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[PMID]:29242020
[Au] Autor:Chen W; Shen S; Dong L; Zhang J; Yang Q
[Ad] Endereço:School of Life Science and Biotechnology, Dalian University of Technology, 2 Linggong Road, Dalian 116024, China.
[Ti] Título:Selective inhibition of ß-N-acetylhexosaminidases by thioglycosyl-naphthalimide hybrid molecules.
[So] Source:Bioorg Med Chem;26(2):394-400, 2018 01 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:To develop selective inhibitors for ß-N-acetylhexosaminidases which are involved in a myriad of physiological processes, a series of novel thioglycosyl-naphthalimide hybrid inhibitors were designed, synthesized and evaluated for inhibition activity against glycosyl hydrolase family 20 and 84 (GH20 and GH84) ß-N-acetylhexosaminidases. These compounds which incorporate groups with varied sizes and lengths at the linker region between thioglycosyl moiety and naphthalimide moiety are designed to improve the selectivity and stacking interactions. The GH84 human O-GlcNAcase (hOGA) was sensitive to the subtle changes in the linker region and the optimal choice is a small size linker with six atoms length. And the GH20 insect ß-N-acetylhexosaminidase OfHex1 could tolerate compounds with a hydrophobic bulky linker. Especially, the compound 5c (hOGA, K = 3.46 µM; OfHex1, K > 200 µM) and the compound 6f (hOGA, K > 200 µM; OfHex1, K = 21.81 µM) displayed high selectivity. The molecular docking results indicated that the inhibition mechanism was different between the two families due to their different structural characteristics beyond the active sites. These results provide some promising clues to improve selectivity of potent molecules against ß-N-acetylhexosaminidases.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Naftalimidas/farmacologia
Tioglicosídeos/farmacologia
beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Estrutura Molecular
Naftalimidas/química
Relação Estrutura-Atividade
Tioglicosídeos/química
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Naphthalimides); 0 (Thioglycosides); EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171216
[St] Status:MEDLINE


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[PMID]:29196265
[Au] Autor:Inoue Y; Moriwaki K; Ueda Y; Takeuchi T; Higuchi K; Asahi M
[Ad] Endereço:Department of Internal Medicine II, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan.
[Ti] Título:Elevated O-GlcNAcylation stabilizes FOXM1 by its reduced degradation through GSK-3ß inactivation in a human gastric carcinoma cell line, MKN45 cells.
[So] Source:Biochem Biophys Res Commun;495(2):1681-1687, 2018 01 08.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors. Given that FOXM1 expression was reported to be elevated in gastric cancer, we examined the effect of high glucose or an inhibitor of O-GlcNAc hydrolase, Thiamet G (TMG), on FOXM1 protein expression in a human gastric cancer cell line, MKN45 cells, and confirmed that FOXM1 protein level and the cell proliferation were upregulated. To investigate the molecular mechanisms by which FOXM1 protein expression is regulated by O-GlcNAcylation, the effect of high glucose and TMG on FOXM1 ubiquitination was examined in MKN45 cells. As a result, the ubiquitination and degradation of FOXM1 protein were both suppressed by high glucose and TMG treatment. However, the O-GlcNAcylation was not detected on FOXM1 but not on GSK-3ß. High glucose and TMG treatment increased phospho-serine 9 GSK-3ß, an inactive form, and the degradation of FOXM1 protein was suppressed by treatment of GSK-3ß inhibitors in MKN45 cells. Taken together, we suggest that high glucose and elevated O-GlcNAcylation stabilize FOXM1 protein by its reduced degradation via GSK-3ß inactivation in MKN45 cells, suggesting that the higher risk of gastric cancer in diabetic patients could be partially due to O-GlcNAcylation-mediated FOXM1 stabilization.
