Base de dados : MEDLINE
Pesquisa : D08.811.520.241.300.950 [Categoria DeCS]
Referências encontradas : 178 [refinar]
Mostrando: 1 .. 10   no formato [Detalhado]

página 1 de 18 ir para página                         

  1 / 178 MEDLINE  
              next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:28334762
[Au] Autor:Blouin JM; Bernardo-Seisdedos G; Sasso E; Esteve J; Ged C; Lalanne M; Sanz-Parra A; Urquiza P; de Verneuil H; Millet O; Richard E
[Ad] Endereço:Université de Bordeaux.
[Ti] Título:Missense UROS mutations causing congenital erythropoietic porphyria reduce UROS homeostasis that can be rescued by proteasome inhibition.
[So] Source:Hum Mol Genet;26(8):1565-1576, 2017 Apr 15.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Congenital erythropoietic porphyria (CEP) is an inborn error of heme biosynthesis characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in deleterious porphyrin accumulation in blood cells responsible for hemolytic anemia and cutaneous photosensitivity. We analyzed here the molecular basis of UROS impairment associated with twenty nine UROS missense mutations actually described in CEP patients. Using a computational and biophysical joint approach we predicted that most disease-causing mutations would affect UROS folding and stability. Through the analysis of enhanced green fluorescent protein-tagged versions of UROS enzyme we experimentally confirmed these data and showed that thermodynamic instability and premature protein degradation is a major mechanism accounting for the enzymatic deficiency associated with twenty UROS mutants in human cells. Since the intracellular loss in protein homeostasis is in excellent agreement with the in vitro destabilization, we used molecular dynamic simulation to rely structural 3D modification with UROS disability. We found that destabilizing mutations could be clustered within three types of mechanism according to side chain rearrangements or contact alterations within the pathogenic UROS enzyme so that the severity degree correlated with cellular protein instability. Furthermore, proteasome inhibition using bortezomib, a clinically available drug, significantly enhanced proteostasis of each unstable UROS mutant. Finally, we show evidence that abnormal protein homeostasis is a prevalent mechanism responsible for UROS deficiency and that modulators of UROS proteolysis such as proteasome inhibitors or chemical chaperones may represent an attractive therapeutic option to reduce porphyrin accumulation and prevent skin photosensitivity in CEP patients when the genotype includes a missense variant.
[Mh] Termos MeSH primário: Mutação de Sentido Incorreto/genética
Porfiria Eritropoética/genética
Relação Estrutura-Atividade
Uroporfirinogênio III Sintetase/genética
[Mh] Termos MeSH secundário: Biologia Computacional
Homeostase
Seres Humanos
Porfiria Eritropoética/metabolismo
Porfiria Eritropoética/patologia
Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos
Complexo de Endopeptidases do Proteassoma/genética
Inibidores de Proteassoma/química
Inibidores de Proteassoma/uso terapêutico
Dobramento de Proteína
Uroporfirinogênio III Sintetase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteasome Inhibitors); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170515
[Lr] Data última revisão:
170515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx067


  2 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27756106
[Au] Autor:Szilágyi A; Györffy D; Závodszky P
[Ad] Endereço:Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
[Ti] Título:Segment swapping aided the evolution of enzyme function: The case of uroporphyrinogen III synthase.
[So] Source:Proteins;85(1):46-53, 2017 Jan.
[Is] ISSN:1097-0134
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In an earlier study, we showed that two-domain segment-swapped proteins can evolve by domain swapping and fusion, resulting in a protein with two linkers connecting its domains. We proposed that a potential evolutionary advantage of this topology may be the restriction of interdomain motions, which may facilitate domain closure by a hinge-like movement, crucial for the function of many enzymes. Here, we test this hypothesis computationally on uroporphyrinogen III synthase, a two-domain segment-swapped enzyme essential in porphyrin metabolism. To compare the interdomain flexibility between the wild-type, segment-swapped enzyme (having two interdomain linkers) and circular permutants of the same enzyme having only one interdomain linker, we performed geometric and molecular dynamics simulations for these species in their ligand-free and ligand-bound forms. We find that in the ligand-free form, interdomain motions in the wild-type enzyme are significantly more restricted than they would be with only one interdomain linker, while the flexibility difference is negligible in the ligand-bound form. We also estimated the entropy costs of ligand binding associated with the interdomain motions, and find that the change in domain connectivity due to segment swapping results in a reduction of this entropy cost, corresponding to ∼20% of the total ligand binding free energy. In addition, the restriction of interdomain motions may also help the functional domain-closure motion required for catalysis. This suggests that the evolution of the segment-swapped topology facilitated the evolution of enzyme function for this protein by influencing its dynamic properties. Proteins 2016; 85:46-53. © 2016 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Thermus thermophilus/química
Uroporfirinogênio III Sintetase/química
Uroporfirinogênios/química
[Mh] Termos MeSH secundário: Biocatálise
Entropia
Evolução Molecular
Ligantes
Simulação de Dinâmica Molecular
Movimento (Física)
Ligação Proteica
Domínios Proteicos
Estrutura Secundária de Proteína
Thermus thermophilus/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Ligands); 0 (Uroporphyrinogens); 71861-60-4 (hydroxymethylbilane); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170724
[Lr] Data última revisão:
170724
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE
[do] DOI:10.1002/prot.25190


