased. Uridine supplementation rescued these abnormalities, suggesting a potential therapy for this new glycosylation disorder.
[Mh] Termos MeSH primário: Aspartato Carbamoiltransferase/genética
Carbamoil Fosfato Sintase (Glutamina-Hidrolizante)/genética
Di-Hidro-Orotase/genética
Doenças Metabólicas/diagnóstico
Processamento de Proteína Pós-Traducional
Pirimidinas/biossíntese
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Células CHO
Pré-Escolar
Cricetinae
Cricetulus
Análise Mutacional de DNA
Estudos de Associação Genética
Glicosilação
Heterozigoto
Seres Humanos
Masculino
Doenças Metabólicas/genética
Mutação de Sentido Incorreto
Deleção de Sequência
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, N.I.H., INTRAMURAL
[Nm] Nome de substância:
0 (CAD trifunctional enzyme); 0 (Pyrimidines); EC 2.1.3.2 (Aspartate Carbamoyltransferase); EC 3.5.2.3 (Dihydroorotase); EC 6.3.5.5 (Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)); K8CXK5Q32L (pyrimidine)
[Em] Mês de entrada:1602
[Cu] Atualização por classe:161019
[Lr] Data última revisão:
161019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150214
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddv057



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