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[PMID]:29324789
[Au] Autor:Choi JH; Shin KC; Oh DK
[Ad] Endereço:Department of Bioscience and Biotechnology, Konkuk University, Seoul, Republic of Korea.
[Ti] Título:An L213A variant of ß-glycosidase from Sulfolobus solfataricus with increased α-L-arabinofuranosidase activity converts ginsenoside Rc to compound K.
[So] Source:PLoS One;13(1):e0191018, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Compound K (C-K) is a crucial pharmaceutical and cosmetic component because of disease prevention and skin anti-aging effects. For industrial application of this active compound, the protopanaxadiol (PPD)-type ginsenosides should be transformed to C-K. ß-Glycosidase from Sulfolobus solfataricus has been reported as an efficient C-K-producing enzyme, using glycosylated PPD-type ginsenosides as substrates. ß-Glycosidase from S. solfataricus can hydrolyze ß-d-glucopyranoside in ginsenosides Rc, C-Mc1, and C-Mc, but not α-l-arabinofuranoside in these ginsenosides. To determine candidate residues involved in α-l-arabinofuranosidase activity, compound Mc (C-Mc) was docking to ß-glycosidase from S. solfataricus in homology model and sequence was aligned with ß-glycosidase from Pyrococcus furiosus that has α-l-arabinofuranosidase activity. A L213A variant ß-glycosidase with increased α-l-arabinofuranosidase activity was selected by substitution of other amino acids for candidate residues. The increased α-l-arabinofuranosidase activity of the L213A variant was confirmed through the determination of substrate specificity, change in binding energy, transformation pathway, and C-K production from ginsenosides Rc and C-Mc. The L213A variant ß-glycosidase catalyzed the conversion of Rc to Rd by hydrolyzing α-l-arabinofuranoside linked to Rc, whereas the wild-type ß-glycosidase did not. The variant enzyme converted ginsenosides Rc and C-Mc into C-K with molar conversions of 97%, which were 1.5- and 2-fold higher, respectively, than those of the wild-type enzyme. Therefore, protein engineering is a useful tool for enhancing the hydrolytic activity on specific glycoside linked to ginsenosides.
[Mh] Termos MeSH primário: Ginsenosídeos/metabolismo
Glicosídeo Hidrolases/metabolismo
Sulfolobus solfataricus/enzimologia
beta-Glucosidase/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Genes Bacterianos
Mutagênese Sítio-Dirigida
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
beta-Glucosidase/química
beta-Glucosidase/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ginsenosides); 0 (ginsenoside M1); 0K83B0L786 (ginsenoside Rc); EC 3.2.1.- (Glycoside Hydrolases); EC 3.2.1.21 (beta-Glucosidase); EC 3.2.1.55 (alpha-N-arabinofuranosidase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180112
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191018


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[PMID]:29272750
[Au] Autor:Galibert M; Wartenberg M; Lecaille F; Saidi A; Mavel S; Joulin-Giet A; Korkmaz B; Brömme D; Aucagne V; Delmas AF; Lalmanach G
[Ad] Endereço:CNRS UPR 4301, Centre de Biophysique Moléculaire, Rue Charles Sadron, Orléans, France.
[Ti] Título:Substrate-derived triazolo- and azapeptides as inhibitors of cathepsins K and S.
[So] Source:Eur J Med Chem;144:201-210, 2018 Jan 20.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Cathepsin (Cat) K is a critical bone-resorbing protease and is a relevant target for the treatment of osteoporosis and bone metastasis, while CatS is an attractive target for drugs in autoimmune diseases (e.g. rheumatoid arthritis), emphysema or neuropathic pain. Despite major achievements, current pharmacological inhibitors are still lacking in safety and may have damaging side effects. A promising strategy for developing safer reversible and competitive inhibitors as new lead compounds could be to insert non-cleavable bonds at the scissile P1-P1' position of selective substrates of CatS and CatK. Accordingly, we introduced a 1,4-disubstituted 1,2,3-triazole heterocycle that mimics most of the features of a trans-amide bond, or we incorporated a semicarbazide bond (azaGly residue) by replacing the α-carbon of the glycyl residue at P1 by a nitrogen atom. AzaGly-containing peptidomimetics inhibited powerfully their respective target proteases in the nM range, while triazolopeptides were weaker inhibitors (Ki in the µM range). The selectivity of the azaGly CatS inhibitor (1b) was confirmed by using spleen lysates from wild-type vs CatS-deficient mice. Alternatively, the azaGly bradykinin-derived CatK inhibitor (2b) potently inhibited CatK (Ki = 9 nM) and impaired its kininase activity in vitro. Molecular modeling studies support that the semicarbazide bond of 2b is more favorable than the 1,2,3-triazole linkage of the bradykinin-derived pseudopeptide 2a to preserve an effective affinity towards CatK, its protease target.
