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[PMID]:28450226
[Au] Autor:Hara A; Endo S; Matsunaga T; El-Kabbani O; Miura T; Nishinaka T; Terada T
[Ad] Endereço:Faculty of Engineering, Gifu University, Gifu 501-1193, Japan.
[Ti] Título:Human carbonyl reductase 1 participating in intestinal first-pass drug metabolism is inhibited by fatty acids and acyl-CoAs.
[So] Source:Biochem Pharmacol;138:185-192, 2017 08 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Human carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase (SDR) superfamily, reduces a variety of carbonyl compounds including endogenous isatin, prostaglandin E and 4-oxo-2-nonenal. It is also a major non-cytochrome P450 enzyme in the phase I metabolism of carbonyl-containing drugs, and is highly expressed in the intestine. In this study, we found that long-chain fatty acids and their CoA ester derivatives inhibit CBR1. Among saturated fatty acids, myristic, palmitic and stearic acids were inhibitory, and stearic acid was the most potent (IC 9µM). Unsaturated fatty acids (oleic, elaidic, γ-linolenic and docosahexaenoic acids) and acyl-CoAs (palmitoyl-, stearoyl- and oleoyl-CoAs) were more potent inhibitors (IC 1.0-2.5µM), and showed high inhibitory selectivity to CBR1 over its isozyme CBR3 and other SDR superfamily enzymes (DCXR and DHRS4) with CBR activity. The inhibition by these fatty acids and acyl-CoAs was competitive with respect to the substrate, showing the K values of 0.49-1.2µM. Site-directed mutagenesis of the substrate-binding residues of CBR1 suggested that the interactions between the fatty acyl chain and the enzyme's Met141 and Trp229 are important for the inhibitory selectivity. We also examined CBR1 inhibition by oleic acid in cellular levels: The fatty acid effectively inhibited CBR1-mediated 4-oxo-2-nonenal metabolism in colon cancer DLD1 cells and increased sensitivity to doxorubicin in the drug-resistant gastric cancer MKN45 cells that highly express CBR1. The results suggest a possible new food-drug interaction through inhibition of CBR1-mediated intestinal first-pass drug metabolism by dietary fatty acids.
[Mh] Termos MeSH primário: Acil Coenzima A/metabolismo
Oxirredutases do Álcool/antagonistas & inibidores
Ácidos Graxos não Esterificados/metabolismo
Mucosa Intestinal/enzimologia
[Mh] Termos MeSH secundário: Oxirredutases do Álcool/genética
Oxirredutases do Álcool/metabolismo
Sítios de Ligação
Ligação Competitiva
Linhagem Celular Tumoral
Resistência a Medicamentos Antineoplásicos
Interações Alimento-Droga
Seres Humanos
Mutação
Ácido Mirístico/metabolismo
Proteínas de Neoplasias/antagonistas & inibidores
Proteínas de Neoplasias/metabolismo
Oxirredutases/antagonistas & inibidores
Oxirredutases/genética
Oxirredutases/metabolismo
Ácido Palmítico/metabolismo
Palmitoil Coenzima A/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Ácidos Esteáricos/metabolismo
Desidrogenase do Álcool de Açúcar/antagonistas & inibidores
Desidrogenase do Álcool de Açúcar/genética
Desidrogenase do Álcool de Açúcar/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acyl Coenzyme A); 0 (Fatty Acids, Nonesterified); 0 (Neoplasm Proteins); 0 (Recombinant Proteins); 0 (Stearic Acids); 0I3V7S25AW (Myristic Acid); 1716-06-9 (oleoyl-coenzyme A); 1763-10-6 (Palmitoyl Coenzyme A); 2V16EO95H1 (Palmitic Acid); 362-66-3 (stearoyl-coenzyme A); 4ELV7Z65AP (stearic acid); EC 1.- (Oxidoreductases); EC 1.1.- (Alcohol Oxidoreductases); EC 1.1.- (Sugar Alcohol Dehydrogenases); EC 1.1.1.10 (L-xylulose reductase); EC 1.1.1.184 (CBR1 protein, human); EC 1.1.1.184 (CBR3 protein, human); EC 1.1.1.184 (DHRS4 protein, human)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE


  2 / 1541 MEDLINE  
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[PMID]:29180010
[Au] Autor:Maeda A; Uchida M; Nishikawa S; Nishino T; Konishi H
[Ad] Endereço:Faculty of Life and Environmental Sciences, Prefectural University of Hiroshima, Shobara, Hiroshima 727-0023, Japan.