[Mh] Termos MeSH primário: Proteína Forkhead Box M1/metabolismo
Glicogênio Sintase Quinase 3 beta/metabolismo
Neoplasias Gástricas/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Acilação
Linhagem Celular Tumoral
Proliferação Celular
Complicações do Diabetes/etiologia
Complicações do Diabetes/metabolismo
Complicações do Diabetes/patologia
Inibidores Enzimáticos/farmacologia
Proteína Forkhead Box M1/química
Glucose/metabolismo
Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores
Glicogênio Sintase Quinase 3 beta/química
Seres Humanos
Processamento de Proteína Pós-Traducional
Estabilidade Proteica/efeitos dos fármacos
Proteólise/efeitos dos fármacos
Piranos/farmacologia
Neoplasias Gástricas/etiologia
Neoplasias Gástricas/patologia
Tiazóis/farmacologia
Ubiquitinação/efeitos dos fármacos
Regulação para Cima/efeitos dos fármacos
beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (FOXM1 protein, human); 0 (Forkhead Box Protein M1); 0 (Pyrans); 0 (Thiazoles); 0 (thiamet G); EC 2.7.11.1 (GSK3B protein, human); EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); IY9XDZ35W2 (Glucose); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:29390898
[Au] Autor:Shen S; Chen W; Dong L; Yang Q; Lu H; Zhang J
[Ad] Endereço:a Department of Applied Chemistry , College of Science, China Agricultural University , Beijing , China.
[Ti] Título:Design and synthesis of naphthalimide group-bearing thioglycosides as novel ß-N-acetylhexosaminidases inhibitors.
[So] Source:J Enzyme Inhib Med Chem;33(1):445-452, 2018 Dec.
[Is] ISSN:1475-6374
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:GH20 human ß-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these ß-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (K = 0.91 µM against hsHexB; K > 100 µM against hOGA) and compound 15b (K = 3.76 µM against hOGA; K = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure-activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific ß-N-acetylhexosaminidase inhibitors.
[Mh] Termos MeSH primário: Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Naftalimidas/farmacologia
Tioglicosídeos/farmacologia
beta-N-Acetil-Hexosaminidases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Biocatálise
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Simulação de Acoplamento Molecular
Estrutura Molecular
Naftalimidas/síntese química
Naftalimidas/química
Relação Estrutura-Atividade
Tioglicosídeos/química
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Naphthalimides); 0 (Thioglycosides); EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180212
[Lr] Data última revisão:
180212
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1080/14756366.2017.1419217


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[PMID]:28742148
[Au] Autor:Groussaud D; Khair M; Tollenaere AI; Waast L; Kuo MS; Mangeney M; Martella C; Fardini Y; Coste S; Souidi M; Benit L; Pique C; Issad T
[Ad] Endereço:INSERM, U1016, Institut Cochin, Paris, France.
[Ti] Título:Hijacking of the O-GlcNAcZYME complex by the HTLV-1 Tax oncoprotein facilitates viral transcription.
[So] Source:PLoS Pathog;13(7):e1006518, 2017 Jul.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The viral Tax oncoprotein plays a key role in both Human T-cell lymphotropic virus type 1 (HTLV-1)-replication and HTLV-1-associated pathologies, notably adult T-cell leukemia. Tax governs the transcription from the viral 5'LTR, enhancing thereby its own expression, via the recruitment of dimers of phosphorylated CREB to cAMP-response elements located within the U3 region (vCRE). In addition to phosphorylation, CREB is also the target of O-GlcNAcylation, another reversible post-translational modification involved in a wide range of diseases, including cancers. O-GlcNAcylation consists in the addition of O-linked-N-acetylglucosamine (O-GlcNAc) on Serine or Threonine residues, a process controlled by two enzymes: O-GlcNAc transferase (OGT), which transfers O-GlcNAc on proteins, and O-GlcNAcase (OGA), which removes it. In this study, we investigated the status of O-GlcNAcylation enzymes in HTLV-1-transformed T cells. We found that OGA mRNA and protein expression levels are increased in HTLV-1-transformed T cells as compared to control T cell lines while OGT expression is unchanged. However, higher OGA production coincides with a reduction in OGA specific activity, showing that HTLV-1-transformed T cells produce high level of a less active form of OGA. Introducing Tax into HEK-293T cells or Tax-negative HTLV-1-transformed TL-om1 T cells is sufficient to inhibit OGA activity and increase total O-GlcNAcylation, without any change in OGT activity. Furthermore, Tax interacts with the OGT/OGA complex and inhibits the activity of OGT-bound OGA. Pharmacological inhibition of OGA increases CREB O-GlcNAcylation as well as HTLV-1-LTR transactivation by Tax and CREB recruitment to the LTR. Moreover, overexpression of wild-type CREB but not a CREB protein mutated on a previously described O-GlcNAcylation site enhances Tax-mediated LTR transactivation. Finally, both OGT and OGA are recruited to the LTR. These findings reveal the interplay between Tax and the O-GlcNAcylation pathway and identify new key molecular actors involved in the assembly of the Tax-dependent transactivation complex.
