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Pesquisa : D08.811.913.400.100 [Categoria DeCS]
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  1 / 25 MEDLINE  
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[PMID]:28542779
[Au] Autor:Chao CC; Wu PH; Huang HC; Chung HY; Chou YC; Cai BH; Kannagi R
[Ad] Endereço:Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
[Ti] Título:Downregulation of miR-199a/b-5p is associated with GCNT2 induction upon epithelial-mesenchymal transition in colon cancer.
[So] Source:FEBS Lett;591(13):1902-1917, 2017 Jul.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:ß-1,6-N-acetylglucosaminyltransferase 2 (GCNT2), which encodes a key glycosyltransferase for blood group I antigen synthesis, is induced upon epithelial-mesenchymal transition (EMT). Our results indicate that GCNT2 is upregulated upon EMT induced with epidermal growth factor and basic FGF in cultured human colon cancer cells. GCNT2 knockdown or overexpression decreases or increases, respectively, malignancy-related characteristics of colon cancer cells and I antigen levels. MiR-199a/b-5p is markedly downregulated upon EMT in colon cancer cells. Here, we find that miR-199a/b-5p consistently regulates GCNT2 expression in reporter assays and that it binds directly to the GCNT2 3' untranslated region intracellularly in RNA-induced silencing complex-trap assays. Overexpression of miR-199a/b-5p decreases GCNT2 expression and suppresses I antigen production. Based on these findings, we propose that miR-199a/b-5p regulates GCNT2 and I antigen expression in colon cancer cells undergoing EMT.
[Mh] Termos MeSH primário: Neoplasias do Colo/patologia
Regulação para Baixo/genética
Transição Epitelial-Mesenquimal/genética
MicroRNAs/genética
N-Acetilexosaminiltransferases/genética
Ativação Transcricional/genética
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Linhagem Celular Tumoral
Neoplasias do Colo/genética
Regulação para Baixo/efeitos dos fármacos
Fator de Crescimento Epidérmico/farmacologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Feminino
Fator 2 de Crescimento de Fibroblastos/farmacologia
Técnicas de Silenciamento de Genes
Antígenos de Histocompatibilidade Classe I/genética
Seres Humanos
Camundongos
Camundongos Endogâmicos BALB C
N-Acetilexosaminiltransferases/deficiência
Ativação Transcricional/efeitos dos fármacos
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0 (Histocompatibility Antigens Class I); 0 (MicroRNAs); 0 (mirn199 microRNA, human); 103107-01-3 (Fibroblast Growth Factor 2); 62229-50-9 (Epidermal Growth Factor); EC 2.4.1.- (GCNT2 protein, human); EC 2.4.1.- (N-Acetylhexosaminyltransferases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12685


  2 / 25 MEDLINE  
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[PMID]:27936067
[Au] Autor:Irum B; Khan SY; Ali M; Daud M; Kabir F; Rauf B; Fatima F; Iqbal H; Khan AO; Al Obaisi S; Naeem MA; Nasir IA; Khan SN; Husnain T; Riazuddin S; Akram J; Eghrari AO; Riazuddin SA
[Ad] Endereço:The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.
[Ti] Título:Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.
[So] Source:PLoS One;11(12):e0167562, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. METHODS: All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. RESULTS: Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. CONCLUSION: Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.
[Mh] Termos MeSH primário: Catarata/genética
N-Acetilexosaminiltransferases/genética
Deleção de Sequência
[Mh] Termos MeSH secundário: Animais
Catarata/congênito
Criança
Pré-Escolar
Consanguinidade
Feminino
Ligação Genética
Loci Gênicos
Seres Humanos
Lactente
Masculino
Camundongos
Repetições de Microssatélites
N-Acetilglucosaminiltransferases/genética
Linhagem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.4.- (N-acetylglucosaminyltransferase IGnT); EC 2.4.1.- (GCNT2 protein, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (N-Acetylhexosaminyltransferases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170706
[Lr] Data última revisão:
170706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0167562


  3 / 25 MEDLINE  
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[PMID]:27609212
[Au] Autor:Happ H; Weh E; Costakos D; Reis LM; Semina EV
[Ad] Endereço:Department of Pediatrics and Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
[Ti] Título:Case report of homozygous deletion involving the first coding exons of GCNT2 isoforms A and B and part of the upstream region of TFAP2A in congenital cataract.