[Ti] Título:Role of N-myristoylation in stability and subcellular localization of the CLPABP protein.
[So] Source:Biochem Biophys Res Commun;495(1):1249-1256, 2018 01 01.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cardiolipin and phosphatidic acid-binding protein (CLPABP) controls the stability of the mRNA harboring an AU-rich element (ARE) in the 3' UTR with the help of the RNA stabilizer, human antigen R (HuR). Although CLPABP is localized on the mitochondrial surface as a large protein-RNA complex, its precise role is not yet known. Recently, CLPABP was identified as an N-myristoylated protein. Here, we demonstrate the effects of N-myristoylation on the functions of CLPABP. In the present study, compared to the wild-type protein that possessed the "MG" motif at the N-terminus for N-myristoylation, the mutant CLPABP protein that lacked N-myristoylation modification site was unstable. Furthermore, the expression of the G/A mutant of CLPABP, which lacked N-myristoylation site, induced morphological alterations in mitochondria. Because pleckstrin homology domain-deleted mutant, which was fused with the N-myristoylation site derived from intact CLPABP, could not colocalize with mitochondria, N-myristoylation of CLPABP was predicted to affect its stability onto the mitochondrial membrane rather than its subcellular localization.
[Mh] Termos MeSH primário: Metabolismo dos Lipídeos/fisiologia
Proteínas Ligadas a Lipídeos/metabolismo
Ácido Mirístico/metabolismo
Prenilação de Proteína/fisiologia
Frações Subcelulares/metabolismo
[Mh] Termos MeSH secundário: Animais
Células COS
Cercopithecus aethiops
Células HEK293
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Lipid-Linked Proteins); 0 (PLEKHN1 protein, human); 0I3V7S25AW (Myristic Acid)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180105
[Lr] Data última revisão:
180105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE


  3 / 1541 MEDLINE  
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[PMID]:28740133
[Au] Autor:Konitsiotis AD; Roßmannek L; Stanoev A; Schmick M; Bastiaens PIH
[Ad] Endereço:Department of Systemic Cell Biology, Max Planck Institute of Molecular Physiology, Dortmund, 44227, Germany.
[Ti] Título:Spatial cycles mediated by UNC119 solubilisation maintain Src family kinases plasma membrane localisation.
[So] Source:Nat Commun;8(1):114, 2017 07 24.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The peripheral membrane proto-oncogene Src family protein tyrosine kinases relay growth factor signals to the cytoplasm of mammalian cells. We unravel the spatial cycles of solubilisation, trapping on perinuclear membrane compartments and vesicular transport that counter entropic equilibration to endomembranes for maintaining the enrichment and activity of Src family protein tyrosine kinases at the plasma membrane. The solubilising factor UNC119 sequesters myristoylated Src family protein tyrosine kinases from the cytoplasm, enhancing their diffusion to effectively release Src family protein tyrosine kinases on the recycling endosome by localised Arl2/3 activity. Src is then trapped on the recycling endosome via electrostatic interactions, whereas Fyn is quickly released to be kinetically trapped on the Golgi by palmitoyl acyl-transferase activity. Vesicular trafficking from these compartments restores enrichment of the Src family protein tyrosine kinases to the plasma membrane. Interference with these spatial cycles by UNC119 knockdown disrupts Src family protein tyrosine kinase localisation and signalling activity, indicating that UNC119 could be a drug target to affect oncogenic Src family protein tyrosine kinase signalling.The peripheral membrane proto-oncogene Src family protein tyrosine kinases (SFKs) transmit growth factor signals to the cytoplasm. Here the authors show that the solubilising factor UNC119 sequesters myristoylated SFKs to maintain its enrichment at the plasma membrane to enable signal transduction.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transdução de Sinal/metabolismo
