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[PMID]:28281081
[Au] Autor:Coelho AI; Rubio-Gozalbo ME; Vicente JB; Rivera I
[Ad] Endereço:Department of Pediatrics and Department of Clinical Genetics, Maastricht University Medical Centre, P. Debyelaan 25, PO Box 5800, 6202 AZ, Maastricht, The Netherlands. a.cruzcoelho@maastrichtuniversity.nl.
[Ti] Título:Sweet and sour: an update on classic galactosemia.
[So] Source:J Inherit Metab Dis;40(3):325-342, 2017 May.
[Is] ISSN:1573-2665
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Classic galactosemia is a rare inherited disorder of galactose metabolism caused by deficient activity of galactose-1-phosphate uridylyltransferase (GALT), the second enzyme of the Leloir pathway. It presents in the newborn period as a life-threatening disease, whose clinical picture can be resolved by a galactose-restricted diet. The dietary treatment proves, however, insufficient in preventing severe long-term complications, such as cognitive, social and reproductive impairments. Classic galactosemia represents a heavy burden on patients' and their families' lives. After its first description in 1908 and despite intense research in the past century, the exact pathogenic mechanisms underlying galactosemia are still not fully understood. Recently, new important insights on molecular and cellular aspects of galactosemia have been gained, and should open new avenues for the development of novel therapeutic strategies. Moreover, an international galactosemia network has been established, which shall act as a platform for expertise and research in galactosemia. Herein are reviewed some of the latest developments in clinical practice and research findings on classic galactosemia, an enigmatic disorder with many unanswered questions warranting dedicated research.
[Mh] Termos MeSH primário: Galactosemias/enzimologia
Galactosemias/metabolismo
UDPglucose-Hexose-1-Fosfato Uridiltransferase/metabolismo
[Mh] Termos MeSH secundário: Animais
Galactose/metabolismo
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase); X2RN3Q8DNE (Galactose)
[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:170311
[St] Status:MEDLINE
[do] DOI:10.1007/s10545-017-0029-3


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[PMID]:26101844
[Au] Autor:Wang S; Fu X; Liu Y; Liu XW; Wang L; Fang J; Wang PG
[Ad] Endereço:National Glycoengineering Research Center, Shandong University, Jinan, Shandong 250100, People's Republic of China; The State Key Laboratory of Microbial Technology and School of Life Sciences, Shandong University, Jinan, Shandong 250100, People's Republic of China.
[Ti] Título:Probing the roles of conserved residues in uridyltransferase domain of Escherichia coli K12 GlmU by site-directed mutagenesis.
[So] Source:Carbohydr Res;413:70-4, 2015 Sep 02.
[Is] ISSN:1873-426X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:N-Acetylglucosamine-1-phosphate uridyltransferase (GlmU) is a bifunctional enzyme that catalyzes both acetyltransfer and uridyltransfer reactions in the prokaryotic UDP-GlcNAc biosynthesis pathway. Our previous study demonstrated that the uridyltransferase domain of GlmU (tGlmU) exhibited a flexible substrate specificity, which could be further applied in unnatural sugar nucleotides preparation. However, the structural basis of tolerating variant substrates is still not clear. Herein, we further investigated the roles of several highly conserved amino acid residues involved in substrate binding and recognition by structure- and sequence-guided site-directed mutagenesis. Out of total 16 mutants designed, tGlmU Q76E mutant which had a novel catalytic activity to convert CTP and GlcNAc-1P into unnatural sugar nucleotide CDP-GlcNAc was identified. Furthermore, tGlmU Y103F and N169R mutants were also investigated to have enhanced uridyltransferase activities compared with wide-type tGlmU.