[So] Source:BMC Med Genet;17(1):64, 2016 Sep 08.
[Is] ISSN:1471-2350
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Congenital cataracts affect 3-6 per 10,000 live births and represent one of the leading causes of blindness in children. Congenital cataracts have a strong genetic component with high heterogeneity and variability. CASE PRESENTATION: Analysis of whole exome sequencing data in a patient affected with congenital cataracts identified a pathogenic deletion which was further defined by other techniques. A ~98-kb homozygous deletion of 6p24.3 involving the first three exons (two non-coding and one coding) of GCNT2 isoform A, the first exon (coding) of GCNT2 isoform B, and part of the intergenic region between GCNT2 and TFAP2A was identified in the patient and her brother while both parents were found to be heterozygous carriers of the deletion. The exact breakpoints were identified and revealed the presence of Alu elements at both sides of the deletion, thus indicating Alu-mediated non-homologous end-joining as the most plausible mechanism for this rearrangement. Recessive mutations in GCNT2 are known to cause an adult i blood group phenotype with congenital cataracts in some cases. The GCNT2 gene has three differentially expressed transcripts, with GCNT2B being the only isoform associated with lens function and GCNT2C being the only isoform expressed in red blood cells based on earlier studies; previously reported mutations/deletions have either affected all three isoforms (causing blood group and cataract phenotype) or the C isoform only (causing blood group phenotype only). Dominant mutations in TFAP2A are associated with syndromic anophthalmia/microphthalmia and other ocular phenotypes as part of Branchio-Ocular-Facial-Syndrome (BOFS). While the patients do not fit a diagnosis of BOFS, one sibling demonstrates mild overlap with the phenotypic spectrum, and therefore an effect of this deletion on the function of TFAP2A cannot be ruled out. CONCLUSIONS: To the best of our knowledge, this is the first case reported in which disruption of the GCNT2 gene does not involve the C isoform. The congenital cataracts phenotype in the affected patients is consistent with the previously defined isoform-specific roles of this gene. The GCNT2-TFAP2A region may be prone to rearrangements through Alu-mediated non-homologous end-joining.
[Mh] Termos MeSH primário: Catarata/congênito
Catarata/genética
N-Acetilglucosaminiltransferases/genética
N-Acetilexosaminiltransferases/genética
Deleção de Sequência
Fator de Transcrição AP-2/genética
[Mh] Termos MeSH secundário: Pontos de Quebra do Cromossomo
Consanguinidade
Éxons
Feminino
Homozigoto
Seres Humanos
Lactente
Isoenzimas/genética
Masculino
Linhagem
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Isoenzymes); 0 (TFAP2A protein, human); 0 (Transcription Factor AP-2); EC 2.4.1.- (GCNT2 protein, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (N-Acetylhexosaminyltransferases)
[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:160910
[St] Status:MEDLINE
[do] DOI:10.1186/s12881-016-0316-0


  4 / 25 MEDLINE  
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[PMID]:27600951
[Au] Autor:Liao YJ; Lee YH; Chang FL; Ho H; Huang CH; Twu YC
[Ad] Endereço:School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University.
[Ti] Título:The SHP2-ERK2 signaling pathway regulates branched I antigen formation by controlling the binding of CCAAT/enhancer binding protein α to the IGnTC promoter region during erythroid differentiation.
[So] Source:Transfusion;56(11):2691-2702, 2016 Nov.
