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  1 / 9057 MEDLINE  
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[PMID]:29447689
[Au] Autor:Popoff MR
[Ad] Endereço:Bacterial Toxins, Institut Pasteur, Paris, France. Electronic address: mpopoff@pasteur.fr.
[Ti] Título:Botulinum Neurotoxins: Still a Privilege of Clostridia?
[So] Source:Cell Host Microbe;23(2):145-146, 2018 02 14.
[Is] ISSN:1934-6069
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Botulinum neurotoxins (BoNTs) are potent bacterial toxins mostly produced by genetically diverse clostridial strains. Recently, BoNT variants have been reported in non-clostridial strains. In this issue of Cell Host & Microbe, Zhang et al. (2018) describe a novel BoNT in Entecoccus faecium.
[Mh] Termos MeSH primário: Toxinas Botulínicas
Neurotoxinas
[Mh] Termos MeSH secundário: Clostridium
Seres Humanos
Hidrolases
[Pt] Tipo de publicação:JOURNAL ARTICLE; COMMENT
[Nm] Nome de substância:
0 (Neurotoxins); EC 3.- (Hydrolases); EC 3.4.24.69 (Botulinum Toxins)
[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:180216
[St] Status:MEDLINE


  2 / 9057 MEDLINE  
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[PMID]:28462999
[Au] Autor:Yao J; Luo H; Wang X
[Ad] Endereço:School of Biological Science and Technology, University of Jinan , Jinan 250022, P. R. China.
[Ti] Título:Understanding the Catalytic Mechanism and the Substrate Specificity of an Engineered Gluten Hydrolase by QM/MM Molecular Dynamics and Free Energy Simulations.
[So] Source:J Chem Inf Model;57(5):1179-1186, 2017 05 22.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Celiac sprue, also known as gluten-sensitive enteropathy, is a chronic disease suffered by approximately 1% of the world's population. Engineered enzymes have been emerging to treat celiac disease by hydrolyzing the pathogenic peptides of gluten. For example, Kuma010 has been studied experimentally and proved to be a promising gluten hydrolase under gastric conditions. However, the detailed catalytic mechanism and the substrate specificity are still unclear. In this paper, quantum-mechanical/molecular-mechanical (QM/MM) molecular dynamics (MD) and free energy simulations were performed to determine the catalytic mechanism, the substrate specificity, and the role of the active-site residues during the reaction. The results given here demonstrate that the Kuma010 has a similar catalytic mechanism but different substrate specificity as wild-type kumamolisin-As. Binding properties of the enzyme (especially mutated residues) and substrate complex are discussed, and activation free energy barriers toward different substrates have also been examined. The computational free energy results are in reasonable agreement with the experimental data. The strategy for developing next-generation gluten hydrolases is discussed.
[Mh] Termos MeSH primário: Glutens/metabolismo
Hidrolases/metabolismo
Simulação de Dinâmica Molecular
[Mh] Termos MeSH secundário: Acilação
Sítios de Ligação
Catálise
Domínio Catalítico
Doença Celíaca/enzimologia
Hidrolases/química
Teoria Quântica
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
8002-80-0 (Glutens); EC 3.- (Hydrolases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00167


  3 / 9057 MEDLINE  
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[PMID]:29374183
[Au] Autor:Joo S; Cho IJ; Seo H; Son HF; Sagong HY; Shin TJ; Choi SY; Lee SY; Kim KJ
[Ad] Endereço:School of Life Sciences (KNU Creative BioResearch Group), KNU Institute for Microorganisms, Kyungpook National University, Daehak-ro 80, Buk-gu, Daegu, 41566, Republic of Korea.
[Ti] Título:Structural insight into molecular mechanism of poly(ethylene terephthalate) degradation.
