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[PMID]:28419689
[Au] Autor:Kartvelishvili E; Tworowski D; Vernon H; Moor N; Wang J; Wong LJ; Chrzanowska-Lightowlers Z; Safro M
[Ad] Endereço:Department of Structural Biology, Weizmann Institute of Science, Israel.
[Ti] Título:Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2.
[So] Source:Protein Sci;26(8):1505-1516, 2017 Aug.
[Is] ISSN:1469-896X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Mutations in the mitochondrial aminoacyl-tRNA synthetases (mtaaRSs) can cause profound clinical presentations, and have manifested as diseases with very selective tissue specificity. To date most of the mtaaRS mutations could be phenotypically recognized, such that clinicians could identify the affected mtaaRS from the symptoms alone. Among the recently reported pathogenic variants are point mutations in FARS2 gene, encoding the human mitochondrial PheRS. Patient symptoms range from spastic paraplegia to fatal infantile Alpers encephalopathy. How clinical manifestations of these mutations relate to the changes in three-dimensional structures and kinetic characteristics remains unclear, although impaired aminoacylation has been proposed as possible etiology of diseases. Here, we report four crystal structures of HsmtPheRS mutants, and extensive MD simulations for wild-type and nine mutants to reveal the structural changes on dynamic trajectories of HsmtPheRS. Using steady-state kinetic measurements of phenylalanine activation and tRNA aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene.
[Mh] Termos MeSH primário: Esclerose Cerebral Difusa de Schilder/genética
Proteínas Mitocondriais/química
Mutação
Paraplegia/genética
Fenilalanina-tRNA Ligase/química
RNA de Transferência de Fenilalanina/química
[Mh] Termos MeSH secundário: Adolescente
Motivos de Aminoácidos
Aminoacilação
Sítios de Ligação
Pré-Escolar
Cristalografia por Raios X
Esclerose Cerebral Difusa de Schilder/diagnóstico
Esclerose Cerebral Difusa de Schilder/metabolismo
Esclerose Cerebral Difusa de Schilder/patologia
Feminino
Seres Humanos
Cinética
Masculino
Mitocôndrias/genética
Mitocôndrias/metabolismo
Mitocôndrias/patologia
Proteínas Mitocondriais/genética
Proteínas Mitocondriais/metabolismo
Simulação de Dinâmica Molecular
Paraplegia/diagnóstico
Paraplegia/metabolismo
Paraplegia/patologia
Fenilalanina-tRNA Ligase/genética
Fenilalanina-tRNA Ligase/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
RNA de Transferência de Fenilalanina/metabolismo
Alinhamento de Sequência
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mitochondrial Proteins); 0 (RNA, Transfer, Phe); EC 6.1.1.20 (FARS2 protein, human); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170824
[Lr] Data última revisão:
170824
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170419
[St] Status:MEDLINE
[do] DOI:10.1002/pro.3176


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[PMID]:28168297
[Au] Autor:Mohler K; Mann R; Bullwinkle TJ; Hopkins K; Hwang L; Reynolds NM; Gassaway B; Aerni HR; Rinehart J; Polymenis M; Faull K; Ibba M
[Ad] Endereço:Department of Microbiology, The Ohio State University, 318 West 12th Avenue, Columbus, OH 43210, USA.
[Ti] Título:Editing of misaminoacylated tRNA controls the sensitivity of amino acid stress responses in Saccharomyces cerevisiae.
[So] Source:Nucleic Acids Res;45(7):3985-3996, 2017 Apr 20.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Amino acid starvation activates the protein kinase Gcn2p, leading to changes in gene expression and translation. Gcn2p is activated by deacylated tRNA, which accumulates when tRNA aminoacylation is limited by lack of substrates or inhibition of synthesis. Pairing of amino acids and deacylated tRNAs is catalyzed by aminoacyl-tRNA synthetases, which use quality control pathways to maintain substrate specificity. Phenylalanyl-tRNA synthetase (PheRS) maintains specificity via an editing pathway that targets non-cognate Tyr-tRNAPhe. While the primary role of aaRS editing is to prevent misaminoacylation, we demonstrate editing of misaminoacylated tRNA is also required for detection of amino acid starvation by Gcn2p. Ablation of PheRS editing caused accumulation of Tyr-tRNAPhe (5%), but not deacylated tRNAPhe during amino acid starvation, limiting Gcn2p kinase activity and suppressing Gcn4p-dependent gene expression. While the PheRS-editing ablated strain grew 50% slower and displayed a 27-fold increase in the rate of mistranslation of Phe codons as Tyr compared to wild type, the increase in mistranslation was insufficient to activate an unfolded protein stress response. These findings show that during amino acid starvation a primary role of aaRS quality control is to help the cell mount an effective stress response, independent of the role of editing in maintaining translational accuracy.