[Is] ISSN:1537-2995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Phosphorylation status of the transcription factor CCAAT/enhancer binding protein α (C/EBPα) has been demonstrated in a human hematopoietic cell model to regulate the formation of branched I antigen by affecting its binding affinity to the promoter region of the IGnTC gene during erythroid and granulocytic differentiation. STUDY DESIGN AND METHODS: The K-562 cell line was induced to differentiate into red blood cells (RBCs) or granulocytes by sodium butyrate or retinoic acid, respectively, to study the involvement of three MAP kinase pathways in I antigen synthesis. The regulatory effects of the extracellular signal-regulated kinase (ERK)2-Src homology region 2 domain-containing phosphatase 2 (SHP2) pathway on phosphorylation status and binding affinities of C/EBPα as well as the subsequent activation of IGnTC and synthesis of surface I formation were studied in wild-type K-562 cells and in mutant cells that overexpress ERK2 and SHP2. RESULTS: We found that SHP2-ERK2 signaling regulates the phosphorylation status of C/EBPα to alter its binding affinity onto the IGnTC promoter region, thereby activating the synthesis of cell surface I antigen formation during erythropoiesis. CONCLUSION: SHP2-ERK2 signaling acts upstream of C/EBPα as a regulator of cell surface I antigen synthesis. Such regulation is specific for RBC but not for granulocyte differentiation.
[Mh] Termos MeSH primário: Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo
Eritropoese
Sistema do Grupo Sanguíneo I/biossíntese
Proteína Quinase 1 Ativada por Mitógeno/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Seres Humanos
Células K562
N-Acetilglucosaminiltransferases/genética
N-Acetilexosaminiltransferases
Fosforilação
Regiões Promotoras Genéticas
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CCAAT-Enhancer-Binding Protein-alpha); 0 (I Blood-Group System); EC 2.4.- (N-acetylglucosaminyltransferase IGnT); EC 2.4.1.- (GCNT2 protein, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (N-Acetylhexosaminyltransferases); EC 2.7.11.24 (MAPK1 protein, human); EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1); EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170525
[Lr] Data última revisão:
170525
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160908
[St] Status:MEDLINE
[do] DOI:10.1111/trf.13796


  5 / 25 MEDLINE  
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[PMID]:24105809
[Au] Autor:Henion TR; Schwarting GA
[Ad] Endereço:Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
[Ti] Título:N-linked polylactosamine glycan synthesis is regulated by co-expression of ß3GnT2 and GCNT2.
[So] Source:J Cell Physiol;229(4):471-8, 2014 Apr.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Poly-N-acetyllactosamine (PLN) is a unique glycan composed of repeating units of the common disaccharide (Galß1,4-GlcNAcß1,3)n . The expression of PLN on glycoprotein core structures minimally requires enzyme activities for ß1,4-galactosyltransferase (ß4GalT) and ß1,3-N-acetylglucosminyltransferase (ß3GnT). Because ß4GalTs are ubiquitous in most cells, PLN expression is generally ascribed to the tissue-specific transcription of eight known ß3GnT genes in mice. In the olfactory epithelium (OE), ß3GnT2 regulates expression of extended PLN chains that are essential for axon guidance and neuronal survival. N-glycan branching and core composition, however, can also modulate the extent of PLN modification. Here, we show for the first time that the ß1,6-branching glycosyltransferase GCNT2 (formerly known as IGnT) is expressed at high levels specifically in the OE and other sensory ganglia. Postnatally, GCNT2 is maintained in mature olfactory neurons that co-express ß3GnT2 and PLN. This highly specific co-expression suggests that GCNT2 and ß3GnT2 function cooperatively in PLN synthesis. In support of this, ß3GnT2 and GCNT2 co-transfection in HEK293T cells results in high levels of PLN expression on the cell surface and on adenylyl cyclase 3, a major carrier of PLN glycans in the OE. These data clearly suggest that GCNT2 functions in vivo together with ß3GnT2 to determine PLN levels in olfactory neurons by regulating ß1,6-branches that promote PLN extension.