Membrana Celular/metabolismo
Transdução de Sinais
Quinases da Família src/metabolismo
[Mh] Termos MeSH secundário: Fatores de Ribosilação do ADP/genética
Fatores de Ribosilação do ADP/metabolismo
Proteínas Adaptadoras de Transdução de Sinal/química
Proteínas Adaptadoras de Transdução de Sinal/genética
Linhagem Celular
Endossomos/metabolismo
Proteínas de Ligação ao GTP/genética
Proteínas de Ligação ao GTP/metabolismo
Complexo de Golgi/metabolismo
Células HT29
Células HeLa
Seres Humanos
Immunoblotting
Microscopia Confocal
Modelos Biológicos
Ácido Mirístico/metabolismo
Ligação Proteica
Proteínas Proto-Oncogênicas c-fyn/genética
Proteínas Proto-Oncogênicas c-fyn/metabolismo
Interferência de RNA
Solubilidade
Quinases da Família src/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Signal Transducing); 0 (UNC119 protein, human); 0I3V7S25AW (Myristic Acid); EC 2.7.10.2 (Proto-Oncogene Proteins c-fyn); EC 2.7.10.2 (src-Family Kinases); EC 3.6.1.- (ARL2 protein, human); EC 3.6.1.- (GTP-Binding Proteins); EC 3.6.5.2 (ADP-Ribosylation Factors); EC 3.6.5.2 (ARL3 protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00116-3


  4 / 1541 MEDLINE  
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[PMID]:28684313
[Au] Autor:Potvin-Fournier K; Valois-Paillard G; Lefèvre T; Cantin L; Salesse C; Auger M
[Ad] Endereço:Département de Chimie, Regroupement Québécois de Recherche sur la Fonction, L'ingénierie et L'application des Protéines (PROTEO), Centre de Recherche sur les Matériaux Avancés (CERMA), Centre Québécois sur les Matériaux Fonctionnels (CQMF), Université Laval, Pavillon Alexandre-Vachon, 1045 Avenue de
[Ti] Título:Membrane fluidity is a driving force for recoverin myristoyl immobilization in zwitterionic lipids.
[So] Source:Biochem Biophys Res Commun;490(4):1268-1273, 2017 Sep 02.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recoverin is the only protein for which the phenomenon of calcium-myristoyl switch has been demonstrated without ambiguity. It is located in rod disk membranes where the highest content in polyunsaturated lipid acyl chains can be found. However, although essential to better understand the inactivation of the phototransduction process, the role of membrane fluidity on recoverin recruitment is unclear. We have therefore investigated the immobilization of the recoverin myristoyl moiety in the presence of phosphocholine bilayers using H solid-state NMR spectroscopy. Several lipids with different acyl chains were selected to investigate model membranes characterized by different fluidity. Immobilization of the recoverin myristoyl moiety was successfully observed but only in the presence of calcium and in specific lipid disordered states, showing that an optimal fluidity is required for recoverin immobilization.
[Mh] Termos MeSH primário: Cálcio/química
Bicamadas Lipídicas/química
Ácido Mirístico/química
Recoverina/química
Tensoativos/química
[Mh] Termos MeSH secundário: Dimiristoilfosfatidilcolina/química
Difenilexatrieno/química
Espectroscopia de Ressonância Magnética
Fluidez de Membrana
Fosfatidilcolinas/química
Fosfatidilgliceróis/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipid Bilayers); 0 (Phosphatidylcholines); 0 (Phosphatidylglycerols); 0 (RCVRN protein, human); 0 (Surface-Active Agents); 0 (didocosahexaenoylphosphatidylcholine); 0I3V7S25AW (Myristic Acid); 135844-11-0 (Recoverin); 1720-32-7 (Diphenylhexatriene); 66322-31-4 (1,2-dioleoyl-sn-glycero-3-phosphoglycerol); EDS2L3ODLV (1,2-oleoylphosphatidylcholine); SY7Q814VUP (Calcium); U86ZGC74V5 (Dimyristoylphosphatidylcholine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE


  5 / 1541 MEDLINE  
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[PMID]:28543306
[Au] Autor:Machiyama H; Yamaguchi T; Watanabe TM; Fujita H
[Ad] Endereço:WPI, Immunology Frontier Research Center, Osaka University, Suita, Osaka, Japan.