[Mh] Termos MeSH primário: Produtos do Gene tax/metabolismo
Infecções por HTLV-I/virologia
Vírus 1 Linfotrópico T Humano/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
Linfócitos T/virologia
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo
Regulação Viral da Expressão Gênica
Produtos do Gene tax/genética
Infecções por HTLV-I/enzimologia
Infecções por HTLV-I/genética
Infecções por HTLV-I/metabolismo
Interações Hospedeiro-Patógeno
Vírus 1 Linfotrópico T Humano/genética
Seres Humanos
N-Acetilglucosaminiltransferases/genética
Processamento de Proteína Pós-Traducional
Linfócitos T/enzimologia
Linfócitos T/metabolismo
Transcrição Genética
beta-N-Acetil-Hexosaminidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclic AMP Response Element-Binding Protein); 0 (Gene Products, tax); 0 (tax protein, Human T-lymphotrophic virus 1); EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006518


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[PMID]:28969384
[Au] Autor:Migdalska-Richards A; Wegrzynowicz M; Rusconi R; Deangeli G; Di Monte DA; Spillantini MG; Schapira AHV
[Ad] Endereço:Department of Clinical Neurosciences, Institute of Neurology, University College London, London NW3 2PF, UK.
[Ti] Título:The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice.
[So] Source:Brain;140(10):2706-2721, 2017 Oct 01.
[Is] ISSN:1460-2156
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson's disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson's disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Glucosilceramidase/genética
Mutação/genética
Neurônios/patologia
Substância Negra/patologia
alfa-Sinucleína/metabolismo
[Mh] Termos MeSH secundário: Fatores Etários
Animais
Encéfalo/metabolismo
Encéfalo/patologia
Glucosilceramidase/deficiência
Seres Humanos
Leucina/genética
Camundongos
Camundongos Transgênicos
Neurônios/metabolismo
Prolina/genética
Desempenho Psicomotor/fisiologia
Olfato/genética
Substância Negra/metabolismo
Transdução Genética
Tirosina 3-Mono-Oxigenase/metabolismo
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (alpha-Synuclein); 9DLQ4CIU6V (Proline); EC 1.14.16.2 (Tyrosine 3-Monooxygenase); EC 3.2.1.45 (Glucosylceramidase); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); GMW67QNF9C (Leucine); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171006
[Lr] Data última revisão:
171006
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171004
[St] Status:MEDLINE
[do] DOI:10.1093/brain/awx221


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[PMID]:28739801
[Au] Autor:Tan EP; McGreal SR; Graw S; Tessman R; Koppel SJ; Dhakal P; Zhang Z; Machacek M; Zachara NE; Koestler DC; Peterson KR; Thyfault JP; Swerdlow RH; Krishnamurthy P; DiTacchio L; Apte U; Slawson C
[Ad] Endereço:From the Departments of Biochemistry and Molecular Biology.