[Mh] Termos MeSH primário: Domínio Catalítico
Sequência Conservada
Escherichia coli K12/enzimologia
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/metabolismo
Complexos Multienzimáticos/química
Complexos Multienzimáticos/metabolismo
Mutagênese Sítio-Dirigida
UDPglucose-Hexose-1-Fosfato Uridiltransferase/química
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Biocatálise
Proteínas de Escherichia coli/genética
Modelos Moleculares
Complexos Multienzimáticos/genética
Mutação
Estrutura Secundária de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Escherichia coli Proteins); 0 (GlmU protein, E coli); 0 (Multienzyme Complexes); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:150810
[Lr] Data última revisão:
150810
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150624
[St] Status:MEDLINE


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[PMID]:25592817
[Au] Autor:Viggiano E; Marabotti A; Burlina AP; Cazzorla C; D'Apice MR; Giordano L; Fasan I; Novelli G; Facchiano A; Burlina AB
[Ad] Endereço:Division of Inborn Metabolic Diseases, Department of Paediatrics, University Hospital of Padova, Italy.
[Ti] Título:Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene.
[So] Source:Gene;559(2):112-8, 2015 Apr 01.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Classical galactosemia is an autosomal recessive inborn error of metabolism due to mutations of the GALT gene leading to toxic accumulation of galactose and derived metabolites. With the benefit of early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. However, despite early diagnosis and treatment, the long term outcome for these patients is still unpredictable because they may go on to develop cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30years. No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications. A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of <1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype-phenotype correlation in classical galactosemia and underlines the importance of molecular diagnostic testing prior to making any treatment.
[Mh] Termos MeSH primário: Galactosemias/genética
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Análise Mutacional de DNA
Feminino
Galactosemias/diagnóstico
Estudos de Associação Genética
Seres Humanos
Lactente
Recém-Nascido
Itália
Masculino
Mutação de Sentido Incorreto
Triagem Neonatal
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1504
[Cu] Atualização por classe:150214
[Lr] Data última revisão:
150214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150117
[St] Status:MEDLINE


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[PMID]:25052314
[Au] Autor:Coelho AI; Lourenço S; Trabuco M; Silva MJ; Oliveira A; Gaspar A; Diogo L; Tavares de Almeida I; Vicente JB; Rivera I
[Ad] Endereço:Metabolism & Genetics Group, Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
[Ti] Título:Functional correction by antisense therapy of a splicing mutation in the GALT gene.
[So] Source:Eur J Hum Genet;23(4):500-6, 2015 Apr.
[Is] ISSN:1476-5438
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:In recent years, antisense therapy has emerged as an increasingly important therapeutic approach to tackle several genetic disorders, including inborn errors of metabolism. Intronic mutations activating cryptic splice sites are particularly amenable to antisense therapy, as the canonical splice sites remain intact, thus retaining the potential for restoring constitutive splicing. Mutational analysis of Portuguese galactosemic patients revealed the intronic variation c.820+13A>G as the second most prevalent mutation, strongly suggesting its pathogenicity. The aim of this study was to functionally characterize this intronic variation, to elucidate its pathogenic molecular mechanism(s) and, ultimately, to correct it by antisense therapy. Minigene splicing assays in two distinct cell lines and patients' transcript analyses showed that the mutation activates a cryptic donor splice site, inducing an aberrant splicing of the GALT pre-mRNA, which in turn leads to a frameshift with inclusion of a premature stop codon (p.D274Gfs*17). Functional-structural studies of the recombinant wild-type and truncated GALT showed that the latter is devoid of enzymatic activity and prone to aggregation. Finally, two locked nucleic acid oligonucleotides, designed to specifically recognize the mutation, successfully restored the constitutive splicing, thus establishing a proof of concept for the application of antisense therapy as an alternative strategy for the clearly insufficient dietary treatment in classic galactosemia.