[Mh] Termos MeSH primário: Regulação Enzimológica da Expressão Gênica/fisiologia
N-Acetilglucosaminiltransferases/metabolismo
N-Acetilexosaminiltransferases/metabolismo
Polissacarídeos/biossíntese
[Mh] Termos MeSH secundário: Animais
Embrião de Mamíferos/metabolismo
Feminino
Regulação da Expressão Gênica no Desenvolvimento/fisiologia
Células HEK293
Seres Humanos
Camundongos
Camundongos Knockout
N-Acetilglucosaminiltransferases/genética
N-Acetilexosaminiltransferases/genética
Gravidez
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Polysaccharides); 82441-98-3 (poly-N-acetyllactosamine); EC 2.4.- (N-acetylglucosaminyltransferase IGnT); EC 2.4.1.- (GCNT2 protein, human); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (N-Acetylhexosaminyltransferases); EC 2.4.1.149 (B3gnt1 protein, mouse)
[Em] Mês de entrada:1402
[Cu] Atualização por classe:170609
[Lr] Data última revisão:
170609
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131010
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.24467


  6 / 25 MEDLINE  
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[PMID]:21335454
[Au] Autor:Merino S; Jimenez N; Molero R; Bouamama L; Regué M; Tomás JM
[Ad] Endereço:Departamento de Microbiología, Facultad de Biología, Universidad Barcelona, Diagonal 645, 08071 Barcelona, Spain.
[Ti] Título:A UDP-HexNAc:polyprenol-P GalNAc-1-P transferase (WecP) representing a new subgroup of the enzyme family.
[So] Source:J Bacteriol;193(8):1943-52, 2011 Apr.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Aeromonas hydrophila AH-3 WecP represents a new class of UDP-HexNAc:polyprenol-P HexNAc-1-P transferases. These enzymes use a membrane-associated polyprenol phosphate acceptor (undecaprenyl phosphate [Und-P]) and a cytoplasmic UDP-d-N-acetylhexosamine sugar nucleotide as the donor substrate. Until now, all the WecA enzymes tested were able to transfer UDP-GlcNAc to the Und-P. In this study, we present in vitro and in vivo proofs that A. hydrophila AH-3 WecP transfers GalNAc to Und-P and is unable to transfer GlcNAc to the same enzyme substrate. The molecular topology of WecP is more similar to that of WbaP (UDP-Gal polyprenol-P transferase) than to that of WecA (UDP-GlcNAc polyprenol-P transferase). WecP is the first UDP-HexNAc:polyprenol-P GalNAc-1-P transferase described.
[Mh] Termos MeSH primário: Aeromonas hydrophila/enzimologia
N-Acetilexosaminiltransferases/metabolismo
Fosfatos de Poli-Isoprenil/metabolismo
Uridina Difosfato N-Acetilgalactosamina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Carboidratos
Modelos Moleculares
Dados de Sequência Molecular
N-Acetilexosaminiltransferases/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Polyisoprenyl Phosphates); 25126-51-6 (undecaprenyl phosphate); 7277-98-7 (Uridine Diphosphate N-Acetylgalactosamine); EC 2.4.1.- (N-Acetylhexosaminyltransferases)
[Em] Mês de entrada:1106
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:110222
[St] Status:MEDLINE
[do] DOI:10.1128/JB.01441-10


  7 / 25 MEDLINE  
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[PMID]:19376878
[Au] Autor:D'Elia MA; Henderson JA; Beveridge TJ; Heinrichs DE; Brown ED
[Ad] Endereço:Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.
[Ti] Título:The N-acetylmannosamine transferase catalyzes the first committed step of teichoic acid assembly in Bacillus subtilis and Staphylococcus aureus.
[So] Source:J Bacteriol;191(12):4030-4, 2009 Jun.
[Is] ISSN:1098-5530
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:There have been considerable strides made in the characterization of the dispensability of teichoic acid biosynthesis genes in recent years. A notable omission thus far has been an early gene in teichoic acid synthesis encoding the N-acetylmannosamine transferase (tagA in Bacillus subtilis; tarA in Staphylococcus aureus), which adds N-acetylmannosamine to complete the synthesis of undecaprenol pyrophosphate-linked disaccharide. Here, we show that the N-acetylmannosamine transferases are dispensable for growth in vitro, making this biosynthetic enzyme the last dispensable gene in the pathway, suggesting that tagA (or tarA) encodes the first committed step in wall teichoic acid synthesis.
