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  1 / 1021 MEDLINE  
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[PMID]:28614667
[Au] Autor:Lee SM; Booe JM; Gingell JJ; Sjoelund V; Hay DL; Pioszak AA
[Ad] Endereço:Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center , 975 NE 10th Street BRC 462B, Oklahoma City, Oklahoma 73104, United States.
[Ti] Título:N-Glycosylation of Asparagine 130 in the Extracellular Domain of the Human Calcitonin Receptor Significantly Increases Peptide Hormone Affinity.
[So] Source:Biochemistry;56(26):3380-3393, 2017 Jul 05.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is activated by the peptide hormones calcitonin and amylin. Calcitonin regulates bone remodeling through CTR, whereas amylin regulates blood glucose and food intake by activating CTR in complex with receptor activity-modifying proteins (RAMPs). These receptors are targeted clinically for the treatment of osteoporosis and diabetes. Here, we define the role of CTR N-glycosylation in hormone binding using purified calcitonin and amylin receptor extracellular domain (ECD) glycoforms and fluorescence polarization/anisotropy and isothermal titration calorimetry peptide-binding assays. N-Glycan-free CTR ECD produced in Escherichia coli exhibited ∼10-fold lower peptide affinity than CTR ECD produced in HEK293T cells, which yield complex N-glycans, or in HEK293S GnTI cells, which yield core N-glycans (Man GlcNAc ). PNGase F-catalyzed removal of N-glycans at N73, N125, and N130 in the CTR ECD decreased peptide affinity ∼10-fold, whereas Endo H-catalyzed trimming of the N-glycans to single GlcNAc residues had no effect on peptide binding. Similar results were observed for an amylin receptor RAMP2-CTR ECD complex. Characterization of peptide-binding affinities of purified N → Q CTR ECD glycan site mutants combined with PNGase F and Endo H treatment strategies and mass spectrometry to define the glycan species indicated that a single GlcNAc residue at CTR N130 was responsible for the peptide affinity enhancement. Molecular modeling suggested that this GlcNAc functions through an allosteric mechanism rather than by directly contacting the peptide. These results reveal an important role for N-linked glycosylation in the peptide hormone binding of a clinically relevant class B GPCR.
[Mh] Termos MeSH primário: Asparagina/metabolismo
Calcitonina/metabolismo
Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo
Modelos Moleculares
Processamento de Proteína Pós-Traducional
Proteína 2 Modificadora da Atividade de Receptores/metabolismo
Receptores da Calcitonina/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/química
Acetilglucosamina/metabolismo
Substituição de Aminoácidos
Asparagina/química
Sítios de Ligação
Calcitonina/química
Glicosilação
Células HEK293
Seres Humanos
Polipeptídeo Amiloide das Ilhotas Pancreáticas/química
Cinética
Ligantes
Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase/genética
Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase/metabolismo
Conformação Molecular
Mutação
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/genética
Fragmentos de Peptídeos/metabolismo
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Domínios e Motivos de Interação entre Proteínas
Proteína 2 Modificadora da Atividade de Receptores/agonistas
Proteína 2 Modificadora da Atividade de Receptores/química
Proteína 2 Modificadora da Atividade de Receptores/genética
Receptores da Calcitonina/agonistas
Receptores da Calcitonina/química
Receptores da Calcitonina/genética
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Islet Amyloid Polypeptide); 0 (Ligands); 0 (Peptide Fragments); 0 (RAMP2 protein, human); 0 (Receptor Activity-Modifying Protein 2); 0 (Receptors, Calcitonin); 0 (Recombinant Fusion Proteins); 7006-34-0 (Asparagine); 9007-12-9 (Calcitonin); EC 3.2.1.96 (Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170615
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00256


  2 / 1021 MEDLINE  
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[PMID]:28512024
[Au] Autor:Bi Y; Might M; Vankayalapati H; Kuberan B
[Ad] Endereço:Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
[Ti] Título:Repurposing of Proton Pump Inhibitors as first identified small molecule inhibitors of endo-ß-N-acetylglucosaminidase (ENGase) for the treatment of NGLY1 deficiency, a rare genetic disease.