  3 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:27086902
[Au] Autor:Aguilera P; Badenas C; Whatley SD; To-Figueras J
[Ad] Endereço:Departments of Dermatology, Biochemistry and Molecular Genetics, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain.
[Ti] Título:Late-onset cutaneous porphyria in a patient heterozygous for a uroporphyrinogen III synthase gene mutation.
[So] Source:Br J Dermatol;175(6):1346-1350, 2016 Dec.
[Is] ISSN:1365-2133
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Deficiency of uroporphyrinogen III synthase (UROS) causes congenital erythropoietic porphyria (CEP). The disease, originating from the inheritance of mutations within the UROS gene, presents a recessive form of transmission. In a few patients, a late-onset CEP-like phenotype without UROS mutations appears to be associated with a myelodysplastic syndrome. We report a 60-year-old man with late-onset signs of cutaneous porphyria and accumulation in urine, plasma and faeces of type I porphyrin isomers characteristic of CEP. Analysis of DNA from peripheral leucocytes, skin and bone marrow aspirate showed that he was a heterozygous carrier of a Cys73Arg (c.217 T>C) mutation within UROS. Sequencing of cDNA from peripheral blood confirmed heterozygosity and expression of the normal allele. Measurement of UROS enzymatic activity in erythrocytes showed values ~70% of normal, indirectly indicating expression of the normal allele. Differently from other cases of late-onset uroporphyria, the patient did not present thrombocytopenia or any evidence of a myelodysplastic syndrome. Five years of clinical follow-up showed persistence of skin signs and increased excretion of porphyrins, independently of lifestyle factors or changes in medication regimes. We hypothesize acquired mosaicism (in the bone marrow) affecting the UROS gene. Thus, unstable cellular clones initiated overproduction of isomer I porphyrins leading to a CEP phenotype. This could be explained either by a clonal expansion of the porphyric (Cys73Arg) allele or by loss of function of the normal allele. Cellular turnover would facilitate release of uroporphyrins into circulation and subsequent skin lesions. This is the first case of a CEP heterozygous carrier presenting clinical manifestations.
[Mh] Termos MeSH primário: Dermatoses da Mão/genética
Transtornos de Início Tardio/genética
Mutação de Sentido Incorreto/genética
Porfirias/genética
Uroporfirinogênio III Sintetase/genética
[Mh] Termos MeSH secundário: Heterozigoto
Seres Humanos
Masculino
Meia-Idade
Porfirinas/metabolismo
[Pt] Tipo de publicação:CASE REPORTS
[Nm] Nome de substância:
0 (Porphyrins); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160419
[St] Status:MEDLINE
[do] DOI:10.1111/bjd.14675