[Mh] Termos MeSH primário: Bacillus subtilis/enzimologia
Proteínas de Bactérias/metabolismo
N-Acetilexosaminiltransferases/metabolismo
Staphylococcus aureus/enzimologia
Ácidos Teicoicos/biossíntese
[Mh] Termos MeSH secundário: Bacillus subtilis/genética
Bacillus subtilis/crescimento & desenvolvimento
Bacillus subtilis/metabolismo
Proteínas de Bactérias/genética
Catálise
N-Acetilexosaminiltransferases/genética
Staphylococcus aureus/genética
Staphylococcus aureus/crescimento & desenvolvimento
Staphylococcus aureus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Teichoic Acids); EC 2.4.1.- (N-Acetylhexosaminyltransferases); EC 2.4.1.- (N-acetylmannosaminyltransferase)
[Em] Mês de entrada:0906
[Cu] Atualização por classe:141210
[Lr] Data última revisão:
141210
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:090421
[St] Status:MEDLINE
[do] DOI:10.1128/JB.00611-08


  8 / 25 MEDLINE  
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[PMID]:15895995
[Au] Autor:Viswanathan K; Narang S; Hinderlich S; Lee YC; Betenbaugh MJ
[Ad] Endereço:Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA.
[Ti] Título:Engineering intracellular CMP-sialic acid metabolism into insect cells and methods to enhance its generation.
[So] Source:Biochemistry;44(20):7526-34, 2005 May 24.
[Is] ISSN:0006-2960
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Previous studies have reported that insect cell lines lack the capacity to generate endogenously the nucleotide sugar, CMP-Neu5Ac, required for sialylation of glycoconjugates. In this study, the biosynthesis of this activated form of sialic acid completely from endogenous metabolites is demonstrated for the first time in insect cells by expressing the mammalian genes required for the multistep conversion of endogenous UDP-GlcNAc to CMP-Neu5Ac. The genes for UDP-GlcNAc-2-epimerase/ManNAc kinase (EK), sialic acid 9-phosphate synthase (SAS), and CMP-sialic acid synthetase (CSAS) were coexpressed in insect cells using baculovirus expression vectors, but the CMP-Neu5Ac and precursor Neu5Ac levels synthesized were found to be lower than those achieved with ManNAc supplementation due to feedback inhibition of the EK enzyme by CMP-Neu5Ac. When sialuria-like mutant EK genes, in which the site for feedback regulation has been mutated, were used, CMP-Neu5Ac was synthesized at levels more than 4 times higher than that achieved with the wild-type EK and 2.5 times higher than that achieved with ManNAc feeding. Addition of N-acetylglucosamine (GlcNAc), a precursor for UDP-GlcNAc, to the media increased the levels of CMP-Neu5Ac even more to a level 7.5 times higher than that achieved with ManNAc supplementation, creating a bottleneck in the conversion of Neu5Ac to CMP-Neu5Ac at higher levels of UDP-GlcNAc. The present study provides a useful biochemical strategy to synthesize and enhance the levels of the sialylation donor molecule, CMP-Neu5Ac, a critical limiting substrate for the generation of complex glycoproteins in insect cells and other cell culture systems.
[Mh] Termos MeSH primário: Ácido N-Acetilneuramínico Citidina Monofosfato/química
Ácido N-Acetilneuramínico Citidina Monofosfato/metabolismo
Líquido Intracelular/química
Líquido Intracelular/metabolismo
Mutagênese Sítio-Dirigida
N-Acilneuraminato Citidililtransferase/biossíntese
Spodoptera/enzimologia
Spodoptera/genética
[Mh] Termos MeSH secundário: Animais
Arginina/genética
Baculoviridae/enzimologia
Baculoviridae/genética
Carboidratos Epimerases/antagonistas & inibidores
Carboidratos Epimerases/biossíntese
Carboidratos Epimerases/genética
Células Cultivadas
Hexosaminas/química
Hexosaminas/metabolismo
Seres Humanos
Leucina/genética
Manosefosfatos
Mariposas/virologia
N-Acetilexosaminiltransferases/biossíntese
N-Acetilexosaminiltransferases/genética
N-Acilneuraminato Citidililtransferase/genética
Ratos
Doença do Armazenamento de Ácido Siálico/genética
Especificidade por Substrato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, U.S. GOV'T, P.H.S.