[Mh] Termos MeSH primário: Fenilalanina-tRNA Ligase/metabolismo
Edição de RNA
RNA de Transferência de Fenilalanina/metabolismo
Saccharomyces cerevisiae/metabolismo
Aminoacilação de RNA de Transferência
Resposta a Proteínas não Dobradas
[Mh] Termos MeSH secundário: Aminoácidos/metabolismo
Fenilalanina/metabolismo
Aminoacil-RNA de Transferência/metabolismo
Saccharomyces cerevisiae/enzimologia
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/crescimento & desenvolvimento
Estresse Fisiológico
Tirosina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (RNA, Transfer, Amino Acyl); 0 (RNA, Transfer, Phe); 42HK56048U (Tyrosine); 47E5O17Y3R (Phenylalanine); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170208
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx077


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[PMID]:28039138
[Au] Autor:Argov T; Rabinovich L; Sigal N; Herskovits AA
[Ad] Endereço:Department of Molecular Microbiology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel.
[Ti] Título:An Effective Counterselection System for Listeria monocytogenes and Its Use To Characterize the Monocin Genomic Region of Strain 10403S.
[So] Source:Appl Environ Microbiol;83(6), 2017 Mar 15.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Construction of mutants by allelic exchange has been laborious and time-consuming due to lack of proficient selection markers for the final recombination event, that is, a marker conveying substance sensitivity to the bacteria bearing it, enabling the exclusion of merodiploids and selection for plasmid loss. In order to address this issue, we engineered a counterselection marker based on a mutated phenylalanyl-tRNA synthetase gene ( ). This mutation renders the phenylalanine-binding site of the enzyme more promiscuous and allows the binding of the toxic -chloro-phenylalanine analog ( -Cl-phe) as a substrate. When is introduced into and highly expressed under control of a constitutively active promoter, the bacteria become sensitive to -Cl-phe supplemented in the medium. This enabled us to utilize as a negative selection marker and generate a novel, efficient suicide vector for allelic exchange in We used this vector to investigate the monocin genomic region in strain 10403S by constructing deletion mutants of the region. We have found this region to be active and to cause bacterial lysis upon mitomycin C treatment. The future applications of such an effective counterselection system, which does not require any background genomic alterations, are vast, as it can be modularly used in various selection systems (e.g., genetic screens). We expect this counterselection marker to be a valuable genetic tool in research on is an opportunistic intracellular pathogen and a widely studied model organism. An efficient counterselection marker is a long-standing need in research for improving the ability to design and perform various genetic manipulations and screening systems for different purposes. We report the construction and utilization of an efficient suicide vector for allelic exchange which can be conjugated, leaves no marker in the bacterial chromosome, and does not require the use of sometimes leaky inducible promoters. This highly efficient genome editing tool for will allow for rapid sequential mutagenesis, introduction of point mutations, and design of screening systems. We anticipate that it will be extensively used by the research community and yield novel insights into the diverse fields studied using this model organism.
[Mh] Termos MeSH primário: Bacteriocinas/genética
Listeria monocytogenes/genética
Mitomicina/farmacologia
Fenilalanina-tRNA Ligase/genética
Fenilalanina/análogos & derivados
[Mh] Termos MeSH secundário: Sítios de Ligação/genética
Sítios de Ligação/fisiologia
Marcadores Genéticos/genética
Listeria monocytogenes/crescimento & desenvolvimento
Fenilalanina/metabolismo
Regiões Promotoras Genéticas/genética
Seleção Genética/genética
Deleção de Sequência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacteriocins); 0 (Genetic Markers); 47E5O17Y3R (Phenylalanine); 50SG953SK6 (Mitomycin); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170101
[St] Status:MEDLINE


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[PMID]:27730334
[Au] Autor:Zhou C; Shi L; Ye B; Feng H; Zhang J; Zhang R; Yan X
[Ad] Endereço:Department of Microbiology, College of Life Sciences, Key Laboratory for Microbiological Engineering of Agricultural, Environment of Ministry of Agriculture, Nanjing Agricultural University, 6 Tongwei Road, Nanjing, Jiangsu, 210095, People's Republic of China.