[So] Source:Nat Commun;9(1):382, 2018 01 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Plastics, including poly(ethylene terephthalate) (PET), possess many desirable characteristics and thus are widely used in daily life. However, non-biodegradability, once thought to be an advantage offered by plastics, is causing major environmental problem. Recently, a PET-degrading bacterium, Ideonella sakaiensis, was identified and suggested for possible use in degradation and/or recycling of PET. However, the molecular mechanism of PET degradation is not known. Here we report the crystal structure of I. sakaiensis PETase (IsPETase) at 1.5 Å resolution. IsPETase has a Ser-His-Asp catalytic triad at its active site and contains an optimal substrate binding site to accommodate four monohydroxyethyl terephthalate (MHET) moieties of PET. Based on structural and site-directed mutagenesis experiments, the detailed process of PET degradation into MHET, terephthalic acid, and ethylene glycol is suggested. Moreover, other PETase candidates potentially having high PET-degrading activities are suggested based on phylogenetic tree analysis of 69 PETase-like proteins.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Burkholderiales/enzimologia
Poluentes Ambientais/química
Hidrolases/química
Polietilenotereftalatos/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biodegradação Ambiental
Burkholderiales/química
Domínio Catalítico
Clonagem Molecular
Cristalografia por Raios X
Poluentes Ambientais/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Etilenoglicol/química
Etilenoglicol/metabolismo
Expressão Gênica
Hidrolases/genética
Hidrolases/metabolismo
Cinética
Simulação de Acoplamento Molecular
Ácidos Ftálicos/química
Ácidos Ftálicos/metabolismo
Polietilenotereftalatos/metabolismo
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Alinhamento de Sequência
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Environmental Pollutants); 0 (Phthalic Acids); 0 (Polyethylene Terephthalates); 0 (Recombinant Proteins); 6S7NKZ40BQ (terephthalic acid); EC 3.- (Hydrolases); FC72KVT52F (Ethylene Glycol)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180222
[Lr] Data última revisão:
180222
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180128
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-018-02881-1


  4 / 9057 MEDLINE  
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[PMID]:28742253
[Au] Autor:Bai Y; Wang C; Liang G; Lai W; Xue H; Ling Y; Cheng M; Liu K
[Ad] Endereço:State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
[Ti] Título:Precisely Designed Isopeptide Bridge-Crosslinking Endows Artificial Hydrolases with High Stability and Catalytic Activity under Extreme Denaturing Conditions.
[So] Source:Chem Asian J;12(19):2539-2543, 2017 Oct 05.
[Is] ISSN:1861-471X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Enzymes normally lose their activities under extreme conditions due to the dissociation of their active tertiary structure. If an enzyme could maintain its catalytic activity under non-physiological or denaturing conditions, it might be used in more applications in the pharmaceutical and chemical industries. Recently, we reported a coiled-coil six-helical bundle (6HB) structure as a scaffold for designing artificial hydrolytic enzymes. Here, intermolecular isopeptide bonds were incorporated to enhance the stability and activity of such biomolecules under denaturing conditions. These isopeptide bridge-tethered 6HB enzymes showed exceptional stability against unfolding and retained or even had increased catalytic activity for a model hydrolysis reaction under thermal and chemical denaturing conditions. Thus, isopeptide bond-tethering represents an efficient route to construct ultrastable artificial hydrolases, with promising potential to maintain biocatalysis under extreme conditions.
[Mh] Termos MeSH primário: Reagentes para Ligações Cruzadas/química
Hidrolases/química
Peptídeos/química
[Mh] Termos MeSH secundário: Biocatálise
Reagentes para Ligações Cruzadas/metabolismo
Estabilidade Enzimática
Hidrolases/metabolismo
Cinética
Peptídeos/metabolismo
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cross-Linking Reagents); 0 (Peptides); EC 3.- (Hydrolases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180219
[Lr] Data última revisão:
180219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/asia.201701021


  5 / 9057 MEDLINE  
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[PMID]:28464395
[Au] Autor:Bayer CD; van Loo B; Hollfelder F
[Ad] Endereço:Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA, Cambridge, UK.