[So] Source:Bioorg Med Chem Lett;27(13):2962-2966, 2017 07 01.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:N-Glycanase deficiency, or NGLY1 deficiency, is an extremely rare human genetic disease. N-Glycanase, encoded by the gene NGLY1, is an important enzyme involved in protein deglycosylation of misfolded proteins. Deglycosylation of misfolded proteins precedes the endoplasmic reticulum (ER)-associated degradation (ERAD) process. NGLY1 patients produce little or no N-glycanase (Ngly1), and the symptoms include global developmental delay, frequent seizures, complex hyperkinetic movement disorder, difficulty in swallowing/aspiration, liver dysfunction, and a lack of tears. Unfortunately, there has not been any therapeutic option available for this rare disease so far. Recently, a proposed molecular mechanism for NGLY1 deficiency suggested that endo-ß-N-acetylglucosaminidase (ENGase) inhibitors may be promising therapeutics for NGLY1 patients. Herein, we performed structure-based virtual screening utilizing FDA-approved drug database on this ENGase target to enable repurposing of existing drugs. Several Proton Pump Inhibitors (PPIs), a series of substituted 1H-benzo [d] imidazole, and 1H-imidazo [4,5-b] pyridines, among other scaffolds, have been identified as potent ENGase inhibitors. An electrophoretic mobility shift assay was employed to assess the inhibition of ENGase activity by these PPIs. Our efforts led to the discovery of Rabeprazole Sodium as the most promising hit with an IC of 4.47±0.44µM. This is the first report that describes the discovery of small molecule ENGase inhibitors, which can potentially be used for the treatment of human NGLY1 deficiency.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Doenças Genéticas Inatas/tratamento farmacológico
Inibidores da Bomba de Prótons/farmacologia
Bombas de Próton/metabolismo
Rabeprazol/farmacologia
Bibliotecas de Moléculas Pequenas/farmacologia
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Doenças Genéticas Inatas/genética
Seres Humanos
Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase/antagonistas & inibidores
Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase/metabolismo
Estrutura Molecular
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Inibidores da Bomba de Prótons/síntese química
Inibidores da Bomba de Prótons/química
Rabeprazol/síntese química
Rabeprazol/química
Bibliotecas de Moléculas Pequenas/síntese química
Bibliotecas de Moléculas Pequenas/química
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Proton Pump Inhibitors); 0 (Proton Pumps); 0 (Small Molecule Libraries); 32828355LL (Rabeprazole); EC 3.2.1.96 (Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170518
[St] Status:MEDLINE


  3 / 1021 MEDLINE  
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[PMID]:28426790
[Au] Autor:Fujihira H; Masahara-Negishi Y; Tamura M; Huang C; Harada Y; Wakana S; Takakura D; Kawasaki N; Taniguchi N; Kondoh G; Yamashita T; Funakoshi Y; Suzuki T
[Ad] Endereço:Glycometabolome Team, Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center, Global Research Cluster, RIKEN, Saitama, Japan.
[Ti] Título:Lethality of mice bearing a knockout of the Ngly1-gene is partially rescued by the additional deletion of the Engase gene.
[So] Source:PLoS Genet;13(4):e1006696, 2017 Apr.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cytoplasmic peptide:N-glycanase (Ngly1 in mammals) is a de-N-glycosylating enzyme that is highly conserved among eukaryotes. It was recently reported that subjects harboring mutations in the NGLY1 gene exhibited severe systemic symptoms (NGLY1-deficiency). While the enzyme obviously has a critical role in mammals, its precise function remains unclear. In this study, we analyzed Ngly1-deficient mice and found that they are embryonic lethal in C57BL/6 background. Surprisingly, the additional deletion of the gene encoding endo-ß-N-acetylglucosaminidase (Engase), which is another de-N-glycosylating enzyme but leaves a single GlcNAc at glycosylated Asn residues, resulted in the partial rescue of the lethality of the Ngly1-deficient mice. Additionally, we also found that a change in the genetic background of C57BL/6 mice, produced by crossing the mice with an outbred mouse strain (ICR) could partially rescue the embryonic lethality of Ngly1-deficient mice. Viable Ngly1-deficient mice in a C57BL/6 and ICR mixed background, however, showed a very severe phenotype reminiscent of the symptoms of NGLY1-deficiency subjects. Again, many of those defects were strongly suppressed by the additional deletion of Engase in the C57BL/6 and ICR mixed background. The defects observed in Ngly1/Engase-deficient mice (C57BL/6 background) and Ngly1-deficient mice (C57BL/6 and ICR mixed background) closely resembled some of the symptoms of patients with an NGLY1-deficiency. These observations strongly suggest that the Ngly1- or Ngly1/Engase-deficient mice could serve as a valuable animal model for studies related to the pathogenesis of the NGLY1-deficiency, and that cytoplasmic ENGase represents one of the potential therapeutic targets for this genetic disorder.