[Mh] Termos MeSH primário: DNA Antissenso/farmacologia
Galactosemias/terapia
Processamento de RNA
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
[Mh] Termos MeSH secundário: Animais
Células COS
Estudos de Casos e Controles
Cercopithecus aethiops
Dicroísmo Circular
Fragmentação do DNA
Galactosemias/genética
Testes Genéticos
Variação Genética
Células HeLa
Seres Humanos
Íntrons
Mutação
Oligonucleotídeos/farmacologia
Precursores de RNA/genética
Sítios de Splice de RNA
RNA Mensageiro/genética
Análise de Sequência de DNA
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (DNA, Antisense); 0 (Oligonucleotides); 0 (RNA Precursors); 0 (RNA Splice Sites); 0 (RNA, Messenger); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140724
[St] Status:MEDLINE
[do] DOI:10.1038/ejhg.2014.149


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[PMID]:25298520
[Au] Autor:Brokate-Llanos AM; Monje JM; Murdoch Pdel S; Muñoz MJ
[Ad] Endereço:Centro Andaluz de Biología del Desarrollo, Consejo Superior de Investigaciones Científicas-Universidad Pablo de Olavide-Junta de Andalucía, 41013 Seville, Spain.
[Ti] Título:Developmental defects in a Caenorhabditis elegans model for type III galactosemia.
[So] Source:Genetics;198(4):1559-69, 2014 Dec.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been hypothesized for humans, whereas a nonlethal partial loss-of-function allele causes a variety of developmental abnormalities, likely resulting from the impairment of the glycosylation process. We also observed that gale-1 mutants are hypersensitive to galactose as well as to infections. Interestingly, we found interactions between gale-1 and the unfolded protein response.
[Mh] Termos MeSH primário: Caenorhabditis elegans/genética
Galactosemias/genética
Galactosemias/metabolismo
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/embriologia
Caenorhabditis elegans/metabolismo
Proteínas de Caenorhabditis elegans/metabolismo
Modelos Animais de Doenças
Suscetibilidade a Doenças
Desintegrinas/metabolismo
Hexosaminas/metabolismo
Redes e Vias Metabólicas
Metaloendopeptidases/metabolismo
Morfogênese/genética
Mutação
Fenótipo
Transporte Proteico
Transdução de Sinais
UDPglucose-Hexose-1-Fosfato Uridiltransferase/deficiência
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
Resposta a Proteínas não Dobradas
Açúcares de Uridina Difosfato/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Disintegrins); 0 (Hexosamines); 0 (MIG-17 protein, C elegans); 0 (Uridine Diphosphate Sugars); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase); EC 3.4.24.- (Metalloendopeptidases)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:151201
[Lr] Data última revisão:
151201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:141010
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.114.170084


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[PMID]:24973740
[Au] Autor:Sartippour MR; Doroudian R; Frampton G; Lorey F; Helmer G; Ho T; Bhandal A
[Ad] Endereço:California Department of Public Health, Genetic Disease Laboratory Branch, Genetic Disease Screening Program, 850 Marina Bay Parkway, Richmond, CA 94804, USA. Electronic address: msartipp@cdph.ca.gov.
[Ti] Título:Identification of galactose-1-phosphate uridyl transferase gene common mutations in dried blood spots.
[So] Source:Clin Chim Acta;436:298-302, 2014 Sep 25.
[Is] ISSN:1873-3492
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The California newborn screening program uses newborns' dried blood spots (DBS) to screen for more than 45 genetic disorders. Deficiency of galactose-1-phosphate uridyl transferase (GALT) is one of the metabolic genetic disorders screened using newborn DBS. During follow-up tests, common mutations of the GALT gene have been identified using whole blood samples. To avoid the stress of drawing an additional blood sample from newborns who are identified as presumptive positive for galactosemia, we developed a method to test common mutations in the GALT gene using blood spots. METHODS: This method involves DNA extraction from DBS, followed by polymerase chain reaction (PCR), and single nucleotide extension (SNE). SNE products were detected by capillary electrophoresis. RESULTS: In a double-blind study, GALT gene common mutations/variants: IVS2-2A>G, p.S135L, p.T138M, p.Q188R, p.L195P, p.Y209C, p.L218L, p.K285N, and p.N314D were detected in seventy-three DBS which had previously been screened and confirmed as positive in the California Newborn Screening Program. Mutations found using blood spots gave 100% concordance with mutations from previously genotyped whole blood samples. CONCLUSIONS: This blood spot method decreases the genomic test turnaround time of GALT screened positive patients and potentially reduces emotional stress on families required to provide an additional blood draw.