[Ti] Título:Specificity Effects of Amino Acid Substitutions in Promiscuous Hydrolases: Context-Dependence of Catalytic Residue Contributions to Local Fitness Landscapes in Nearby Sequence Space.
[So] Source:Chembiochem;18(11):1001-1015, 2017 06 01.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Catalytic promiscuity can facilitate evolution of enzyme functions-a multifunctional catalyst may act as a springboard for efficient functional adaptation. We test the effect of single mutations on multiple activities in two groups of promiscuous AP superfamily members to probe this hypothesis. We quantify the effect of site-saturating mutagenesis of an analogous, nucleophile-flanking residue in two superfamily members: an arylsulfatase (AS) and a phosphonate monoester hydrolase (PMH). Statistical analysis suggests that no one physicochemical characteristic alone explains the mutational effects. Instead, these effects appear to be dominated by their structural context. Likewise, the effect of changing the catalytic nucleophile itself is not reaction-type-specific. Mapping of "fitness landscapes" of four activities onto the possible variation of a chosen sequence position revealed tremendous potential for respecialization of AP superfamily members through single-point mutations, highlighting catalytic promiscuity as a powerful predictor of adaptive potential.
[Mh] Termos MeSH primário: Substituição de Aminoácidos/genética
Evolução Molecular Direcionada
Hidrolases/genética
[Mh] Termos MeSH secundário: Fosfatase Alcalina/genética
Bactérias/enzimologia
Bactérias/genética
Catálise
Domínio Catalítico
Mutagênese Sítio-Dirigida
Fosfotransferases/genética
Especificidade por Substrato
Sulfatases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
EC 2.7.- (Phosphotransferases); EC 3.- (Hydrolases); EC 3.1.3.1 (Alkaline Phosphatase); EC 3.1.6.- (Sulfatases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180122
[Lr] Data última revisão:
180122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600657


  6 / 9057 MEDLINE  
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[PMID]:27778288
[Au] Autor:Baggelaar MP; Van der Stelt M
[Ad] Endereço:Department of Bio-organic Synthesis, Leiden University, 9500, Einsteinweg 55, 2333 CC, Leiden, The Netherlands. m.p.baggelaar@chem.leidenuniv.nl.
[Ti] Título:Competitive ABPP of Serine Hydrolases: A Case Study on DAGL-Alpha.
[So] Source:Methods Mol Biol;1491:161-169, 2017.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Competitive activity-based protein profiling is a highly efficient chemical biology technique to determine target engagement and selectivity profiles of enzyme inhibitors in complex proteomes. Fluorophosphonate-based fluorescent inhibitors are widely used as broad-spectrum probes for serine hydrolases. However, diacylglycerol lipase-α is not labeled by fluorophosphonate-based probes. To overcome this problem, we have developed a tailor-made activity-based probe that reacts with diacylglycerol lipase-α. Here we describe a case study in which we apply competitive activity-based protein profiling using a broad-spectrum and a tailor-made activity-based probe to establish selectivity and activity profiles of inhibitors targeting diacylglycerol lipase-α in the mouse brain proteome.
[Mh] Termos MeSH primário: Hidrolases/metabolismo
Lipase Lipoproteica/metabolismo
Serina/química
[Mh] Termos MeSH secundário: Animais
Encéfalo/enzimologia
Encéfalo/metabolismo
Hidrolases/química
Camundongos
Proteoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Proteome); 452VLY9402 (Serine); EC 3.- (Hydrolases); EC 3.1.1.34 (Lipoprotein Lipase); EC 3.1.1.34 (diacylglycerol lipase alpha, human)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161026
[St] Status:MEDLINE


  7 / 9057 MEDLINE  
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[PMID]:27770417
[Au] Autor:Roy I; Mukherjee J; Gupta MN
[Ad] Endereço:Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab, India.
[Ti] Título:Cross-Linked Enzyme Aggregates for Applications in Aqueous and Nonaqueous Media.