[Mh] Termos MeSH primário: Catepsina K/antagonistas & inibidores
Catepsinas/antagonistas & inibidores
Inibidores de Proteases/química
Inibidores de Proteases/farmacologia
Triazóis/química
Triazóis/farmacologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Catepsina K/metabolismo
Catepsinas/metabolismo
Seres Humanos
Camundongos Endogâmicos C57BL
Simulação de Acoplamento Molecular
Peptídeos/química
Peptídeos/farmacologia
Peptidomiméticos/química
Peptidomiméticos/farmacologia
Relação Estrutura-Atividade
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Peptides); 0 (Peptidomimetics); 0 (Protease Inhibitors); 0 (Triazoles); EC 3.4.- (Cathepsins); EC 3.4.22.27 (cathepsin S); EC 3.4.22.38 (Cathepsin K)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171223
[St] Status:MEDLINE


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[PMID]:29216817
[Au] Autor:Nivala O; Faccio G; Arvas M; Permi P; Buchert J; Kruus K; Mattinen ML
[Ad] Endereço:VTT Technical Research Centre of Finland, Ltd., P.O. Box 1000, FI-02044, Espoo, Finland. outi.nivala@helsinki.fi.
[Ti] Título:Characterization of sulfhydryl oxidase from Aspergillus tubingensis.
[So] Source:BMC Biochem;18(1):15, 2017 12 08.
[Is] ISSN:1471-2091
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Despite of the presence of sulfhydryl oxidases (SOXs) in the secretomes of industrially relevant organisms and their many potential applications, only few of these enzymes have been biochemically characterized. In addition, basic functions of most of the SOX enzymes reported so far are not fully understood. In particular, the physiological role of secreted fungal SOXs is unclear. RESULTS: The recently identified SOX from Aspergillus tubingensis (AtSOX) was produced, purified and characterized in the present work. AtSOX had a pH optimum of 6.5, and showed a good pH stability retaining more than 80% of the initial activity in a pH range 4-8.5 within 20 h. More than 70% of the initial activity was retained after incubation at 50 °C for 20 h. AtSOX contains a non-covalently bound flavin cofactor. The enzyme oxidised a sulfhydryl group of glutathione to form a disulfide bond, as verified by nuclear magnetic resonance spectroscopy. AtSOX preferred glutathione as a substrate over cysteine and dithiothreitol. The activity of the enzyme was totally inhibited by 10 mM zinc sulphate. Peptide- and protein-bound sulfhydryl groups in bikunin, gliotoxin, holomycin, insulin B chain, and ribonuclease A, were not oxidised by the enzyme. Based on the analysis of 33 fungal genomes, SOX enzyme encoding genes were found close to nonribosomal peptide synthetases (NRPS) but not with polyketide synthases (PKS). In the phylogenetic tree, constructed from 25 SOX and thioredoxin reductase sequences from IPR000103 InterPro family, AtSOX was evolutionary closely related to other Aspergillus SOXs. Oxidoreductases involved in the maturation of nonribosomal peptides of fungal and bacterial origin, namely GliT, HlmI and DepH, were also evolutionary closely related to AtSOX whereas fungal thioreductases were more distant. CONCLUSIONS: AtSOX (55 kDa) is a fungal secreted flavin-dependent enzyme with good stability to both pH and temperature. A Michaelis-Menten behaviour was observed with reduced glutathione as a substrate. Based on the location of SOX enzyme encoding genes close to NRPSs, SOXs could be involved in the secondary metabolism and act as an accessory enzyme in the production of nonribosomal peptides.