[Mh] Termos MeSH primário: Análise Mutacional de DNA/métodos
Teste em Amostras de Sangue Seco
Mutação
UDPglucose-Hexose-1-Fosfato Uridiltransferase/sangue
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
[Mh] Termos MeSH secundário: Método Duplo-Cego
Técnicas de Genotipagem
Seres Humanos
Recém-Nascido
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1508
[Cu] Atualização por classe:140809
[Lr] Data última revisão:
140809
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:140629
[St] Status:MEDLINE


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[PMID]:24014529
[Au] Autor:De Bruyn F; Beauprez J; Maertens J; Soetaert W; De Mey M
[Ad] Endereço:Centre of Expertise-Industrial Biotechnology and Biocatalysis, Department of Biochemical and Microbial Technology, Ghent University, Ghent, Belgium.
[Ti] Título:Unraveling the Leloir pathway of Bifidobacterium bifidum: significance of the uridylyltransferases.
[So] Source:Appl Environ Microbiol;79(22):7028-35, 2013 Nov.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The GNB/LNB (galacto-N-biose/lacto-N-biose) pathway plays a crucial role in bifidobacteria during growth on human milk or mucin from epithelial cells. It is thought to be the major route for galactose utilization in Bifidobacterium longum as it is an energy-saving variant of the Leloir pathway. Both pathways are present in B. bifidum, and galactose 1-phosphate (gal1P) is considered to play a key role. Due to its toxic nature, gal1P is further converted into its activated UDP-sugar through the action of poorly characterized uridylyltransferases. In this study, three uridylyltransferases (galT1, galT2, and ugpA) from Bifidobacterium bifidum were cloned in an Escherichia coli mutant and screened for activity on the key intermediate gal1P. GalT1 and GalT2 showed UDP-glucose-hexose-1-phosphate uridylyltransferase activity (EC 2.7.7.12), whereas UgpA showed promiscuous UTP-hexose-1-phosphate uridylyltransferase activity (EC 2.7.7.10). The activity of UgpA toward glucose 1-phosphate was about 33-fold higher than that toward gal1P. GalT1, as part of the bifidobacterial Leloir pathway, was about 357-fold more active than GalT2, the functional analog in the GNB/LNB pathway. These results suggest that GalT1 plays a more significant role than previously thought and predominates when B. bifidum grows on lactose and human milk oligosaccharides. GalT2 activity is required only during growth on substrates with a GNB core such as mucin glycans.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Bifidobacterium/enzimologia
Oligossacarídeos/metabolismo
UDPglucose-Hexose-1-Fosfato Uridiltransferase/metabolismo
UTP-Hexose-1-Fosfato Uridililtransferase/metabolismo
[Mh] Termos MeSH secundário: Bifidobacterium/crescimento & desenvolvimento
Clonagem Molecular
Escherichia coli/genética
Escherichia coli/metabolismo
Galactosefosfatos/metabolismo
Deleção de Genes
Seres Humanos
Leite Humano/química
Dados de Sequência Molecular
Família Multigênica
Plasmídeos/genética
Reprodutibilidade dos Testes
Análise de Sequência de DNA
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Galactosephosphates); 0 (Oligosaccharides); 2255-14-3 (galactose-1-phosphate); EC 2.7.7.10 (UTP-Hexose-1-Phosphate Uridylyltransferase); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1405
[Cu] Atualização por classe:150422
[Lr] Data última revisão:
150422
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130910
[St] Status:MEDLINE
[do] DOI:10.1128/AEM.02460-13


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[PMID]:23583749
[Au] Autor:McCorvie TJ; Gleason TJ; Fridovich-Keil JL; Timson DJ
[Ad] Endereço:School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK.