[Ti] Título:pheS , an effective host-genotype-independent counter-selectable marker for marker-free chromosome deletion in Bacillus amyloliquefaciens.
[So] Source:Appl Microbiol Biotechnol;101(1):217-227, 2017 Jan.
[Is] ISSN:1432-0614
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Aside from applications in the production of commercial enzymes and metabolites, Bacillus amyloliquefaciens is also an important group of plant growth-promoting rhizobacteria that supports plant growth and suppresses phytopathogens. A host-genotype-independent counter-selectable marker would enable rapid genetic manipulation and metabolic engineering, accelerating the study of B. amyloliquefaciens and its development as both a microbial cell factory and plant growth-promoting rhizobacteria. Here, a host-genotype-independent counter-selectable marker pheS was constructed through a point mutation of the gene pheS, which encodes the α-subunit of phenylalanyl-tRNA synthetase in Bacillus subtilis strain 168. In the presence of 5 mM p-chloro-phenylalanine, 100 % of B. amyloliquefaciens strain SQR9 cells carrying pheS were killed, whereas the wild-type strain SQR9 showed resistance to p-chloro-phenylalanine. A simple pheS and overlap-PCR-based strategy was developed to create the marker-free deletion of the amyE gene as well as a 37-kb bmy cluster in B. amyloliquefaciens SQR9. The effectiveness of pheS as a counter-selectable marker in B. amyloliquefaciens was further confirmed through the deletion of amyE genes in strains B. amyloliquefaciens FZB42 and NJN-6. In addition, the potential use of pheS in other Bacillus species was preliminarily assessed. The expression of PheS in B. subtilis strain 168 and B. cereus strain ATCC 14579 caused pronounced sensitivity of both hosts to p-chloro-phenylalanine, indicating that pheS could be used as a counter-selectable marker (CSM) in these strains.
[Mh] Termos MeSH primário: Bacillus amyloliquefaciens/genética
Técnicas de Inativação de Genes/métodos
Genética Microbiana/métodos
Fenilalanina-tRNA Ligase/genética
Seleção Genética
[Mh] Termos MeSH secundário: Antibacterianos/toxicidade
Bacillus amyloliquefaciens/fisiologia
Bacillus subtilis/genética
Bacillus subtilis/fisiologia
Fenclonina/toxicidade
Genótipo
Viabilidade Microbiana/efeitos dos fármacos
Proteínas Mutantes/genética
Proteínas Mutantes/metabolismo
Fenilalanina-tRNA Ligase/metabolismo
Mutação Puntual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Mutant Proteins); EC 6.1.1.20 (Phenylalanine-tRNA Ligase); R5J7E3L9SP (Fenclonine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170620
[Lr] Data última revisão:
170620
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161013
[St] Status:MEDLINE
[do] DOI:10.1007/s00253-016-7906-9


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[PMID]:27639596
[Au] Autor:Kino Y; Nakayama-Imaohji H; Fujita M; Tada A; Yoneda S; Murakami K; Hashimoto M; Hayashi T; Okazaki K; Kuwahara T
[Ad] Endereço:Department of Microbiology, Faculty of Medicine, Kagawa University, 1750-1, Miki, Kagawa 761-0793, Japan.
[Ti] Título:Counterselection employing mutated pheS for markerless genetic deletion in Bacteroides species.
[So] Source:Anaerobe;42:81-88, 2016 Dec.