[Mh] Termos MeSH primário: Aspergillus/enzimologia
Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Dissulfetos
Estabilidade Enzimática
Glutationa/metabolismo
Concentração de Íons de Hidrogênio
Oxirredutases/química
Oxirredutases/genética
Oxirredutases/isolamento & purificação
Peptídeo Sintases
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Disulfides); EC 1.- (Oxidoreductases); EC 1.8.3.- (sulfhydryl oxidase); EC 6.3.2.- (Peptide Synthases); EC 6.3.2.- (non-ribosomal peptide synthase); GAN16C9B8O (Glutathione)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1186/s12858-017-0090-4


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[PMID]:29051067
[Au] Autor:Wang Y; Ryu BH; Yoo W; Lee CW; Kim KK; Lee JH; Kim TD
[Ad] Endereço:Department of Chemistry, College of Natural Science, Sookmyung Women's University, Seoul 04310, Republic of Korea.
[Ti] Título:Identification, characterization, immobilization, and mutational analysis of a novel acetylesterase with industrial potential (LaAcE) from Lactobacillus acidophilus.
[So] Source:Biochim Biophys Acta;1862(1):197-210, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Lactic acid bacteria, which are involved in the fermentation of vegetables, meats, and dairy products, are widely used for the productions of small organic molecules and bioactive peptides. Here, a novel acetylesterase (LaAcE) from Lactobacillus acidophilus NCFM was identified, functionally characterized, immobilized, and subjected to site-directed mutagenesis for biotechnological applications. The enzymatic properties of LaAcE were investigated using biochemical and biophysical methods including native polyacrylamide gel electrophoresis, acetic acid release, biochemical assays, enzyme kinetics, and spectroscopic methods. Interestingly, LaAcE exhibited the ability to act on a broad range of substrates including glucose pentaacetate, glyceryl tributyrate, fish oil, and fermentation-related compounds. Furthermore, immobilization of LaAcE showed good recycling ability and high thermal stability compared with free LaAcE. A structural model of LaAcE was used to guide mutational analysis of hydrophobic substrate-binding region, which was composed of Leu , Phe , and Val . Five mutants (L156A, F164A, V204A, L156A/F164A, and L156A/V204A) were generated and investigated to elucidate the roles of these hydrophobic residues in substrate specificity. This work provided valuable insights into the properties of LaAcE, and demonstrated that LaAcE could be used as a model enzyme of acetylesterase in lactic acid bacteria, making LaAcE a great candidate for industrial applications.
[Mh] Termos MeSH primário: Acetilesterase
Proteínas de Bactérias
Enzimas Imobilizadas
Lactobacillus acidophilus
Modelos Moleculares
Mutação de Sentido Incorreto
[Mh] Termos MeSH secundário: Acetilesterase/química
Acetilesterase/genética
Substituição de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Enzimas Imobilizadas/química
Enzimas Imobilizadas/genética
Lactobacillus acidophilus/enzimologia
Lactobacillus acidophilus/genética
Especificidade por Substrato/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Enzymes, Immobilized); EC 3.1.1.6 (Acetylesterase)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171021
[St] Status:MEDLINE


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[PMID]:28461165
[Au] Autor:Ahmed FRS; Amin R; Hasan I; Asaduzzaman AKM; Kabir SR
[Ad] Endereço:Department of Biochemistry and Molecular Biology, Faculty of Science, University of Rajshahi, Rajshahi 6205, Bangladesh.
[Ti] Título:Antitumor properties of a methyl-ß-d-galactopyranoside specific lectin from Kaempferia rotunda against Ehrlich ascites carcinoma cells.