[Ti] Título:Misfolding of galactose 1-phosphate uridylyltransferase can result in type I galactosemia.
[So] Source:Biochim Biophys Acta;1832(8):1279-93, 2013 Aug.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Type I galactosemia is a genetic disorder that is caused by the impairment of galactose-1-phosphate uridylyltransferase (GALT; EC 2.7.7.12). Although a large number of mutations have been detected through genetic screening of the human GALT (hGALT) locus, for many it is not known how they cause their effects. The majority of these mutations are missense, with predicted substitutions scattered throughout the enzyme structure and thus causing impairment by other means rather than direct alterations to the active site. To clarify the fundamental, molecular basis of hGALT impairment we studied five disease-associated variants p.D28Y, p.L74P, p.F171S, p.F194L and p.R333G using both a yeast model and purified, recombinant proteins. In a yeast expression system there was a correlation between lysate activity and the ability to rescue growth in the presence of galactose, except for p.R333G. Kinetic analysis of the purified proteins quantified each variant's level of enzymatic impairment and demonstrated that this was largely due to altered substrate binding. Increased surface hydrophobicity, altered thermal stability and changes in proteolytic sensitivity were also detected. Our results demonstrate that hGALT requires a level of flexibility to function optimally and that altered folding is the underlying reason of impairment in all the variants tested here. This indicates that misfolding is a common, molecular basis of hGALT deficiency and suggests the potential of pharmacological chaperones and proteostasis regulators as novel therapeutic approaches for type I galactosemia.
[Mh] Termos MeSH primário: Galactosemias/enzimologia
Deficiências na Proteostase/enzimologia
UDPglucose-Hexose-1-Fosfato Uridiltransferase/química
UDPglucose-Hexose-1-Fosfato Uridiltransferase/metabolismo
[Mh] Termos MeSH secundário: Galactosemias/etiologia
Galactosemias/genética
Seres Humanos
Cinética
Modelos Moleculares
Mutagênese Sítio-Dirigida
Mutação
Ligação Proteica
Desnaturação Proteica
Deficiências na Proteostase/etiologia
Deficiências na Proteostase/genética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Saccharomyces cerevisiae/genética
Saccharomyces cerevisiae/metabolismo
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Recombinant Proteins); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130416
[St] Status:MEDLINE


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[PMID]:22773758
[Au] Autor:Jumbo-Lucioni PP; Hopson ML; Hang D; Liang Y; Jones DP; Fridovich-Keil JL
[Ad] Endereço:Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
[Ti] Título:Oxidative stress contributes to outcome severity in a Drosophila melanogaster model of classic galactosemia.
[So] Source:Dis Model Mech;6(1):84-94, 2013 Jan.
[Is] ISSN:1754-8411
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.