[Ti] Título:Sustained GlcNAcylation reprograms mitochondrial function to regulate energy metabolism.
[So] Source:J Biol Chem;292(36):14940-14962, 2017 Sep 08.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dysfunctional mitochondria and generation of reactive oxygen species (ROS) promote chronic diseases, which have spurred interest in the molecular mechanisms underlying these conditions. Previously, we have demonstrated that disruption of post-translational modification of proteins with ß-linked -acetylglucosamine ( -GlcNAcylation) via overexpression of the GlcNAc-regulating enzymes GlcNAc transferase (OGT) or GlcNAcase (OGA) impairs mitochondrial function. Here, we report that sustained alterations in GlcNAcylation either by pharmacological or genetic manipulation also alter metabolic function. Sustained GlcNAc elevation in SH-SY5Y neuroblastoma cells increased OGA expression and reduced cellular respiration and ROS generation. Cells with elevated GlcNAc levels had elongated mitochondria and increased mitochondrial membrane potential, and RNA-sequencing analysis indicated transcriptome reprogramming and down-regulation of the NRF2-mediated antioxidant response. Sustained GlcNAcylation in mouse brain and liver validated the metabolic phenotypes observed in the cells, and OGT knockdown in the liver elevated ROS levels, impaired respiration, and increased the NRF2 antioxidant response. Moreover, elevated GlcNAc levels promoted weight loss and lowered respiration in mice and skewed the mice toward carbohydrate-dependent metabolism as determined by indirect calorimetry. In summary, sustained elevation in GlcNAcylation coupled with increased OGA expression reprograms energy metabolism, a finding that has potential implications for the etiology, development, and management of metabolic diseases.
[Mh] Termos MeSH primário: Acetilglucosamina/metabolismo
Metabolismo Energético
Mitocôndrias/metabolismo
N-Acetilglucosaminiltransferases/metabolismo
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Animais
Glicosilação
Seres Humanos
Masculino
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
N-Acetilglucosaminiltransferases/deficiência
N-Acetilglucosaminiltransferases/genética
Células Tumorais Cultivadas
beta-N-Acetil-Hexosaminidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.4.1.- (N-Acetylglucosaminyltransferases); EC 2.4.1.- (O-GlcNAc transferase); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.797944


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[PMID]:28734737
[Au] Autor:Wang L; Zhang F; Cao Z; Xiao Y; Li S; Yu B; Qi J
[Ad] Endereço:Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing 211198, PR China; Department of preparation, Nanjing General Hospital of Nanjing Military Region, PLA, Nanjing 210002, PR China.
[Ti] Título:Ginsenoside F2 induces the release of mediators associated with Anaphylactoid reactions.
[So] Source:Fitoterapia;121:223-228, 2017 Sep.
[Is] ISSN:1873-6971
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Recently, the allergenicity of ginsenosides, as main active components in ginseng, has attracted much attention. Ginsenoside Rb1 and Rd. have been reported to induce anaphylactoid reaction. In this study, the allergenicity of a series of 20(S)-protopanaxadiol (PPD) type ginsenosides, including Rb1, Rd., F2, Compound K and 20(S)-PPD, was evaluated in rat basophilic leukemia 2H3 (RBL2H3) cells. As a result, 20(S)-PPD had no effect on the mast cell degranulation, but other components showed anaphylactoid potential to different extent. The allergenicity was stronger and stronger according to the order "Rb1, Rd., F2, Compound K". Then, F2 was further verified in RBL-2H3 cells, mouse peritoneal mast cells (MPMCs), Laboratory of Allergic Disease 2 (LAD2) human mast cells in vitro and mice in vivo. Results showed that F2 could induce a significant increase of histamine release and translocation of phosphatidylserine in RBL-2H3 cells. F2 also increased ß-hexosaminidase release and the intracellular Ca concentration of MPMCs and LAD2 cells. In addition, histamine level in serum of mice was elevated dose-dependently. Our study revealed the potential structure-allergenicity relationship of 20(S)-PPD type ginsenosides and first verified the allergenicity of ginsenoside F2. This study could guide the establishment of quality standards for safe application of ginsenoside-containing preparations.