[So] Source:Int J Biol Macromol;102:952-959, 2017 Sep.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:A lectin was isolated from the tuberous rhizome of Keampferia rotunda by using different chromatographic methods with the molecular weight of 21±1kDa. The lectin contained highest percentage of leucine and lowest percentage of tryptophan residues as determined by LC-MS. The lectin agglutinated mice and human erythrocytes and the hemagglutination activity was inhibited by Methyl-ß-d-galactopyranoside. The lectin did not lose its activity in the presence of urea but the activity abolished completely when treated with EDTA. The lectin exhibited its activity at the pH ranging from 6.0 to 9.0 and in a temperature range of 30-80°C. Antiproliferative activity was studied against Ehrlich ascites carcinoma (EAC) and U87 cell lines. No inhibitory effect was observed against U87 cell line whereas 43.7% cell growth inhibition was observed in vitro against EAC cells at 160µg/ml. The lectin was injected (i.p.) in EAC bearing Swiss albino mice at the doses of 3.0 and 6.0mg/kg/day for five consecutive days and 41 and 59% of EAC cell growth inhibition was observed, respectively. The cell growth inhibition was due to the induction of apoptosis in the EAC cells which was confirmed by cell morphological study, caspase-3 inhibitor and apoptosis-related gene expression.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Carcinoma de Ehrlich/patologia
Galactose/metabolismo
Lectinas de Plantas/farmacologia
Zingiberaceae/química
[Mh] Termos MeSH secundário: Animais
Antineoplásicos/química
Antineoplásicos/isolamento & purificação
Antineoplásicos/metabolismo
Apoptose/efeitos dos fármacos
Apoptose/genética
Caspases/metabolismo
Bovinos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Hemaglutinação/efeitos dos fármacos
Seres Humanos
Concentração de Íons de Hidrogênio
Camundongos
Peso Molecular
Lectinas de Plantas/química
Lectinas de Plantas/isolamento & purificação
Lectinas de Plantas/metabolismo
Especificidade por Substrato
Temperatura Ambiente
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Plant Lectins); EC 3.4.22.- (Caspases); X2RN3Q8DNE (Galactose)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29410408
[Au] Autor:Kuncha SK; Mazeed M; Singh R; Kattula B; Routh SB; Sankaranarayanan R
[Ad] Endereço:CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500007, India.
[Ti] Título:A chiral selectivity relaxed paralog of DTD for proofreading tRNA mischarging in Animalia.
[So] Source:Nat Commun;9(1):511, 2018 02 06.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:D-aminoacyl-tRNA deacylase (DTD), a bacterial/eukaryotic trans-editing factor, removes D-amino acids mischarged on tRNAs and achiral glycine mischarged on tRNA . An invariant cross-subunit Gly-cisPro motif forms the mechanistic basis of L-amino acid rejection from the catalytic site. Here, we present the identification of a DTD variant, named ATD (Animalia-specific tRNA deacylase), that harbors a Gly-transPro motif. The cis-to-trans switch causes a "gain of function" through L-chiral selectivity in ATD resulting in the clearing of L-alanine mischarged on tRNA (G4•U69) by eukaryotic AlaRS. The proofreading activity of ATD is conserved across diverse classes of phylum Chordata. Animalia genomes enriched in tRNA (G4•U69) genes are in strict association with the presence of ATD, underlining the mandatory requirement of a dedicated factor to proofread tRNA misaminoacylation. The study highlights the emergence of ATD during genome expansion as a key event associated with the evolution of Animalia.
[Mh] Termos MeSH primário: Alanina/química
Aminoaciltransferases/química
Aminoacil-RNA de Transferência/química
Treonina/química
Aminoacilação de RNA de Transferência/genética
[Mh] Termos MeSH secundário: Alanina/genética
Alanina/metabolismo
Sequência de Aminoácidos
Aminoaciltransferases/genética
Aminoaciltransferases/metabolismo
Animais
Apicomplexa/genética
Apicomplexa/metabolismo
Bactérias/genética
Bactérias/metabolismo
Sítios de Ligação
Evolução Biológica
Clonagem Molecular
Cristalografia por Raios X
Expressão Gênica
Seres Humanos
Modelos Moleculares
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Aminoacil-RNA de Transferência/genética
Aminoacil-RNA de Transferência/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
Treonina/genética
Treonina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (RNA, Transfer, Amino Acyl); 0 (Recombinant Proteins); 2ZD004190S (Threonine); EC 2.3.2.- (Aminoacyltransferases); OF5P57N2ZX (Alanine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180307
[Lr] Data última revisão:
180307
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180208
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02204-w


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[PMID]:28747400
[Au] Autor:Gupta A; Milias-Argeitis A; Khammash M
[Ad] Endereço:Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
[Ti] Título:Dynamic disorder in simple enzymatic reactions induces stochastic amplification of substrate.
[So] Source:J R Soc Interface;14(132), 2017 Jul.