  4 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:26969896
[Au] Autor:Di Pierro E; Brancaleoni V; Granata F
[Ad] Endereço:U.O. di Medicina Interna, Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico, Milano, Italy.
[Ti] Título:Advances in understanding the pathogenesis of congenital erythropoietic porphyria.
[So] Source:Br J Haematol;173(3):365-79, 2016 May.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Congenital erythropoietic porphyria (CEP) is a rare genetic disease resulting from the remarkable deficient activity of uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. This enzyme defect results in overproduction of the non-physiological and pathogenic porphyrin isomers, uroporphyrin I and coproporphyrin I. The predominant clinical characteristics of CEP include bullous cutaneous photosensitivity to visible light from early infancy, progressive photomutilation and chronic haemolytic anaemia. The severity of clinical manifestations is markedly heterogeneous among patients; and interdependence between disease severity and porphyrin amount in the tissues has been pointed out. A more pronounced endogenous production of porphyrins concomitant to activation of ALAS2, the first and rate-limiting of the haem synthesis enzymes in erythroid cells, has also been reported. CEP is inherited as autosomal recessive or X-linked trait due to mutations in UROS or GATA1 genes; however an involvement of other causative or modifier genes cannot be ruled out.
[Mh] Termos MeSH primário: Porfiria Eritropoética/patologia
[Mh] Termos MeSH secundário: Fator de Transcrição GATA1/genética
Heme/biossíntese
Seres Humanos
Mutação
Fenótipo
Porfiria Eritropoética/etiologia
Porfiria Eritropoética/genética
Porfiria Eritropoética/metabolismo
Porfirinas/biossíntese
Porfirinas/metabolismo
Uroporfirinogênio III Sintetase
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (GATA1 Transcription Factor); 0 (GATA1 protein, human); 0 (Porphyrins); 42VZT0U6YR (Heme); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160313
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.13978


  5 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:25352395
[Au] Autor:Jiao L; Wang L; Qiu Z; Wang Q; Zhou Q; Huang X
[Ad] Endereço:State Key Laboratory of Food Science and Technology, College of Environmental and Civil Engineering, Jiangnan University, Wuxi, 214122, China.
[Ti] Título:Effects of bisphenol A on chlorophyll synthesis in soybean seedlings.
[So] Source:Environ Sci Pollut Res Int;22(8):5877-86, 2015 Apr.
[Is] ISSN:1614-7499
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Bisphenol A (BPA), as an emerging environmental pollutant, is potentially harmful to plant growth. Chlorophyll (Chl) is critical in photosynthesis that provides matter and energy for plant growth. How BPA affects the chlorophyll content remains largely unknown. Here, the effects of BPA on Chl synthesis in soybean seedlings were investigated. Exposure to 1.5 mg/L BPA decreased the 5-aminolevulinic acid (ALA) content and increased protoporphyrin IX (Proto IX), magnesium protoporphyrin, and protochlorophyll contents and 5-aminolaevulinic acid dehydratase, porphobilinogen deaminase, uroporphyrinogen III synthase, uroporphyrinogen III decarboxylase, and protoporphyrinogen oxidase activities. Exposure to 17.2 and 50.0 mg/L BPA exerted the opposite effects on these four intermediates and five enzymes. Following the withdrawal of BPA exposure, the aforementioned parameters gradually recovered, except magnesium protoporphyrin content in exposure to 50.0 mg/L BPA. Our findings revealed that exposure to low-concentration BPA increased the Chl content in soybean seedlings through improving Chl synthesis, especially the conversion from ALA to Proto IX, whereas exposure to high-concentration BPA decreased the Chl content through inhibiting Chl synthesis, especially the conversion from ALA to Proto IX. The dual effects of BPA were largely reversed following the withdrawal of BPA exposure.
[Mh] Termos MeSH primário: Compostos Benzidrílicos/toxicidade
Vias Biossintéticas/efeitos dos fármacos
Poluentes Ambientais/toxicidade
Fenóis/toxicidade
Fotossíntese/efeitos dos fármacos
Plântulas/efeitos dos fármacos
Feijão de Soja/efeitos dos fármacos
[Mh] Termos MeSH secundário: Ácido Aminolevulínico/metabolismo
Análise de Variância
Clorofila/análogos & derivados
Clorofila/metabolismo
Hidroximetilbilano Sintase/metabolismo
Folhas de Planta/química
Sintase do Porfobilinogênio/metabolismo
Protoporfirinogênio Oxidase/metabolismo
Protoporfirinas/metabolismo
Plântulas/metabolismo
Feijão de Soja/metabolismo
Espectrometria de Fluorescência
Uroporfirinogênio Descarboxilase/metabolismo
Uroporfirinogênio III Sintetase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Benzhydryl Compounds); 0 (Environmental Pollutants); 0 (Phenols); 0 (Protoporphyrins); 1406-65-1 (Chlorophyll); 14751-08-7 (protochlorophyll); 14947-11-6 (magnesium protoporphyrin); 88755TAZ87 (Aminolevulinic Acid); C2K325S808 (protoporphyrin IX); EC 1.3.3.4 (Protoporphyrinogen Oxidase); EC 2.5.1.61 (Hydroxymethylbilane Synthase); EC 4.1.1.37 (Uroporphyrinogen Decarboxylase); EC 4.2.1.24 (Porphobilinogen Synthase); EC 4.2.1.75 (Uroporphyrinogen III Synthetase); MLT3645I99 (bisphenol A)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:171121
[Lr] Data última revisão:
171121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141030
[St] Status:MEDLINE
[do] DOI:10.1007/s11356-014-3764-0