[Is] ISSN:1095-8274
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Markerless gene deletion is necessary for multiple gene disruptions due to the limited number of antibiotic resistant markers for some bacteria. However, even in transformable strains, obtaining the expected mutation without a marker requires laborious screening of a large number of colonies. Previous studies had success in various bacteria with a counter-selection system where a conditional lethal gene was incorporated into the vector. We examined the efficacy of the mutated pheS gene (pheS*) as a counter-selective marker for gene deletion in Bacteroides. This mutation produces an amino acid substitution (A303G) in the alpha subunit of Bacteroides phenylalanyl tRNA synthetase, which in E. coli alters the specificity of the tRNA synthetase resulting in a conditional lethal mutation due to the incorporation of p-chloro-phenylalanine (p-Cl-Phe) into protein. B. fragilis YCH46 and B. thetaiotaomicron VPI-5482 transformed with a pheS*-harboring shuttle vector were clearly growth-inhibited in the presence of >5 mM p-Cl-Phe in liquid defined minimal media (DMM) and on DMM agar plates. A targeting plasmid was constructed to delete the genetic region for capsular polysaccharide PS2 in B. fragilis or PS1 in B. thetaiotaomicron. After counterselection, p-Cl-Phe-resistant colonies were generated at a frequency of 8.1 × 10 for B. fragilis and 1.7 × 10 for B. thetaiotaomicron. Of the p-Cl-Phe-resistant colonies, 4.2% and 72% harbored the correct genetic deletion for B. fragilis and B. thetaiotaomicron, respectively. These results indicate that mutated pheS is a useful counter-selective gene to construct markerless genetic deletions in Bacteroides.
[Mh] Termos MeSH primário: Proteínas de Bactérias/genética
Bacteroides/genética
Deleção de Genes
Mutação
Fenilalanina-tRNA Ligase/genética
Subunidades Proteicas/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos
Cápsulas Bacterianas/metabolismo
Proteínas de Bactérias/metabolismo
Bacteroides/metabolismo
Meios de Cultura/farmacologia
Escherichia coli/genética
Escherichia coli/metabolismo
Fenclonina/farmacologia
Expressão Gênica
Genes Letais
Engenharia Genética
Marcadores Genéticos
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Fenilalanina-tRNA Ligase/metabolismo
Polissacarídeos Bacterianos/metabolismo
Subunidades Proteicas/metabolismo
Alinhamento de Sequência
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Culture Media); 0 (Genetic Markers); 0 (Polysaccharides, Bacterial); 0 (Protein Subunits); EC 6.1.1.20 (Phenylalanine-tRNA Ligase); R5J7E3L9SP (Fenclonine)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:27602946
[Au] Autor:Kato N; Comer E; Sakata-Kato T; Sharma A; Sharma M; Maetani M; Bastien J; Brancucci NM; Bittker JA; Corey V; Clarke D; Derbyshire ER; Dornan GL; Duffy S; Eckley S; Itoe MA; Koolen KM; Lewis TA; Lui PS; Lukens AK; Lund E; March S; Meibalan E; Meier BC; McPhail JA; Mitasev B; Moss EL; Sayes M; Van Gessel Y; Wawer MJ; Yoshinaga T; Zeeman AM; Avery VM; Bhatia SN; Burke JE; Catteruccia F; Clardy JC; Clemons PA; Dechering KJ; Duvall JR; Foley MA; Gusovsky F; Kocken CH; Marti M; Morningstar ML; Munoz B; Neafsey DE; Sharma A; Winzeler EA; Wirth DF
[Ad] Endereço:Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, Massachusetts 02142, USA.
[Ti] Título:Diversity-oriented synthesis yields novel multistage antimalarial inhibitors.
[So] Source:Nature;538(7625):344-349, 2016 Oct 20.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Antimalarial drugs have thus far been chiefly derived from two sources-natural products and synthetic drug-like compounds. Here we investigate whether antimalarial agents with novel mechanisms of action could be discovered using a diverse collection of synthetic compounds that have three-dimensional features reminiscent of natural products and are underrepresented in typical screening collections. We report the identification of such compounds with both previously reported and undescribed mechanisms of action, including a series of bicyclic azetidines that inhibit a new antimalarial target, phenylalanyl-tRNA synthetase. These molecules are curative in mice at a single, low dose and show activity against all parasite life stages in multiple in vivo efficacy models. Our findings identify bicyclic azetidines with the potential to both cure and prevent transmission of the disease as well as protect at-risk populations with a single oral dose, highlighting the strength of diversity-oriented synthesis in revealing promising therapeutic targets.