[Mh] Termos MeSH primário: Doenças Genéticas Inatas/genética
Manosil-Glicoproteína Endo-beta-N-Acetilglucosaminidase/genética
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética
[Mh] Termos MeSH secundário: Animais
Citoplasma/enzimologia
Doenças Genéticas Inatas/terapia
Glicosilação
Seres Humanos
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Modelos Animais
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Deleção de Sequência/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.2.1.96 (Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006696


  4 / 1021 MEDLINE  
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[PMID]:28351617
[Au] Autor:Terao Y; Fujita H; Horibe S; Sato J; Minami S; Kobayashi M; Matsuoka I; Sasaki N; Satomi-Kobayashi S; Hirata KI; Rikitake Y
[Ad] Endereço:Department of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, Hyogo 658-8558, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan.
[Ti] Título:Interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1): Implication of N-glycosylation in FAM5C secretion.
[So] Source:Biochem Biophys Res Commun;486(3):811-816, 2017 May 06.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:N-glycosylation of proteins is important for protein folding and function. We have recently reported that FAM5C/BRINP3 contributes to the tumor necrosis factor-α-induced expression of leukocyte adhesion molecules in vascular endothelial cells (ECs). However, regulatory mechanism of the FAM5C biosynthesis is poorly understood. Co-immunoprecipitation assay revealed the interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), a glycoprotein folding-sensor enzyme. FAM5C ectopically expressed in HEK293 cells was localized to the endoplasmic reticulum and co-localized with endogenously expressed UGGT1. Molecular size of FAM5C was reduced by treatment with N-glycosidase F and in FAM5C-expressing cells cultured in the presence of the N-glycosylation inhibitor tunicamycin. FAM5C was secreted by the cells and the secretion of FAM5C was blocked by tunicamycin. Among six potential N-glycosylation sites, the potential site at Asn was not N-glycosylated, and Asn , Asn , Asn , Asn , and Asn mutants were poorly secreted by the cells. These results demonstrated that FAM5C is an N-glycosylated protein and N-glycosylation is necessary for the secretion of FAM5C.
[Mh] Termos MeSH primário: Asparagina/metabolismo
Proteínas de Ligação a DNA/secreção
Glucosiltransferases/metabolismo
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Proteínas de Ligação a DNA/genética
Proteínas de Ligação a DNA/metabolismo
Retículo Endoplasmático/efeitos dos fármacos
Retículo Endoplasmático/metabolismo
Expressão Gênica
Glucosiltransferases/genética
Glicosilação/efeitos dos fármacos
Células HEK293
Seres Humanos
Mutação
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Dobramento de Proteína
Tunicamicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA-Binding Proteins); 0 (FAM5C protein, human); 11089-65-9 (Tunicamycin); 7006-34-0 (Asparagine); EC 2.4.1.- (Glucosyltransferases); EC 2.4.1.- (UGGT1 protein, human); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170602
[Lr] Data última revisão:
170602
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170330
[St] Status:MEDLINE


  5 / 1021 MEDLINE  
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[PMID]:28334446
[Au] Autor:Donczo B; Szarka M; Tovari J; Ostoros G; Csanky E; Guttman A
[Ad] Endereço:Horváth Csaba Laboratory of Bioseparation Sciences, University of Debrecen, Hungary.