  6 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:25092523
[Au] Autor:Glomglao W; Treesucon A; Roothumnong E; Thongnoppakhun W; Siraprapapat P; Suwanthol L; Sanpakit K; Tanphaichitr VS
[Ad] Endereço:Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
[Ti] Título:Identification of mutations in the uroporphyrinogen III synthase gene in a Thai girl patient with congenital erythropoietic porphyria.
[So] Source:Int J Lab Hematol;37(2):e44-7, 2015 Apr.
[Is] ISSN:1751-553X
[Cp] País de publicação:England
[La] Idioma:eng
[Mh] Termos MeSH primário: Mutação
Porfiria Eritropoética/diagnóstico
Porfiria Eritropoética/genética
Uroporfirinogênio III Sintetase/genética
[Mh] Termos MeSH secundário: Transplante de Medula Óssea
Análise Mutacional de DNA
Feminino
Hepatomegalia
Seres Humanos
Lactente
Fenótipo
Porfiria Eritropoética/terapia
Esplenomegalia
Tailândia
Transplante Homólogo
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; LETTER
[Nm] Nome de substância:
EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:150316
[Lr] Data última revisão:
150316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140806
[St] Status:MEDLINE
[do] DOI:10.1111/ijlh.12282


  7 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:24925316
[Au] Autor:ben Bdira F; González E; Pluta P; Laín A; Sanz-Parra A; Falcon-Perez JM; Millet O
[Ad] Endereço:Structural Biology Unit and Metabolomics Unit, CIC bioGUNE, Bizkaia Technology Park, Building 800-801A, Derio 48160, Spain and.
[Ti] Título:Tuning intracellular homeostasis of human uroporphyrinogen III synthase by enzyme engineering at a single hotspot of congenital erythropoietic porphyria.
[So] Source:Hum Mol Genet;23(21):5805-13, 2014 Nov 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Congenital erythropoietic porphyria (CEP) results from a deficiency in uroporphyrinogen III synthase enzyme (UROIIIS) activity that ultimately stems from deleterious mutations in the uroS gene. C73 is a hotspot for these mutations and a C73R substitution, which drastically reduces the enzyme activity and stability, is found in almost one-third of all reported CEP cases. Here, we have studied the structural basis, by which mutations in this hotspot lead to UROIIIS destabilization. First, a strong interdependency is observed between the volume of the side chain at position 73 and the folded protein. Moreover, there is a correlation between the in vitro half-life of the mutated proteins and their expression levels in eukaryotic cell lines. Molecular modelling was used to rationalize the results, showing that the mutation site is coupled to the hinge region separating the two domains. Namely, mutations at position 73 modulate the inter-domain closure and ultimately affect protein stability. By incorporating residues capable of interacting with R73 to stabilize the hinge region, catalytic activity was fully restored and a moderate increase in the kinetic stability of the enzyme was observed. These results provide an unprecedented rationale for a destabilizing missense mutation and pave the way for the effective design of molecular chaperones as a therapy against CEP.
[Mh] Termos MeSH primário: Homeostase
Porfiria Eritropoética/metabolismo
Engenharia de Proteínas
Uroporfirinogênio III Sintetase/metabolismo
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Catálise
Ativação Enzimática
Estabilidade Enzimática
Seres Humanos
Espaço Intracelular/metabolismo
Cinética
Modelos Moleculares
Mutação
Porfiria Eritropoética/enzimologia
Porfiria Eritropoética/genética
Conformação Proteica
Uroporfirinogênio III Sintetase/química
Uroporfirinogênio III Sintetase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:141009
[Lr] Data última revisão:
141009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140614
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddu298