[Mh] Termos MeSH primário: Ginsenosídeos/efeitos adversos
Hipersensibilidade/fisiopatologia
Mastócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Linhagem Celular Tumoral
Histamina/metabolismo
Seres Humanos
Hipersensibilidade/metabolismo
Masculino
Mastócitos/metabolismo
Camundongos
Camundongos Endogâmicos ICR
Estrutura Molecular
Fosfatidilserinas/metabolismo
Ratos
beta-N-Acetil-Hexosaminidases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ginsenosides); 0 (Phosphatidylserines); 0 (ginsenoside F2); 0 (ginsenoside M1); 820484N8I3 (Histamine); EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE


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[PMID]:28695569
[Au] Autor:Intra J; Veltri C; De Caro D; Perotti ME; Pasini ME
[Ad] Endereço:Department of Biosciences, University of Milano, Milano, Italy.
[Ti] Título:In vitro evidence for the participation of Drosophila melanogaster sperm ß-N-acetylglucosaminidases in the interactions with glycans carrying terminal N-acetylglucosamine residues on the egg's envelopes.
[So] Source:Arch Insect Biochem Physiol;96(1), 2017 Sep.
[Is] ISSN:1520-6327
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fertilization is a complex and multiphasic process, consisting of several steps, where egg-coating envelope's glycoproteins and sperm surface receptors play a critical role. Sperm-associated ß-N-acetylglucosaminidases, also known as hexosaminidases, have been identified in a variety of organisms. Previously, two isoforms of hexosaminidases, named here DmHEXA and DmHEXB, were found as intrinsic proteins in the sperm plasma membrane of Drosophila melanogaster. In the present work, we carried out different approaches using solid-phase assays in order to analyze the oligosaccharide recognition ability of D. melanogaster sperm hexosaminidases to interact with well-defined carbohydrate chains that might functionally mimic egg glycoconjugates. Our results showed that Drosophila hexosaminidases prefer glycans carrying terminal ß-N-acetylglucosamine, but not core ß-N-acetylglucosamine residues. The capacity of sperm ß-N-acetylhexosaminidases to bind micropylar chorion and vitelline envelope was examined in vitro assays. Binding was completely blocked when ß-N-acetylhexosaminidases were preincubated with the glycoproteins ovalbumin and transferrin, and the monosaccharide ß-N-acetylglucosamine. Overall, these data support the hypothesis of the potential role of these glycosidases in sperm-egg interactions in Drosophila.
[Mh] Termos MeSH primário: Drosophila melanogaster/enzimologia
Fertilização/fisiologia
Óvulo/metabolismo
Espermatozoides/enzimologia
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
beta-N-Acetil-Hexosaminidases/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170712
[St] Status:MEDLINE
[do] DOI:10.1002/arch.21403


  9 / 2436 MEDLINE  
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[PMID]:28627871
[Au] Autor:De Leon CA; Levine PM; Craven TW; Pratt MR
[Ti] Título:The Sulfur-Linked Analogue of O-GlcNAc (S-GlcNAc) Is an Enzymatically Stable and Reasonable Structural Surrogate for O-GlcNAc at the Peptide and Protein Levels.