[Mh] Termos MeSH primário: Galactosemias/genética
Galactosemias/metabolismo
[Mh] Termos MeSH secundário: Animais
Antioxidantes/farmacologia
Ácido Ascórbico/farmacologia
Cisteína/metabolismo
Dimetil Sulfóxido/toxicidade
Modelos Animais de Doenças
Proteínas de Drosophila/deficiência
Proteínas de Drosophila/genética
Proteínas de Drosophila/metabolismo
Drosophila melanogaster/efeitos dos fármacos
Drosophila melanogaster/enzimologia
Drosophila melanogaster/genética
Galactose/metabolismo
Galactose/toxicidade
Galactosemias/tratamento farmacológico
Galactosemias/etiologia
Galactosefosfatos/metabolismo
Expressão Gênica/efeitos dos fármacos
Técnicas de Inativação de Genes
Genes de Insetos
Glutationa/metabolismo
Glutationa Transferase/genética
Glutationa Transferase/metabolismo
Seres Humanos
Mutação
Estresse Oxidativo/efeitos dos fármacos
Paraquat/toxicidade
Espécies Reativas de Oxigênio/metabolismo
UDPglucose-Hexose-1-Fosfato Uridiltransferase/deficiência
UDPglucose-Hexose-1-Fosfato Uridiltransferase/genética
Xantonas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Antioxidants); 0 (Drosophila Proteins); 0 (Galactosephosphates); 0 (Reactive Oxygen Species); 0 (Xanthones); 2255-14-3 (galactose-1-phosphate); EC 2.5.1.18 (Glutathione Transferase); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase); GAN16C9B8O (Glutathione); K848JZ4886 (Cysteine); PLG39H7695 (Paraquat); PQ6CK8PD0R (Ascorbic Acid); U6RIV93RU1 (mangostin); X2RN3Q8DNE (Galactose); YOW8V9698H (Dimethyl Sulfoxide)
[Em] Mês de entrada:1306
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120710
[St] Status:MEDLINE
[do] DOI:10.1242/dmm.010207


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[PMID]:22585921
[Au] Autor:Kitaoka M
[Ad] Endereço:National Food Research Institute, National Agriculture and Food Research Organization, Tsukuba, Ibaraki, Japan. mkitaoka@affrc.go.jp
[Ti] Título:Bifidobacterial enzymes involved in the metabolism of human milk oligosaccharides.
[So] Source:Adv Nutr;3(3):422S-9S, 2012 May 01.
[Is] ISSN:2156-5376
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Intestinal colonization of bifidobacteria is important for the health of infants. Human milk oligosaccharides (HMO) have been identified as growth factors for bifidobacteria. Recently, a bifidobacterial enzymatic system to metabolize HMO was identified. 1,3-ß-Galactosyl-N-acetylhexosamine phosphorylase (GLNBP, EC 2.4.1.211), which catalyzes the reversible phosphorolysis of galacto-N-biose (GNB) (Galß1→3GalNAc)] and lacto-N-biose I (LNB) (Galß1→3GlcNAc), is a key enzyme to explain the metabolism of HMO. Infant-type bifidobacteria possess the intracellular pathway to specifically metabolize GNB and LNB (GNB/LNB pathway). Bifidobacterium bifidum possesses extracellular enzymes to liberate LNB from HMO. However, Bifidobacterium longum subsp. infantis imports intact HMO to be hydrolyzed by intracellular enzymes. Bifidobacterial enzymes related to the metabolism of HMO are useful tools for preparing compounds related to HMO. For instance, LNB and GNB were produced from sucrose and GlcNAc/GalNAc in 1 pot using 4 bifidobacterial enzymes, including GLNBP. LNB is expected to be a selective bifidus factor for infant-type strains.
[Mh] Termos MeSH primário: Bifidobacterium/enzimologia
Bifidobacterium/crescimento & desenvolvimento
Leite Humano/química
Oligossacarídeos/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/análogos & derivados
Acetilglucosamina/metabolismo
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Galactosiltransferases/metabolismo
Seres Humanos
Lactente
Intestinos/metabolismo
Intestinos/microbiologia
Fosforilases/metabolismo
UDPglucose-Hexose-1-Fosfato Uridiltransferase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Oligosaccharides); 50787-09-2 (galactosyl-1,3-N-acetylglucosamine); EC 2.4.1.- (Galactosyltransferases); EC 2.4.1.- (Phosphorylases); EC 2.4.1.- (beta-1,3-galactosyl-N-acetylhexosamine phosphorylase); EC 2.4.1.- (galacto-N-biose-lacto-N-biose I phosphorylase, Bifidobacterium longum); EC 2.7.7.12 (UDPglucose-Hexose-1-Phosphate Uridylyltransferase); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1210
[Cu] Atualização por classe:150225
[Lr] Data última revisão:
150225
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120516
[St] Status:MEDLINE
[do] DOI:10.3945/an.111.001420



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