[Ti] Título:A novel c-Src recruitment pathway from the cytosol to focal adhesions.
[So] Source:FEBS Lett;591(13):1940-1946, 2017 Jul.
[Is] ISSN:1873-3468
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The role of myristoylation in the localization and catalytic activity of Src at focal adhesions was investigated by live-cell imaging and site-directed mutagenesis. Although the majority of activated Src molecules are localized at focal adhesions, it is unclear how activated Src molecules are recruited to focal adhesions. Because Src is activated at the cell membrane, translocation of Src to cell membranes is considered to be essential for its recruitment to focal adhesions. Membrane-targeting-deficient Src mutant SrcG2A localizes at focal adhesions, indicating direct recruitment of Src from cytosol to focal adhesions. Furthermore, directly recruited Src molecules are shown to enhance paxillin dynamics at focal adhesions. These results reveal that the regulation of Src activation and translocation is more complex than previously suggested.
[Mh] Termos MeSH primário: Citosol/metabolismo
Adesões Focais/metabolismo
Quinases da Família src/metabolismo
[Mh] Termos MeSH secundário: Membrana Celular/metabolismo
Quinase 1 de Adesão Focal/metabolismo
Células HeLa
Seres Humanos
Mecanotransdução Celular
Mutação
Ácido Mirístico/metabolismo
Transporte Proteico
Quinases da Família src/genética
[Pt] Tipo de publicação:LETTER
[Nm] Nome de substância:
0I3V7S25AW (Myristic Acid); EC 2.7.10.2 (CSK tyrosine-protein kinase); EC 2.7.10.2 (Focal Adhesion Kinase 1); EC 2.7.10.2 (PTK2 protein, human); EC 2.7.10.2 (src-Family Kinases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1002/1873-3468.12696


  6 / 1541 MEDLINE  
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[PMID]:28431246
[Au] Autor:Tang H; Han M
[Ad] Endereço:Howard Hughes Medical Institute and Department of MCDB of the University of Colorado at Boulder, Boulder, CO 80309, USA.
[Ti] Título:Fatty Acids Regulate Germline Sex Determination through ACS-4-Dependent Myristoylation.
[So] Source:Cell;169(3):457-469.e13, 2017 Apr 20.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Fat metabolism has been linked to fertility and reproductive adaptation in animals and humans, and environmental sex determination potentially plays a role in the process. To investigate the impact of fatty acids (FA) on sex determination and reproductive development, we examined and observed an impact of FA synthesis and mobilization by lipolysis in somatic tissues on oocyte fate in Caenorhabditis elegans. The subsequent genetic analysis identified ACS-4, an acyl-CoA synthetase and its FA-CoA product, as key germline factors that mediate the role of FA in promoting oocyte fate through protein myristoylation. Further tests indicated that ACS-4-dependent protein myristoylation perceives and translates the FA level into regulatory cues that modulate the activities of MPK-1/MAPK and key factors in the germline sex-determination pathway. These findings, including a similar role of ACS-4 in a male/female species, uncover a likely conserved mechanism by which FA, an environmental factor, regulates sex determination and reproductive development.