[So] Source:Biochemistry;56(27):3507-3517, 2017 Jul 11.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Synthetic proteins bearing site-specific posttranslational modifications have revolutionized our understanding of their biological functions in vitro and in vivo. One such modification, O-GlcNAcylation, is the dynamic addition of ß-N-acetyl glucosamine to the side chains of serine and threonine residues of proteins, yet our understanding of the site-specific impact of O-GlcNAcylation remains difficult to evaluate in vivo because of the potential for enzymatic removal by endogenous O-GlcNAcase (OGA). Thioglycosides are generally perceived to be enzymatically stable structural mimics of O-GlcNAc; however, in vitro experiments with small-molecule GlcNAc thioglycosides have demonstrated that OGA can hydrolyze these linkages, indicating that S-linked ß-N-acetyl glucosamine (S-GlcNAc) on peptides or proteins may not be completely stable. Here, we first develop a robust synthetic route to access an S-GlcNAcylated cysteine building block for peptide and protein synthesis. Using this modified amino acid, we establish that S-GlcNAc is an enzymatically stable surrogate for O-GlcNAcylation in its native protein setting. We also applied nuclear magnetic resonance spectroscopy and computational modeling to find that S-GlcNAc is an good structural mimic of O-GlcNAc. Finally, we demonstrate that site-specific S-GlcNAcylation results in biophysical characteristics that are the same as those of O-GlcNAc within the context of the protein α-synuclein. While this study is limited in focus to two model systems, these data suggest that S-GlcNAc broadly resembles O-GlcNAc and that it is indeed a stable analogue in the context of peptides and proteins.
[Mh] Termos MeSH primário: Acetilglucosamina/análogos & derivados
Modelos Moleculares
Processamento de Proteína Pós-Traducional
Serina/análogos & derivados
Treonina/análogos & derivados
alfa-Sinucleína/metabolismo
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Acetilglucosamina/metabolismo
Animais
Dicroísmo Circular
Biologia Computacional
Seres Humanos
Ressonância Magnética Nuclear Biomolecular
Fragmentos de Peptídeos/química
Fragmentos de Peptídeos/metabolismo
Dobramento de Proteína
Estabilidade Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Especificidade por Substrato
Treonina/metabolismo
alfa-Sinucleína/química
alfa-Sinucleína/genética
beta-N-Acetil-Hexosaminidases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptide Fragments); 0 (Recombinant Proteins); 0 (alpha-Synuclein); 2ZD004190S (Threonine); 452VLY9402 (Serine); EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases); V956696549 (Acetylglucosamine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170915
[Lr] Data última revisão:
170915
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170620
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00268


  10 / 2436 MEDLINE  
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[PMID]:28604694
[Au] Autor:Selvan N; Williamson R; Mariappa D; Campbell DG; Gourlay R; Ferenbach AT; Aristotelous T; Hopkins-Navratilova I; Trost M; van Aalten DMF
[Ad] Endereço:MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK.
[Ti] Título:A mutant O-GlcNAcase enriches Drosophila developmental regulators.
[So] Source:Nat Chem Biol;13(8):882-887, 2017 Aug.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein O-GlcNAcylation is a reversible post-translational modification of serines and threonines on nucleocytoplasmic proteins. It is cycled by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (O-GlcNAcase or OGA). Genetic approaches in model organisms have revealed that protein O-GlcNAcylation is essential for early embryogenesis. The Drosophila melanogaster gene supersex combs (sxc), which encodes OGT, is a polycomb gene, whose null mutants display homeotic transformations and die at the pharate adult stage. However, the identities of the O-GlcNAcylated proteins involved and the underlying mechanisms linking these phenotypes to embryonic development are poorly understood. Identification of O-GlcNAcylated proteins from biological samples is hampered by the low stoichiometry of this modification and by limited enrichment tools. Using a catalytically inactive bacterial O-GlcNAcase mutant as a substrate trap, we have enriched the O-GlcNAc proteome of the developing Drosophila embryo, identifying, among others, known regulators of Hox genes as candidate conveyors of OGT function during embryonic development.
[Mh] Termos MeSH primário: Drosophila melanogaster/embriologia
Drosophila melanogaster/enzimologia
Mutação
beta-N-Acetil-Hexosaminidases/genética
beta-N-Acetil-Hexosaminidases/metabolismo
[Mh] Termos MeSH secundário: Animais
Drosophila melanogaster/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.2.1.50 (hexosaminidase C); EC 3.2.1.52 (beta-N-Acetylhexosaminidases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2404



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