[Nm] Nome de substância:
0 (2-acetamido-2-deoxy-mannose-6-phosphate); 0 (Hexosamines); 0 (Mannosephosphates); 3063-71-6 (Cytidine Monophosphate N-Acetylneuraminic Acid); 94ZLA3W45F (Arginine); EC 2.4.1.- (N-Acetylhexosaminyltransferases); EC 2.4.1.- (N-acetylmannosaminyltransferase); EC 2.7.7.43 (N-Acylneuraminate Cytidylyltransferase); EC 5.1.3.- (Carbohydrate Epimerases); EC 5.1.3.14 (UDP acetylglucosamine-2-epimerase); GMW67QNF9C (Leucine); X80PR7P73R (N-acetylmannosamine)
[Em] Mês de entrada:0508
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:050518
[St] Status:MEDLINE


  9 / 25 MEDLINE  
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[PMID]:15498763
[Au] Autor:Benie AJ; Blume A; Schmidt RR; Reutter W; Hinderlich S; Peters T
[Ad] Endereço:Institute of Chemistry, University of Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany.
[Ti] Título:Characterization of ligand binding to the bifunctional key enzyme in the sialic acid biosynthesis by NMR: II. Investigation of the ManNAc kinase functionality.
[So] Source:J Biol Chem;279(53):55722-7, 2004 Dec 31.
[Is] ISSN:0021-9258
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-Acetylmannosamine (ManNAc) is the physiological precursors to all sialic acids that occur in nature. As variations in the sialic acid decoration of cell surfaces can profoundly affect cell-cell, pathogen-cell, or drug-cell interactions, the enzymes that convert ManNAc into sialic acid are attractive targets for the development of drugs that specifically interrupt sialic acid biosynthesis or lead to modified sialic acids on the surface of cells. The first step in the enzymatic conversion of ManNAc into sialic acid is phosphorylation, yielding N-acetylmannosamine-6-phosphate. The enzyme that catalyzes this conversion is the N-acetylmannosamine kinase (ManNAc kinase) as part of the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. Here, we employed saturation transfer difference (STD) NMR experiments to study the binding of ManNAc and related ligands to the ManNAc kinase. It is shown that the configuration of C1 and C4 of ManNAc is crucial for binding to the enzyme, whereas the C2 position not only accepts variations in the attached N-acyl side chain but also tolerates inversion of configuration. Our experiments also show that ManNAc kinase maintains its functionality, even in the absence of Mg(2+). From the analysis of the STD NMR-derived binding epitopes, it is concluded that the binding mode of the N-acylmannosamines critically depends on the N-acyl side chain. In conjunction with the relative binding affinities of the ligands obtained from STD NMR titrations, it is possible to derive a structure-binding affinity relationship. This provides a cornerstone for the rational design of drugs for novel therapeutic applications by altering the sialic acid decorations of cell walls.
[Mh] Termos MeSH primário: Espectroscopia de Ressonância Magnética/métodos
N-Acetilexosaminiltransferases/química
Ácido N-Acetilneuramínico/biossíntese
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Animais
Carboidratos Epimerases/química
Linhagem Celular
Membrana Celular/metabolismo
Epitopos/química
Hexosaminas/química
Insetos
Cinética
Ligantes
Magnésio/química
Modelos Químicos
Modelos Moleculares
Fosfatos/química
Ligação Proteica
Estrutura Terciária de Proteína
Relação Estrutura-Atividade
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Epitopes); 0 (Hexosamines); 0 (Ligands); 0 (Phosphates); 2636-92-2 (mannosamine); 8L70Q75FXE (Adenosine Triphosphate); EC 2.4.1.- (N-Acetylhexosaminyltransferases); EC 2.4.1.- (N-acetylmannosaminyltransferase); EC 5.1.3.- (Carbohydrate Epimerases); EC 5.1.3.14 (UDP acetylglucosamine-2-epimerase); GZP2782OP0 (N-Acetylneuraminic Acid); I38ZP9992A (Magnesium)
[Em] Mês de entrada:0502
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:041023
[St] Status:MEDLINE


  10 / 25 MEDLINE  
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[PMID]:15491132
[Au] Autor:Xu L; Appell M; Kennedy S; Momany FA; Price NP
[Ad] Endereço:University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
[Ti] Título:Conformational analysis of chirally deuterated tunicamycin as an active site probe of UDP-N-acetylhexosamine:polyprenol-P N-acetylhexosamine-1-P translocases.