[Ti] Título:Molecular glycopathology by capillary electrophoresis: Analysis of the N-glycome of formalin-fixed paraffin-embedded mouse tissue samples.
[So] Source:Electrophoresis;38(12):1602-1608, 2017 06.
[Is] ISSN:1522-2683
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection was used to analyze endoglycosidase released and fluorophore-labeled N-glycans from formalin-fixed paraffin-embedded (FFPE) mouse tissue samples of lung, brain, heart, spleen, liver, kidney and intestine. The FFPE samples were first deparaffinized followed by solubilization and glycoprotein retrieval. PNGase F mediated release of the N-linked oligosaccharides was followed by labeling with aminopyrene trisulfonate. After CE-LIF glycoprofiling of the FFPE mouse tissues, the N-glycan pool of the lung specimen was subject to further investigation by exoglycosidase array based carbohydrate sequencing. Structural assignment of the oligosaccharides was accomplished by the help of the GUcal software and the associated database, based on the mobility shifts after treatments with the corresponding exoglycosidase reaction mixtures. Sixteen major N-linked carbohydrate structures were sequenced from the mouse lung FFPE tissue glycome and identified, as high mannose (3) neutral biantennary (3) sialylated monoantennary (1) and sialylated bianennary (9) oligosaccharides. Two of these latter ones also possessed alpha(1-3) linked galactose residues.
[Mh] Termos MeSH primário: Eletroforese Capilar/métodos
Oligossacarídeos/química
Polissacarídeos/análise
[Mh] Termos MeSH secundário: Animais
Configuração de Carboidratos
Sequência de Carboidratos
Corantes Fluorescentes
Galactose/química
Glicoproteínas/química
Masculino
Manose/química
Camundongos SCID
Especificidade de Órgãos
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química
Polissacarídeos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Fluorescent Dyes); 0 (Glycoproteins); 0 (Oligosaccharides); 0 (Polysaccharides); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase); PHA4727WTP (Mannose); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170324
[St] Status:MEDLINE
[do] DOI:10.1002/elps.201600558


  6 / 1021 MEDLINE  
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[PMID]:28104755
[Au] Autor:Traini M; Kumaran R; Thaysen-Andersen M; Kockx M; Jessup W; Kritharides L
[Ad] Endereço:Atherosclerosis Laboratory, ANZAC Research Institute, University of Sydney, NSW, Australia mathew.traini@sydney.edu.au.
[Ti] Título:N-glycosylation of human sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is essential for stability, secretion and activity.
[So] Source:Biochem J;474(7):1071-1092, 2017 Mar 08.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A) is a recently identified phosphodiesterase, which is a secreted -linked glycoprotein. SMPDL3A is highly homologous to acid sphingomyelinase (aSMase), but unlike aSMase cannot cleave sphingomyelin. Rather, SMPDL3A hydrolyzes nucleotide tri- and diphosphates and their derivatives. While recent structural studies have shed light on these unexpected substrate preferences, many other aspects of SMPDL3A biology, which may give insight into its function , remain obscure. Here, we investigate the roles of N-glycosylation in the expression, secretion and activity of human SMPDL3A, using inhibitors of N-glycosylation and site-directed mutagenesis, with either THP-1 macrophages or CHO cells expressing human SMPDL3A. Tunicamycin (TM) treatment resulted in expression of non-glycosylated SMPDL3A that was not secreted, and was largely degraded by the proteasome. Proteasomal inhibition restored levels of SMPDL3A in TM-treated cells, although this non-glycosylated protein lacked phosphodiesterase activity. Enzymatic deglycosylation of purified recombinant SMPDL3A also resulted in significant loss of phosphodiesterase activity. Site-directed mutagenesis of individual N-glycosylation sites in SMPDL3A identified glycosylation of Asn69 and Asn222 as affecting maturation of its -glycans and secretion. Glycosylation of Asn356 in SMPDL3A, an linked site conserved throughout the aSMase-like family, was critical for protection against proteasomal degradation and preservation of enzymatic activity. We provide the first experimental evidence for a predicted 22 residue N-terminal signal peptide in SMPDL3A, which is essential for facilitating glycosylation and is removed from the mature protein secreted from CHO cells. In conclusion, site-specific N-glycosylation is essential for the intracellular stability, secretion and activity of human SMPDL3A.