[Is] ISSN:1742-5662
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A growing amount of evidence over the last two decades points to the fact that many enzymes exhibit fluctuations in their catalytic activity, which are associated with conformational changes on a broad range of timescales. The experimental study of this phenomenon, termed dynamic disorder, has become possible thanks to advances in single-molecule enzymology measurement techniques, through which the catalytic activity of individual enzyme molecules can be tracked in time. The biological role and importance of these fluctuations in a system with a small number of enzymes, such as a living cell, have only recently started being explored. In this work, we examine a simple stochastic reaction system consisting of an inflowing substrate and an enzyme with a randomly fluctuating catalytic reaction rate that converts the substrate into an outflowing product. To describe analytically the effect of rate fluctuations on the average substrate abundance at steady state, we derive an explicit formula that connects the relative speed of enzymatic fluctuations with the mean substrate level. Under fairly general modelling assumptions, we demonstrate that the relative speed of rate fluctuations can have a dramatic effect on the mean substrate, and lead to large positive deviations from predictions based on the assumption of deterministic enzyme activity. Our results also establish an interesting connection between the amplification effect and the mixing properties of the Markov process describing the enzymatic activity fluctuations, which can be used to easily predict the fluctuation speed above which such deviations become negligible. As the techniques of single-molecule enzymology continuously evolve, it may soon be possible to study the stochastic phenomena due to enzymatic activity fluctuations within living cells. Our work can be used to formulate experimentally testable hypotheses regarding the nature and magnitude of these fluctuations, as well as their phenotypic consequences.
[Mh] Termos MeSH primário: Enzimas/metabolismo
Modelos Biológicos
[Mh] Termos MeSH secundário: Simulação por Computador
Enzimas/química
Cinética
Conformação Proteica
Processos Estocásticos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzymes)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE


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[PMID]:29374258
[Au] Autor:Hirata T; Mishra SK; Nakamura S; Saito K; Motooka D; Takada Y; Kanzawa N; Murakami Y; Maeda Y; Fujita M; Yamaguchi Y; Kinoshita T
[Ad] Endereço:Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan.
[Ti] Título:Identification of a Golgi GPI-N-acetylgalactosamine transferase with tandem transmembrane regions in the catalytic domain.
[So] Source:Nat Commun;9(1):405, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Many eukaryotic proteins are anchored to the cell surface via the glycolipid glycosylphosphatidylinositol (GPI). Mammalian GPIs have a conserved core but exhibit diverse N-acetylgalactosamine (GalNAc) modifications, which are added via a yet unresolved process. Here we identify the Golgi-resident GPI-GalNAc transferase PGAP4 and show by mass spectrometry that PGAP4 knockout cells lose GPI-GalNAc structures. Furthermore, we demonstrate that PGAP4, in contrast to known Golgi glycosyltransferases, is not a single-pass membrane protein but contains three transmembrane domains, including a tandem transmembrane domain insertion into its glycosyltransferase-A fold as indicated by comparative modeling. Mutational analysis reveals a catalytic site, a DXD-like motif for UDP-GalNAc donor binding, and several residues potentially involved in acceptor binding. We suggest that a juxtamembrane region of PGAP4 accommodates various GPI-anchored proteins, presenting their acceptor residue toward the catalytic center. In summary, we present insights into the structure of PGAP4 and elucidate the initial step of GPI-GalNAc biosynthesis.
[Mh] Termos MeSH primário: Acetilgalactosamina/química
Glicosilfosfatidilinositóis/química
Complexo de Golgi/metabolismo
N-Acetilgalactosaminiltransferases/química
[Mh] Termos MeSH secundário: Acetilgalactosamina/biossíntese
Motivos de Aminoácidos
Animais
Células CHO
Domínio Catalítico
Cricetulus
Cristalografia por Raios X
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Glicosilfosfatidilinositóis/metabolismo
Complexo de Golgi/ultraestrutura
Seres Humanos
Camundongos
Camundongos Knockout
Modelos Moleculares
Mutação
N-Acetilgalactosaminiltransferases/genética
N-Acetilgalactosaminiltransferases/metabolismo
Ligação Proteica
Conformação Proteica em alfa-Hélice
Conformação Proteica em Folha beta
Domínios e Motivos de Interação entre Proteínas
Homologia Estrutural de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Glycosylphosphatidylinositols); EC 2.4.1.- (N-Acetylgalactosaminyltransferases); EC 2.4.1.41 (polypeptide N-acetylgalactosaminyltransferase); KM15WK8O5T (Acetylgalactosamine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02799-0


  9 / 89904 MEDLINE  
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[PMID]:29343827
[Au] Autor:Page BDG; Valerie NCK; Wright RHG; Wallner O; Isaksson R; Carter M; Rudd SG; Loseva O; Jemth AS; Almlöf I; Font-Mateu J; Llona-Minguez S; Baranczewski P; Jeppsson F; Homan E; Almqvist H; Axelsson H; Regmi S; Gustavsson AL; Lundbäck T; Scobie M; Strömberg K; Stenmark P; Beato M; Helleday T
[Ad] Endereço:Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Solna, SE-171 21, Sweden. brent.page@scilifelab.se.