[So] Source:Methods Mol Biol;1504:109-123, 2017.
[Is] ISSN:1940-6029
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Extensive cross-linking of a precipitate of a protein by a cross-linking reagent (glutaraldehyde has been most commonly used) creates an insoluble enzyme preparation called cross-linked enzyme aggregates (CLEAs). CLEAs show high stability and performance in conventional aqueous as well as nonaqueous media. These are also stable at fairly high temperatures. CLEAs with more than one kind of enzyme activity can be prepared, and such CLEAs are called combi-CLEAs or multipurpose CLEAs. Extent of cross-linking often influences their morphology, stability, activity, and enantioselectivity.
[Mh] Termos MeSH primário: Reagentes para Ligações Cruzadas/química
Enzimas Imobilizadas/química
Glutaral/química
[Mh] Termos MeSH secundário: Animais
Aspergillus niger/enzimologia
Burkholderia cepacia/enzimologia
Candida/enzimologia
Bovinos
Estabilidade Enzimática
Enzimas Imobilizadas/metabolismo
Hidrolases/química
Hidrolases/metabolismo
Lipase/química
Lipase/metabolismo
Penicilina Amidase/química
Penicilina Amidase/metabolismo
Poligalacturonase/química
Poligalacturonase/metabolismo
Agregados Proteicos
Soroalbumina Bovina/metabolismo
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cross-Linking Reagents); 0 (Enzymes, Immobilized); 0 (Protein Aggregates); 27432CM55Q (Serum Albumin, Bovine); EC 3.- (Hydrolases); EC 3.1.1.3 (Lipase); EC 3.2.1.15 (Polygalacturonase); EC 3.5.1.11 (Penicillin Amidase); T3C89M417N (Glutaral)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180115
[Lr] Data última revisão:
180115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE


  8 / 9057 MEDLINE  
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[PMID]:29235857
[Au] Autor:Camargo TP; Neves A; Peralta RA; Chaves C; Maia ECP; Lizarazo-Jaimes EH; Gomes DA; Bortolotto T; Norberto DR; Terenzi H; Tierney DL; Schenk G
[Ti] Título:Second-Sphere Effects in Dinuclear Fe Zn Hydrolase Biomimetics: Tuning Binding and Reactivity Properties.
[So] Source:Inorg Chem;57(1):187-203, 2018 Jan 02.
[Is] ISSN:1520-510X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Herein, we report the synthesis and characterization of two dinuclear Fe Zn complexes [Fe Zn LP1] (1) and [Fe Zn LP2] (2), in which LP1 and LP2 are conjugated systems containing one and two pyrene groups, respectively, connected via the diamine -HN(CH ) NH- spacer to the well-known N O -donor H L ligand (H L = 2-bis{[(2-pyridylmethyl)aminomethyl]-6-[(2-hydroxybenzyl)(2-pyridylmethyl)]aminomethyl}-4-methylphenol). The complex [Fe Zn L1] (3), in which H L was modified to H L1, with a carbonyl group attached to the terminal phenol group, was included in this study for comparison purposes. Both complexes 1 and 2 were satisfactorily characterized in the solid state and in solution. Extended X-ray absorption fine structure data for 1 and 3 in an acetonitrile solution show that the multiply bridged structure seen in the solid state of 3 is retained in solution. Potentiometric and UV-vis titration of 1 and 2 show that electrostatic interaction between the protonated amino groups and coordinated water molecules significantly decreases the pK of the iron(III)-bound water compared to those of 3. On the other hand, catalytic activity studies using 1 and 2 in the hydrolysis of the activated substrate bis(2,4-dinitrophenyl)phosphate (BDNPP) resulted in a significant increase in the association of the substrate (K ≅ 1/K ) compared to that of 3 because of electrostatic and hydrophobic interactions between BDNPP and the side-chain diaminopyrene of the ligands H LP1 and H LP2. In addition, the introduction of the pyrene motifs in 1 and 2 enhanced their activity toward DNA and as effective antitumor drugs, although the biochemical mechanism of the latter effect is currently under investigation. These complexes represent interesting examples of how to promote an increase in the activity of traditional artificial metal nucleases by introducing second-coordination-sphere effects.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Biomimética