  8 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
Texto completo
[PMID]:23953398
[Au] Autor:Guo S; Wang L; Li X; Nie G; Li M; Han B
[Ad] Endereço:CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, No. 11 Zhongguancun Beiyitiao, Beijing 100190, China. Electronic address: guoss@nanoctr.cn.
[Ti] Título:Identification of a novel UROS mutation in a Chinese patient affected by congenital erythropoietic porphyria.
[So] Source:Blood Cells Mol Dis;52(1):57-8, 2014 Jan.
[Is] ISSN:1096-0961
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Éxons
Mutação de Sentido Incorreto
Porfiria Eritropoética/genética
Uroporfirinogênio III Sintetase/genética
[Mh] Termos MeSH secundário: Grupo com Ancestrais do Continente Asiático
Consanguinidade
Homozigoto
Seres Humanos
Masculino
Porfiria Eritropoética/etnologia
Porfiria Eritropoética/patologia
Adulto Jovem
[Pt] Tipo de publicação:CASE REPORTS; LETTER
[Nm] Nome de substância:
EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1407
[Cu] Atualização por classe:131203
[Lr] Data última revisão:
131203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130820
[St] Status:MEDLINE


  9 / 178 MEDLINE  
              first record previous record next record last record
seleciona
para imprimir
Fotocópia
PubMed Central Texto completo
Texto completo
[PMID]:24145442
[Au] Autor:Blouin JM; Duchartre Y; Costet P; Lalanne M; Ged C; Lain A; Millet O; de Verneuil H; Richard E
[Ad] Endereço:Biothérapies des Maladies Génétiques et Cancers, Institut National de la Santé et de la Recherche Médicale U1035, Université Victor Segalen Bordeaux, F-33000 Bordeaux, France.
[Ti] Título:Therapeutic potential of proteasome inhibitors in congenital erythropoietic porphyria.
[So] Source:Proc Natl Acad Sci U S A;110(45):18238-43, 2013 Nov 05.
[Is] ISSN:1091-6490
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Congenital erythropoietic porphyria (CEP) is a rare autosomal recessive disorder characterized by uroporphyrinogen III synthase (UROS) deficiency resulting in massive porphyrin accumulation in blood cells, which is responsible for hemolytic anemia and skin photosensitivity. Among the missense mutations actually described up to now in CEP patients, the C73R and the P248Q mutations lead to a profound UROS deficiency and are usually associated with a severe clinical phenotype. We previously demonstrated that the UROS(C73R) mutant protein conserves intrinsic enzymatic activity but triggers premature degradation in cellular systems that could be prevented by proteasome inhibitors. We show evidence that the reduced kinetic stability of the UROS(P248Q) mutant is also responsible for increased protein turnover in human erythroid cells. Through the analysis of EGFP-tagged versions of UROS enzyme, we demonstrate that both UROS(C73R) and UROS(P248Q) are equally destabilized in mammalian cells and targeted to the proteasomal pathway for degradation. We show that a treatment with proteasomal inhibitors, but not with lysosomal inhibitors, could rescue the expression of both EGFP-UROS mutants. Finally, in CEP mice (Uros(P248Q/P248Q)) treated with bortezomib (Velcade), a clinically approved proteasome inhibitor, we observed reduced porphyrin accumulation in circulating RBCs and urine, as well as reversion of skin photosensitivity on bortezomib treatment. These results of medical importance pave the way for pharmacologic treatment of CEP disease by preventing certain enzymatically active UROS mutants from early degradation by using proteasome inhibitors or chemical chaperones.
[Mh] Termos MeSH primário: Modelos Moleculares
Porfiria Eritropoética/tratamento farmacológico
Inibidores de Proteassoma/uso terapêutico
Uroporfirinogênio III Sintetase/genética
Uroporfirinogênio III Sintetase/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Ácidos Borônicos/farmacologia
Ácidos Borônicos/uso terapêutico
Bortezomib
Dicroísmo Circular
Primers do DNA/genética
Células Eritroides/metabolismo
Seres Humanos
Camundongos
Mutação de Sentido Incorreto/genética
Porfiria Eritropoética/genética
Porfirinas/sangue
Porfirinas/urina
Dobramento de Proteína
Pirazinas/farmacologia
Pirazinas/uso terapêutico
Reação em Cadeia da Polimerase em Tempo Real
Espectrometria de Fluorescência
Uroporfirinogênio III Sintetase/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Boronic Acids); 0 (DNA Primers); 0 (Porphyrins); 0 (Proteasome Inhibitors); 0 (Pyrazines); 69G8BD63PP (Bortezomib); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1312
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131023
[St] Status:MEDLINE
[do] DOI:10.1073/pnas.1314177110