[Mh] Termos MeSH primário: Monócitos/enzimologia
Proteínas Recombinantes de Fusão/química
Esfingomielina Fosfodiesterase/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Células CHO
Linhagem Celular
Cricetulus
Glicosilação/efeitos dos fármacos
Seres Humanos
Indolizinas/farmacologia
Leupeptinas/farmacologia
Monócitos/citologia
Monócitos/efeitos dos fármacos
Mutagênese Sítio-Dirigida
Mutação
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química
Inibidores de Proteases/farmacologia
Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos
Complexo de Endopeptidases do Proteassoma/metabolismo
Sinais Direcionadores de Proteínas
Estabilidade Proteica/efeitos dos fármacos
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/secreção
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Esfingomielina Fosfodiesterase/genética
Esfingomielina Fosfodiesterase/secreção
Swainsonina/farmacologia
Tunicamicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Indolizines); 0 (Leupeptins); 0 (Protease Inhibitors); 0 (Protein Sorting Signals); 0 (Recombinant Fusion Proteins); 11089-65-9 (Tunicamycin); EC 3.1.4.12 (SMPDL3A protein, human); EC 3.1.4.12 (Sphingomyelin Phosphodiesterase); EC 3.4.25.1 (Proteasome Endopeptidase Complex); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase); Q0I3184XM7 (castanospermine); RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde); RSY4RK37KQ (Swainsonine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170121
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160735


  7 / 1021 MEDLINE  
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[PMID]:27988289
[Au] Autor:Sheng L; He Z; Chen J; Liu Y; Ma M; Cai Z
[Ad] Endereço:National Research and Development Center for Egg Processing, College of Food Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China.
[Ti] Título:The impact of N-glycosylation on conformation and stability of immunoglobulin Y from egg yolk.
[So] Source:Int J Biol Macromol;96:129-136, 2017 Mar.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Immunoglobulin Y (IgY) is a new therapeutic antibody, and its applications in industry are very broad. To provide insight into the effects of N-glycosylation on IgY, its conformation and stability were studied. In this research, IgY was extracted from egg yolk and then digested by peptide-N4-(N-acetyl-beta-glucosaminyl) asparagine-amidase. SDS-PAGE and infrared absorption spectrum showed that carbohydrates were distinctly reduced after enzymolysis. The circular dichroism spectrum indicated that the IgY molecule became more flexible and disordered after removal of N-glycan. The fluorescence intensity revealed that Trp residues were buried in a more hydrophobic environment after disposal of N-glycan. Storage stability decreased with the removal of oligosaccharide chains based on size-exclusion chromatography analysis. Deglycosylated IgY exhibited less resistance to guanidine hydrochloride-induced unfolding. After deglycosylation, IgY was more sensitive to pepsin. Therefore, N-glycosylation played an important role in the maintenance of the structure and stability of IgY.
[Mh] Termos MeSH primário: Gema de Ovo/química
Imunoglobulinas/química
Imunoglobulinas/metabolismo
Nitrogênio/metabolismo
[Mh] Termos MeSH secundário: Animais
Glicosilação
Guanidina/farmacologia
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Conformação Proteica
Desnaturação Proteica/efeitos dos fármacos
Estabilidade Proteica
Proteólise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (IgY); 0 (Immunoglobulins); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase); JU58VJ6Y3B (Guanidine); N762921K75 (Nitrogen)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170410
[Lr] Data última revisão:
170410
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161219
[St] Status:MEDLINE


  8 / 1021 MEDLINE  
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[PMID]:27885678
[Au] Autor:Might M; Might CC
[Ad] Endereço:Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
[Ti] Título:What happens when N = 1 and you want plus 1?
[So] Source:Prenat Diagn;37(1):70-72, 2017 Jan.