[Ti] Título:Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells.
[So] Source:Nat Commun;9(1):250, 2018 01 17.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:With a diverse network of substrates, NUDIX hydrolases have emerged as a key family of nucleotide-metabolizing enzymes. NUDT5 (also called NUDIX5) has been implicated in ADP-ribose and 8-oxo-guanine metabolism and was recently identified as a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. Here, we further elucidate the physiological relevance of known NUDT5 substrates and underscore the biological requirement for NUDT5 in gene regulation and proliferation of breast cancer cells. We confirm the involvement of NUDT5 in ADP-ribose metabolism and dissociate a relationship to oxidized nucleotide sanitation. Furthermore, we identify potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Lead compound, TH5427, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. We herein present TH5427 as a promising, targeted inhibitor that can be used to further study NUDT5 activity and ADP-ribose metabolism.
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Progestinas/metabolismo
Pirofosfatases/antagonistas & inibidores
Transdução de Sinais/efeitos dos fármacos
[Mh] Termos MeSH secundário: Adenosina Difosfato Ribose/metabolismo
Trifosfato de Adenosina/metabolismo
Neoplasias da Mama/genética
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Linhagem Celular Tumoral
Núcleo Celular/efeitos dos fármacos
Núcleo Celular/metabolismo
Proliferação Celular/efeitos dos fármacos
Proliferação Celular/genética
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Feminino
Células HL-60
Seres Humanos
Estrutura Molecular
Pirofosfatases/genética
Pirofosfatases/metabolismo
Interferência de RNA
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Progestins); 20762-30-5 (Adenosine Diphosphate Ribose); 8L70Q75FXE (Adenosine Triphosphate); EC 3.6.1.- (NUDT5 protein, human); EC 3.6.1.- (Pyrophosphatases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02293-7


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Texto completo
[PMID]:28448738
[Au] Autor:Anton T; Bultmann S
[Ad] Endereço:a Department of Biology II and Center for Integrated Protein Science Munich (CIPSM) , LMU Munich , Martinsried , Germany.
[Ti] Título:Site-specific recruitment of epigenetic factors with a modular CRISPR/Cas system.
[So] Source:Nucleus;8(3):279-286, 2017 May 04.
[Is] ISSN:1949-1042
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Dissecting the complex network of epigenetic modifications requires tools that combine precise recognition of DNA sequences with the capability to modify epigenetic marks. The CRISPR/Cas system has been proven to be a valuable addition to existing methodologies that fulfill these tasks. So far, sequence-specific editing of epigenetic modifications such as DNA methylation and histone posttranslational modifications relied on direct fusions of enzymatically inactivated Cas9 (dCas9) with epigenetic effectors. Here, we report a novel, modular system that facilitates the recruitment of any GFP-tagged protein to desired genomic loci. By fusing dCas9 to a GFP-binding nanobody (GBP) we demonstrate that prevalent epigenetic modifications at mouse major satellite repeats can be erased or set de novo by recruiting GFP-coupled catalytic domains of TET1 and DNMT3A, respectively. Furthermore, we construct an inducible expression system that enables a temporally controlled expression of both GBP-dCas9 and the effector protein. Thus, our approach further expands the CRISPR/Cas toolbox for site-specific manipulation of epigenetic modifications with a modular and easy-to-use system.
[Mh] Termos MeSH primário: Sistemas CRISPR-Cas/genética
Epigênese Genética
[Mh] Termos MeSH secundário: Animais
Sequência de Bases
Sítios de Ligação
Linhagem Celular
Metilases de Modificação do DNA/metabolismo
Doxiciclina/farmacologia
Proteínas de Fluorescência Verde/genética
Camundongos
Regiões Promotoras Genéticas/genética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
147336-22-9 (Green Fluorescent Proteins); EC 2.1.1.- (DNA Modification Methylases); N12000U13O (Doxycycline)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170428
[St] Status:MEDLINE
[do] DOI:10.1080/19491034.2017.1292194



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