DNA/efeitos dos fármacos
Compostos Férricos/farmacologia
Hidrolases/metabolismo
Compostos Organometálicos/farmacologia
Zinco/farmacologia
[Mh] Termos MeSH secundário: Antineoplásicos/química
Antineoplásicos/metabolismo
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cristalografia por Raios X
Clivagem do DNA/efeitos dos fármacos
Relação Dose-Resposta a Droga
Ensaios de Seleção de Medicamentos Antitumorais
Compostos Férricos/química
Compostos Férricos/metabolismo
Seres Humanos
Hidrolases/química
Ligantes
Modelos Moleculares
Conformação Molecular
Compostos Organometálicos/química
Compostos Organometálicos/metabolismo
Relação Estrutura-Atividade
Células Tumorais Cultivadas
Zinco/química
Zinco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Ferric Compounds); 0 (Ligands); 0 (Organometallic Compounds); 9007-49-2 (DNA); EC 3.- (Hydrolases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180109
[Lr] Data última revisão:
180109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171214
[St] Status:MEDLINE
[do] DOI:10.1021/acs.inorgchem.7b02384


  9 / 9057 MEDLINE  
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[PMID]:28542883
[Au] Autor:Liu J; Chen J; Fan Y; Huang X; Han B
[Ad] Endereço:Beijing Laboratory for Food Quality and Safety, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.
[Ti] Título:Biochemical characterisation and dominance of different hydrolases in different types of Daqu - a Chinese industrial fermentation starter.
[So] Source:J Sci Food Agric;98(1):113-121, 2018 Jan.
[Is] ISSN:1097-0010
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Daqu is a fermentative saccharification agent that is used to initiate fermentation in the production of Chinese liquor and vinegar. This study investigated the differences of amylase, protease and esterase in dominance of different types of Daqu, which can be useful for quality control and flavor improvement of Daqu production by enzyme technology. RESULTS: Hydrolase activities in different Daqu samples were compared by principal component analysis (PCA). Based on protein electrophoresis and H NMR spectroscopy, the protein patterns and metabolites in Daqu were further analysed. The results indicated that the highest amylase activities and diversities were found in low/medium-temperature of Daqu which had light-flavour and strong-flavour. Proteases play a significant role in determining the quality of high-temperature Daqu samples which had a sauce-flavour. Furthermore, the contributions of esterase to both strong and sauce flavour development in high-temperature Daqu are similar. CONCLUSION: Results from the present work showed that differences in amylase, protease and esterase play a leading role in different types of Daqu, which can be useful for quality control and technology development of Daqu. © 2017 Society of Chemical Industry.
[Mh] Termos MeSH primário: Bebidas Alcoólicas/análise
Proteínas de Bactérias/análise
Hidrolases/análise
Lactobacillaceae/metabolismo
[Mh] Termos MeSH secundário: Bebidas Alcoólicas/microbiologia
Proteínas de Bactérias/metabolismo
China
Fermentação
Aromatizantes/análise
Aromatizantes/metabolismo
Hidrolases/metabolismo
Lactobacillaceae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Flavoring Agents); EC 3.- (Hydrolases)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/jsfa.8445


  10 / 9057 MEDLINE  
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[PMID]:28455445
[Au] Autor:Chen R; Jin G; McIntyre TM
[Ad] Endereço:From the Departments of Cellular and Molecular Medicine and.
[Ti] Título:The soluble protease ADAMDEC1 released from activated platelets hydrolyzes platelet membrane pro-epidermal growth factor (EGF) to active high-molecular-weight EGF.