[Is] ISSN:1097-0223
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:We present a personal case study of what happens when a family has a child with an undiagnosed genetic disorder yet wishes to have more children free of the disease. After an intractable diagnostic odyssey for our oldest son, our family turned to exome sequencing. Exome sequencing found likely pathogenic variants of uncertain significance in the gene NGLY1. We used social media to uncover more cases for the newly discovered disorder and confirm the diagnosis in the process. With a diagnosis, we then explored and experienced a broad range of options for conceiving a child free of the disorder. Our success in having another child free of the disorder created a pathway for other families in our newly discovered disease community to do the same. © 2016 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Análise Mutacional de DNA
Exoma
Doenças Genéticas Inatas/diagnóstico
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/genética
Diagnóstico Pré-Natal
[Mh] Termos MeSH secundário: Pré-Escolar
Feminino
Doenças Genéticas Inatas/genética
Seres Humanos
Lactente
Masculino
Técnicas de Reprodução Assistida
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.5.1.52 (NGLY1 protein, human); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161126
[St] Status:MEDLINE
[do] DOI:10.1002/pd.4975


  9 / 1021 MEDLINE  
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[PMID]:27718394
[Au] Autor:Sroka-Bartnicka A; Karlsson I; Ndreu L; Quaranta A; Pijnappel M; Thorsén G
[Ad] Endereço:Department of Environmental Science and Analytical Chemistry, Stockholm University, Stockholm, Sweden.
[Ti] Título:Particle-based N-linked glycan analysis of selected proteins from biological samples using nonglycosylated binders.
[So] Source:J Pharm Biomed Anal;132:125-132, 2017 Jan 05.
[Is] ISSN:1873-264X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Glycosylation is one of the most common and important post-translational modifications, influencing both the chemical and the biological properties of proteins. Studying the glycosylation of the entire protein population of a sample can be challenging because variations in the concentrations of certain proteins can enhance or obscure changes in glycosylation. Furthermore, alterations in the glycosylation pattern of individual proteins, exhibiting larger variability in disease states, have been suggested as biomarkers for different types of cancer, as well as inflammatory and neurodegenerative diseases. In this paper, we present a rapid and efficient method for glycosylation analysis of individual proteins focusing on changes in the degree of fucosylation or other alterations to the core structure of the glycans, such as the presence of bisecting N-acetylglucosamines and a modified degree of branching. Streptavidin-coated magnetic beads are used in combination with genetically engineered immunoaffinity binders, called VHH antibody fragments. A major advantage of the VHHs is that they are nonglycosylated; thus, enzymatic release of glycans from the targeted protein can be performed directly on the beads. After deglycosylation, the glycans are analyzed by MALDI-TOF-MS. The developed method was evaluated concerning its specificity, and thereafter implemented for studying the glycosylation pattern of two different proteins, alpha-1-antitrypsin and transferrin, in human serum and cerebrospinal fluid. To our knowledge, this is the first example of a protein array-type experiment that employs bead-based immunoaffinity purification in combination with mass spectrometry analysis for fast and efficient glycan analysis of individual proteins in biological fluid.
[Mh] Termos MeSH primário: Polissacarídeos/química
Proteínas/química
Estreptavidina/química
[Mh] Termos MeSH secundário: Automação
Carbono/química
Eletroforese Capilar
Engenharia Genética
Glicosilação
Seres Humanos
Fragmentos de Imunoglobulinas/química
Magnetismo
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química
Porosidade
Ligação Proteica
Reprodutibilidade dos Testes
Ácidos Siálicos/química
Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
Transferrina/líquido cefalorraquidiano
Transferrina/química
alfa 1-Antitripsina/sangue
alfa 1-Antitripsina/líquido cefalorraquidiano
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Immunoglobulin Fragments); 0 (Polysaccharides); 0 (Proteins); 0 (Sialic Acids); 0 (Transferrin); 0 (alpha 1-Antitrypsin); 7440-44-0 (Carbon); 9013-20-1 (Streptavidin); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161009
[St] Status:MEDLINE


  10 / 1021 MEDLINE  
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[PMID]:27641734
[Au] Autor:Yang LY; Liu XF; Yang Y; Yang LL; Liu KW; Tang YB; Zhang M; Tan MJ; Cheng SM; Xu YC; Yang HY; Liu ZJ; Song GJ; Huang W
[Ad] Endereço:CAS Key Laboratory of Receptor Research, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
[Ti] Título:Biochemical features of the adhesion G protein-coupled receptor CD97 related to its auto-proteolysis and HeLa cell attachment activities.