  10 / 178 MEDLINE  
              first record previous record
seleciona
para imprimir
Fotocópia
[PMID]:23648857
[Au] Autor:Lee MJ; Kim HJ; Lee JY; Kwon AS; Jun SY; Kang SH; Kim P
[Ad] Endereço:Department of Biotechnology, The Catholic University of Korea, Bucheon, Gyeonggi 420-742, Korea.
[Ti] Título:Effect of gene amplifications in porphyrin pathway on heme biosynthesis in a recombinant Escherichia coli.
[So] Source:J Microbiol Biotechnol;23(5):668-73, 2013 May.
[Is] ISSN:1738-8872
[Cp] País de publicação:Korea (South)
[La] Idioma:eng
[Ab] Resumo:A recombinant E. coli co-expressing ALA synthase (hemA), NADP-dependent malic enzyme (maeB), and dicarboxylic acid transporter (dctA) was reported to synthesize porphyrin derivatives including iron-containing heme. To enhance the synthesis of bacterial heme, five genes of the porphyrin biosynthetic pathway [pantothenate kinase (coaA), ALA dehydratase (hemB), 1-hydroxymethylbilane synthase (hemC), uroporphyrinogen III synthase (hemD), and uroporphyrinogen III decarboxylase (hemE)] were amplified in the recombinant E. coli co-expressing hemA-maeB-dctA. Pantothenate kinase expression enabled the recombinant E. coli to accumulate intracellular CoA. Intracellular ALA was the most enhanced by uroporphyrinogen III synthase expression, porphobilinogen by ALA dehydratase expression, and uroporphyrin and coproporphyrin by 1- hydroxymethylbilane synthase expression. The strain coexpressing coaA, hemA, maeB, and dctA produced heme of 0.49 micromol/g-DCW, which was twice as much from the strain without coaA expression. Further strain improvement for the porphyrin derivatives is discussed based on the results.
[Mh] Termos MeSH primário: Proteínas de Escherichia coli/genética
Escherichia coli/genética
Escherichia coli/metabolismo
Amplificação de Genes
Heme/biossíntese
Porfirinas/metabolismo
[Mh] Termos MeSH secundário: Vias Biossintéticas
Escherichia coli/enzimologia
Proteínas de Escherichia coli/metabolismo
Hidroximetilbilano Sintase/genética
Hidroximetilbilano Sintase/metabolismo
Malato Desidrogenase/genética
Malato Desidrogenase/metabolismo
Uroporfirinogênio III Sintetase/genética
Uroporfirinogênio III Sintetase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Escherichia coli Proteins); 0 (Porphyrins); 42VZT0U6YR (Heme); EC 1.1.1.37 (Malate Dehydrogenase); EC 1.1.1.40 (malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+)); EC 2.5.1.61 (Hydroxymethylbilane Synthase); EC 4.2.1.75 (Uroporphyrinogen III Synthetase)
[Em] Mês de entrada:1311
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130508
[St] Status:MEDLINE



página 1 de 18 ir para página                         
   


Refinar a pesquisa
  Base de dados : MEDLINE Formulário avançado   

    Pesquisar no campo  
1  
2
3
 
           



Search engine: iAH v2.6 powered by WWWISIS

BIREME/OPAS/OMS - Centro Latino-Americano e do Caribe de Informação em Ciências da Saúde