[So] Source:Biochemistry;43(42):13248-55, 2004 Oct 26.
[Is] ISSN:0006-2960
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tunicamycins are potent inhibitors of UDP-N-acetyl-D-hexosamine:polyprenol-phosphate N-acetylhexosamine-1-phosphate translocases (D-HexNAc-1-P translocases), a family of enzymes involved in bacterial cell wall synthesis and eukaryotic protein N-glycosylation. Structurally, tunicamycins consist of an 11-carbon dialdose core sugar called tunicamine that is N-linked at C-1' to uracil and O-linked at C-11' to N-acetylglucosamine (GlcNAc). The C-11' O-glycosidic linkage is highly unusual because it forms an alpha/beta anomeric-to-anomeric linkage to the 1-position of the GlcNAc residue. We have assigned the (1)H and (13)C NMR spectra of tunicamycin and have undertaken a conformational analysis from rotating angle nuclear Overhauser effect (ROESY) data. In addition, chirally deuterated tunicamycins produced by fermentation of Streptomyces chartreusis on chemically synthesized, monodeuterated (S-6)-[(2)H(1)]glucose have been used to assign the geminal H-6'a, H-6'b methylene bridge of the 11-carbon dialdose sugar, tunicamine. The tunicamine residue is shown to assume pseudo-D-ribofuranose and (4)C(1) pseudo-D-galactopyranosaminyl ring conformers. Conformation about the C-6' methylene bridge determines the relative orientation of these rings. The model predicts that tunicamycin forms a right-handed cupped structure, with the potential for divalent metal ion coordination at 5'-OH, 8'-OH, and the pseudogalactopyranosyl 7'-O ring oxygen. The formation of tunicamycin complexes with various divalent metal ions was confirmed experimentally by MALDI-TOF mass spectrometry. Our data support the hypothesis that tunicamycin is a structural analogue of the UDP-D-HexNAc substrate and is reversibly coordinated to the divalent metal cofactor in the D-HexNAc-1-P translocase active site.
[Mh] Termos MeSH primário: Medição da Troca de Deutério
Galactosamina/análogos & derivados
Metano/análogos & derivados
Sondas Moleculares/metabolismo
N-Acetilexosaminiltransferases/química
N-Acetilexosaminiltransferases/metabolismo
Tunicamicina/química
Tunicamicina/metabolismo
[Mh] Termos MeSH secundário: Sítios de Ligação
Configuração de Carboidratos
Cátions Bivalentes/metabolismo
Medição da Troca de Deutério/métodos
Dissacarídeos/química
Galactosamina/química
Glicosídeos/química
Hidrocarbonetos
Isomerismo
Magnésio/metabolismo
Metano/química
Ressonância Magnética Nuclear Biomolecular/métodos
Ligação Proteica
Conformação Proteica
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Streptomyces/enzimologia
Especificidade por Substrato
Uracila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cations, Divalent); 0 (Disaccharides); 0 (Glycosides); 0 (Hydrocarbons); 0 (Molecular Probes); 11089-65-9 (Tunicamycin); 2465-56-7 (carbene); 56HH86ZVCT (Uracil); 66054-53-3 (tunicamine); 7535-00-4 (Galactosamine); EC 2.4.1.- (N-Acetylhexosaminyltransferases); I38ZP9992A (Magnesium); OP0UW79H66 (Methane)
[Em] Mês de entrada:0412
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:041020
[St] Status:MEDLINE



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