[So] Source:Acta Pharmacol Sin;38(1):56-68, 2017 Jan.
[Is] ISSN:1745-7254
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CD97 belongs to the adhesion GPCR family characterized by a long ECD linked to the 7TM via a GPCR proteolytic site (GPS) and plays important roles in modulating cell migration and invasion. CD97 (EGF1-5) is a splicing variant of CD97 that recognizes a specific ligand chondroitin sulfate on cell membranes and the extracellular matrix. The aim of this study was to elucidate the extracellular molecular basis of the CD97 EGF1-5 isoform in protein expression, auto-proteolysis and cell adhesion, including epidermal growth factor (EGF)-like domain, GPCR autoproteolysis-inducing (GAIN) domain, as well as GPS mutagenesis and N-glycosylation. Both wild-type (WT) CD97-ECD and its truncated, GPS mutated, PNGase F-deglycosylated, and N-glycosylation site mutated forms were expressed and purified. The auto-proteolysis of the proteins was analyzed with Western blotting and SDS-PAGE. Small angle X-ray scattering (SAXS) and molecular modeling were used to determine a structural profile of the properly expressed receptor. Potential N-glycosylation sites were identified using MS and were modulated with PNGase F digestion and glyco-site mutations. A flow cytometry-based HeLa cell attachment assay was used for all aforementioned CD97 variants to elucidate the molecular basis of CD97-HeLa interactions. A unique concentration-dependent GPS auto-proteolysis was observed in CD97 EGF1-5 isoform with the highest concentration (4 mg/mL) per sample was self-cleaved much faster than the lower concentration (0.1 mg/mL), supporting an intermolecular mechanism of auto-proteolysis that is distinct to the reported intramolecular mechanism for other CD97 isoforms. N-glycosylation affected the auto-proteolysis of CD97 EGF1-5 isoform in a similar way as the other previously reported CD97 isoforms. SAXS data for WT and deglycosylated CD97ECD revealed a spatula-like shape with GAIN and EGF domains constituting the body and handle, respectively. Structural modeling indicated a potential interaction between the GAIN and EGF5 domains accounting for the absence of expression of the GAIN domain itself, although EGF5-GAIN was expressed similarly in the wild-type protein. For HeLa cell adhesion, the GAIN-truncated forms showed dramatically reduced binding affinity. The PNGase F-deglycosylated and GPS mutated forms also exhibited reduced HeLa attachment compared with WT CD97. However, neither N-glycosylation mutagenesis nor auto-proteolysis inhibition caused by N-glycosylation mutagenesis affected CD97-HeLa cell interactions. A comparison of the HeLa binding affinities of PNGase F-digested, GPS-mutated and N-glycosylation-mutated CD97 samples revealed diverse findings, suggesting that the functions of CD97 ECD were complex, and various technologies for function validation should be utilized to avoid single-approach bias when investigating N-glycosylation and auto-proteolysis of CD97. A unique mechanism of concentration-dependent auto-proteolysis of the CD97 EGF1-5 isoform was characterized, suggesting an intermolecular mechanism that is distinct from that of other previously reported CD97 isoforms. The EGF5 and GAIN domains are likely associated with each other as CD97 expression and SAXS data revealed a potential interaction between the two domains. Finally, the GAIN and EGF domains are also important for CD97-HeLa adhesion, whereas N-glycosylation of the CD97 GAIN domain and GPS auto-proteolysis are not required for HeLa cell attachment.
[Mh] Termos MeSH primário: Antígenos CD/metabolismo
Adesão Celular/fisiologia
Proteólise
[Mh] Termos MeSH secundário: Antígenos CD/genética
Glicosilação
Células HeLa
Seres Humanos
Modelos Estruturais
Mutagênese
Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo
Isoformas de Proteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (CD97 protein, human); 0 (Protein Isoforms); EC 3.5.1.52 (Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160920
[St] Status:MEDLINE
[do] DOI:10.1038/aps.2016.89



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