[Mh] Termos MeSH primário: Antimaláricos/síntese química
Antimaláricos/farmacologia
Azetidinas/uso terapêutico
Descoberta de Drogas
Estágios do Ciclo de Vida/efeitos dos fármacos
Malária Falciparum/tratamento farmacológico
Plasmodium falciparum/efeitos dos fármacos
Plasmodium falciparum/crescimento & desenvolvimento
[Mh] Termos MeSH secundário: Animais
Antimaláricos/administração & dosagem
Antimaláricos/uso terapêutico
Compostos Azabicíclicos/administração & dosagem
Compostos Azabicíclicos/síntese química
Compostos Azabicíclicos/farmacologia
Compostos Azabicíclicos/uso terapêutico
Azetidinas/administração & dosagem
Azetidinas/efeitos adversos
Azetidinas/farmacologia
Citosol/enzimologia
Modelos Animais de Doenças
Feminino
Fígado/efeitos dos fármacos
Fígado/parasitologia
Macaca mulatta/parasitologia
Malária Falciparum/prevenção & controle
Malária Falciparum/transmissão
Masculino
Camundongos
Fenilalanina-tRNA Ligase/antagonistas & inibidores
Compostos de Fenilureia/administração & dosagem
Compostos de Fenilureia/síntese química
Compostos de Fenilureia/farmacologia
Compostos de Fenilureia/uso terapêutico
Plasmodium falciparum/citologia
Plasmodium falciparum/enzimologia
Segurança
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antimalarials); 0 (Azabicyclo Compounds); 0 (Azetidines); 0 (BRD7929); 0 (Phenylurea Compounds); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170720
[Lr] Data última revisão:
170720
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160908
[St] Status:MEDLINE
[do] DOI:10.1038/nature19804


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[PMID]:27549011
[Au] Autor:Raviglione F; Conte G; Ghezzi D; Parazzini C; Righini A; Vergaro R; Legati A; Spaccini L; Gasperini S; Garavaglia B; Mastrangelo M
[Ad] Endereço:Paediatric Neurology Unit, Children's Hospital V. Buzzi, Milan, Italy. federico.raviglione@asst-fbf-sacco.it.
[Ti] Título:Clinical findings in a patient with FARS2 mutations and early-infantile-encephalopathy with epilepsy.
[So] Source:Am J Med Genet A;170(11):3004-3007, 2016 Nov.
[Is] ISSN:1552-4833
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The FARS2 gene encodes the mitochondrial phenylalanyl-tRNA synthetase and is implicated in autosomal recessive combined oxidative phosphorylation deficiency 14, a clinical condition characterized by infantile onset epilepsy and encephalopathy. Mutations in FARS2 have been reported in only few patients, but a detailed description of seizures, electroencephalographic patterns, magnetic resonance imaging findings, and long-term follow-up is still needed. We provide a clinical report of a child with FARS2-related disease manifesting drug-resistant infantile spasms associated with focal seizures. By comparative genomic hybridization analysis we identified a heterozygous microdeletion in the short arm of chromosome 6, inherited from the mother, that encompasses the first coding exon of FARS2. By sequencing of the FARS2 gene we identified a variant c.1156C>G; p.(R386G), inherited from the father. By using standard spectrophotometric techniques in skin fibroblasts, we found a combined abnormality of complexes I and IV of the mitochondrial respiratory chain. The main clinical features of the patient included axial hypotonia, mild distal hypertonia, and psychomotor delay. The magnetic resonance imaging showed microcephaly, frontal cerebral atrophy, and signal changes of dentate nuclei. At the age of 3 years and 6 months, the patient was still under treatment with vigabatrin and he has been seizure free for the last 23 months. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Proteínas Mitocondriais/genética
Mutação
Fenilalanina-tRNA Ligase/genética
Espasmos Infantis/diagnóstico
Espasmos Infantis/genética
[Mh] Termos MeSH secundário: Anticonvulsivantes/uso terapêutico
Encéfalo/patologia
Deleção Cromossômica
Cromossomos Humanos Par 6
Hibridização Genômica Comparativa
Eletroencefalografia
Éxons
Heterozigoto
Seres Humanos
Lactente
Imagem por Ressonância Magnética
Masculino
Fenótipo
Espasmos Infantis/tratamento farmacológico
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anticonvulsants); 0 (Mitochondrial Proteins); EC 6.1.1.20 (FARS2 protein, human); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160824
[St] Status:MEDLINE
[do] DOI:10.1002/ajmg.a.37836


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[PMID]:27226603
[Au] Autor:Moghal A; Hwang L; Faull K; Ibba M
[Ad] Endereço:From the Ohio State Biochemistry Program, Department of Microbiology, The Ohio State University, Columbus, Ohio 43210 and.