[So] Source:J Biol Chem;292(24):10112-10122, 2017 06 16.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Platelets are the sole source of EGF in circulation, yet how EGF is stored or released from stimulated cells is undefined. In fact, we found platelets did not store EGF, synthesized as a single 6-kDa domain in pro-EGF, but rather expressed intact pro-EGF precursor on granular and plasma membranes. Activated platelets released high-molecular-weight (HMW)-EGF, produced by a single cleavage between the EGF and the transmembrane domains of pro-EGF. We synthesized a fluorogenic peptide encompassing residues surrounding the putative sessile arginyl residue and found stimulated platelets released soluble activity that cleaved this pro-EGF peptide. High throughput screening identified chymostatins, bacterial peptides with a central cyclic arginyl structure, as inhibitors of this activity. In contrast, the matrix metalloproteinase/TACE (tumor necrosis factor-α-converting enzyme) inhibitor GM6001 was ineffective. Stimulated platelets released the soluble protease ADAMDEC1, recombinant ADAMDEC1 hydrolyzed pro-EGF , and this activity was inhibited by chymostatin and not GM6001. Biotinylating platelet surface proteins showed ADAMDEC1 hydrolyzed surface pro-EGF to HMW-EGF that stimulated HeLa EGF receptor (EGFR) reporter cells and EGFR-dependent tumor cell migration. This proteolysis was inhibited by chymostatin and not GM6001. Metabolizing pro-EGF Arg to citrulline with recombinant polypeptide arginine deiminase 4 (PAD4) abolished ADAMDEC1-catalyzed pro-EGF peptidolysis, while pretreating intact platelets with PAD4 suppressed ADAMDEC1-, thrombin-, or collagen-induced release of HMW-EGF. We conclude that activated platelets release ADAMDEC1, which hydrolyzes pro-EGF to soluble HMW-EGF, that HMW-EGF is active, that proteolytic cleavage of pro-EGF first occurs at the C-terminal arginyl residue of the EGF domain, and that proteolysis is the regulated and rate-limiting step in generating soluble EGF bioactivity from activated platelets.
[Mh] Termos MeSH primário: Proteínas ADAM/metabolismo
Plaquetas/enzimologia
Membrana Celular/enzimologia
Fator de Crescimento Epidérmico/metabolismo
Ativação Plaquetária
Precursores de Proteínas/metabolismo
Receptor do Fator de Crescimento Epidérmico/agonistas
[Mh] Termos MeSH secundário: Proteínas ADAM/antagonistas & inibidores
Proteínas ADAM/química
Proteínas ADAM/genética
Animais
Plaquetas/metabolismo
Células CHO
Linhagem Celular Tumoral
Membrana Celular/metabolismo
Cricetulus
Fator de Crescimento Epidérmico/química
Fator de Crescimento Epidérmico/genética
Seres Humanos
Hidrolases/genética
Hidrolases/metabolismo
Cinética
Peso Molecular
Oligopeptídeos/farmacologia
Inibidores de Proteases/farmacologia
Domínios e Motivos de Interação entre Proteínas
Precursores de Proteínas/química
Precursores de Proteínas/genética
Processamento de Proteína Pós-Traducional/efeitos dos fármacos
Desiminases de Arginina em Proteínas
Proteólise/efeitos dos fármacos
Receptor do Fator de Crescimento Epidérmico/genética
Receptor do Fator de Crescimento Epidérmico/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Solubilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Oligopeptides); 0 (Protease Inhibitors); 0 (Protein Precursors); 0 (Recombinant Proteins); 62229-50-9 (Epidermal Growth Factor); 9076-44-2 (chymostatin); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 3.- (Hydrolases); EC 3.4.24.- (ADAM Proteins); EC 3.4.24.- (decysin); EC 3.5.3.15 (Protein-Arginine Deiminases); EC 3.5.3.15 (peptidylarginine deiminase type IV)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171228
[Lr] Data última revisão:
171228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170430
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M116.771642



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