[Ti] Título:Multiple Quality Control Pathways Limit Non-protein Amino Acid Use by Yeast Cytoplasmic Phenylalanyl-tRNA Synthetase.
[So] Source:J Biol Chem;291(30):15796-805, 2016 07 22.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Non-protein amino acids, particularly isomers of the proteinogenic amino acids, present a threat to proteome integrity if they are mistakenly inserted into proteins. Quality control during aminoacyl-tRNA synthesis reduces non-protein amino acid incorporation by both substrate discrimination and proofreading. For example phenylalanyl-tRNA synthetase (PheRS) proofreads the non-protein hydroxylated phenylalanine derivative m-Tyr after its attachment to tRNA(Phe) We now show in Saccharomyces cerevisiae that PheRS misacylation of tRNA(Phe) with the more abundant Phe oxidation product o-Tyr is limited by kinetic discrimination against o-Tyr-AMP in the transfer step followed by o-Tyr-AMP release from the synthetic active site. This selective rejection of a non-protein aminoacyl-adenylate is in addition to known kinetic discrimination against certain non-cognates in the activation step as well as catalytic hydrolysis of mispaired aminoacyl-tRNA(Phe) species. We also report an unexpected resistance to cytotoxicity by a S. cerevisiae mutant with ablated post-transfer editing activity when supplemented with o-Tyr, cognate Phe, or Ala, the latter of which is not a substrate for activation by this enzyme. Our phenotypic, metabolomic, and kinetic analyses indicate at least three modes of discrimination against non-protein amino acids by S. cerevisiae PheRS and support a non-canonical role for SccytoPheRS post-transfer editing in response to amino acid stress.
[Mh] Termos MeSH primário: Fenilalanina-tRNA Ligase/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/enzimologia
[Mh] Termos MeSH secundário: Acilação
Monofosfato de Adenosina/genética
Monofosfato de Adenosina/metabolismo
Alanina/genética
Alanina/metabolismo
Mutação
Fenilalanina/genética
Fenilalanina/metabolismo
Fenilalanina-tRNA Ligase/genética
RNA Fúngico/genética
RNA Fúngico/metabolismo
RNA de Transferência de Fenilalanina/genética
RNA de Transferência de Fenilalanina/metabolismo
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (RNA, Fungal); 0 (RNA, Transfer, Phe); 0 (Saccharomyces cerevisiae Proteins); 415SHH325A (Adenosine Monophosphate); 47E5O17Y3R (Phenylalanine); EC 6.1.1.20 (Phenylalanine-tRNA Ligase); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160527
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.726828


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[PMID]:27028506
[Au] Autor:Kwon I; Choi ES
[Ad] Endereço:School of Materials Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, Republic of Korea.
[Ti] Título:Forced Ambiguity of the Leucine Codons for Multiple-Site-Specific Incorporation of a Noncanonical Amino Acid.
[So] Source:PLoS One;11(3):e0152826, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Multiple-site-specific incorporation of a noncanonical amino acid into a recombinant protein would be a very useful technique to generate multiple chemical handles for bioconjugation and multivalent binding sites for the enhanced interaction. Previously combination of a mutant yeast phenylalanyl-tRNA synthetase variant and the yeast phenylalanyl-tRNA containing the AAA anticodon was used to incorporate a noncanonical amino acid into multiple UUU phenylalanine (Phe) codons in a site-specific manner. However, due to the less selective codon recognition of the AAA anticodon, there was significant misincorporation of a noncanonical amino acid into unwanted UUC Phe codons. To enhance codon selectivity, we explored degenerate leucine (Leu) codons instead of Phe degenerate codons. Combined use of the mutant yeast phenylalanyl-tRNA containing the CAA anticodon and the yPheRS_naph variant allowed incorporation of a phenylalanine analog, 2-naphthylalanine, into murine dihydrofolate reductase in response to multiple UUG Leu codons, but not to other Leu codon sites. Despite the moderate UUG codon occupancy by 2-naphthylalaine, these results successfully demonstrated that the concept of forced ambiguity of the genetic code can be achieved for the Leu codons, available for multiple-site-specific incorporation.
[Mh] Termos MeSH primário: Alanina/análogos & derivados
Códon/metabolismo
Leucina/metabolismo
Naftalenos/metabolismo
Fenilalanina-tRNA Ligase/metabolismo
Proteínas de Saccharomyces cerevisiae/metabolismo
Saccharomyces cerevisiae/metabolismo
[Mh] Termos MeSH secundário: Alanina/genética
Alanina/metabolismo
Anticódon/genética
Anticódon/metabolismo
Códon/genética
Leucina/genética
Fenilalanina-tRNA Ligase/genética
Saccharomyces cerevisiae/genética
Proteínas de Saccharomyces cerevisiae/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (2-naphthylalanine); 0 (Anticodon); 0 (Codon); 0 (Naphthalenes); 0 (Saccharomyces cerevisiae Proteins); EC 6.1.1.20 (Phenylalanine-tRNA Ligase); GMW67QNF9C (Leucine); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160331
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0152826


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[PMID]:26858451
[Au] Autor:Bullwinkle TJ; Ibba M
[Ad] Endereço:Department of Microbiology, The Ohio State University, Columbus, OH 43210.
[Ti] Título:Translation quality control is critical for bacterial responses to amino acid stress.
[So] Source:Proc Natl Acad Sci U S A;113(8):2252-7, 2016 Feb 23.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Gene expression relies on quality control for accurate transmission of genetic information. One mechanism that prevents amino acid misincorporation errors during translation is editing of misacylated tRNAs by aminoacyl-tRNA synthetases. In the absence of editing, growth is limited upon exposure to excess noncognate amino acid substrates and other stresses, but whether these physiological effects result solely from mistranslation remains unclear. To explore if translation quality control influences cellular processes other than protein synthesis, an Escherichia coli strain defective in Tyr-tRNA(Phe) editing was used. In the absence of editing, cellular levels of aminoacylated tRNA(Phe) were elevated during amino acid stress, whereas in the wild-type strain these levels declined under the same growth conditions. In the editing-defective strain, increased levels of aminoacylated tRNA(Phe) led to continued synthesis of the PheL leader peptide and attenuation of pheA transcription under amino acid stress. Consequently, in the absence of editing, activation of the phenylalanine biosynthetic operon becomes less responsive to phenylalanine limitation. In addition to raising aminoacylated tRNA levels, the absence of editing lowered the amount of deacylated tRNA(Phe) in the cell. This reduction in deacylated tRNA was accompanied by decreased synthesis of the second messenger guanosine tetraphosphate and limited induction of stringent response-dependent gene expression in editing-defective cells during amino acid stress. These data show that a single quality-control mechanism, the editing of misacylated aminoacyl-tRNAs, provides a critical checkpoint both for maintaining the accuracy of translation and for determining the sensitivity of transcriptional responses to amino acid stress.
[Mh] Termos MeSH primário: Aminoácidos/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Fenilalanina-tRNA Ligase/genética
Fenilalanina-tRNA Ligase/metabolismo
Biossíntese de Proteínas
Edição de RNA
RNA Bacteriano/genética
RNA Bacteriano/metabolismo
Aminoacil-RNA de Transferência/genética
Aminoacil-RNA de Transferência/metabolismo
Estresse Fisiológico
Aminoacilação de RNA de Transferência
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Nm] Nome de substância:
0 (Amino Acids); 0 (Escherichia coli Proteins); 0 (RNA, Bacterial); 0 (RNA, Transfer, Amino Acyl); EC 6.1.1.20 (Phenylalanine-tRNA Ligase)
[Em] Mês de entrada:1607
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160210
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1525206113



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