[Mh] Termos MeSH primário: Acetato-CoA Ligase/metabolismo
Proteínas de Caenorhabditis elegans/metabolismo
Caenorhabditis elegans/fisiologia
Ácidos Graxos/metabolismo
Ácido Mirístico/metabolismo
Processamento de Proteína Pós-Traducional
Processos de Determinação Sexual
[Mh] Termos MeSH secundário: Acetato-CoA Ligase/genética
Animais
Proteínas de Caenorhabditis elegans/genética
Mutação
Oócitos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caenorhabditis elegans Proteins); 0 (Fatty Acids); 0I3V7S25AW (Myristic Acid); EC 6.2.1.1 (Acetate-CoA Ligase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170623
[Lr] Data última revisão:
170623
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170422
[St] Status:MEDLINE


  7 / 1541 MEDLINE  
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[PMID]:28423323
[Au] Autor:Tillo SE; Xiong WH; Takahashi M; Miao S; Andrade AL; Fortin DA; Yang G; Qin M; Smoody BF; Stork PJS; Zhong H
[Ad] Endereço:Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
[Ti] Título:Liberated PKA Catalytic Subunits Associate with the Membrane via Myristoylation to Preferentially Phosphorylate Membrane Substrates.
[So] Source:Cell Rep;19(3):617-629, 2017 Apr 18.
[Is] ISSN:2211-1247
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Protein kinase A (PKA) has diverse functions in neurons. At rest, the subcellular localization of PKA is controlled by A-kinase anchoring proteins (AKAPs). However, the dynamics of PKA upon activation remain poorly understood. Here, we report that elevation of cyclic AMP (cAMP) in neuronal dendrites causes a significant percentage of the PKA catalytic subunit (PKA-C) molecules to be released from the regulatory subunit (PKA-R). Liberated PKA-C becomes associated with the membrane via N-terminal myristoylation. This membrane association does not require the interaction between PKA-R and AKAPs. It slows the mobility of PKA-C and enriches kinase activity on the membrane. Membrane-residing PKA substrates are preferentially phosphorylated compared to cytosolic substrates. Finally, the myristoylation of PKA-C is critical for normal synaptic function and plasticity. We propose that activation-dependent association of PKA-C renders the membrane a unique PKA-signaling compartment. Constrained mobility of PKA-C may synergize with AKAP anchoring to determine specific PKA function in neurons.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/metabolismo
Ácido Mirístico/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Ancoragem à Quinase A/metabolismo
Animais
Citosol/metabolismo
Ativação Enzimática
Células HEK293
Seres Humanos
Plasticidade Neuronal
Neurônios/metabolismo
Fosforilação
Ligação Proteica
Ratos
Especificidade por Substrato
Sinapses/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (A Kinase Anchor Proteins); 0I3V7S25AW (Myristic Acid); EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinase Catalytic Subunits)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170714
[Lr] Data última revisão:
170714
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170420
[St] Status:MEDLINE


  8 / 1541 MEDLINE  
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[PMID]:28398555
[Au] Autor:Helassa N; Antonyuk SV; Lian LY; Haynes LP; Burgoyne RD
[Ad] Endereço:Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69?3BX, UK.
[Ti] Título:Biophysical and functional characterization of hippocalcin mutants responsible for human dystonia.
[So] Source:Hum Mol Genet;26(13):2426-2435, 2017 Jul 01.
[Is] ISSN:1460-2083
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dystonia is a neurological movement disorder that forces the body into twisting, repetitive movements or sometimes painful abnormal postures. With the advent of next-generation sequencing technologies, the homozygous mutations T71N and A190T in the neuronal calcium sensor (NCS) hippocalcin were identified as the genetic cause of primary isolated dystonia (DYT2 dystonia). However, the effect of these mutations on the physiological role of hippocalcin has not yet been elucidated. Using a multidisciplinary approach, we demonstrated that hippocalcin oligomerises in a calcium-dependent manner and binds to voltage-gated calcium channels. Mutations T71N and A190T in hippocalcin did not affect stability, calcium-binding affinity or translocation to cellular membranes (Ca2+/myristoyl switch). We obtained the first crystal structure of hippocalcin and alignment with other NCS proteins showed significant variability in the orientation of the C-terminal part of the molecule, the region expected to be important for target binding. We demonstrated that the disease-causing mutations did not affect the structure of the protein, however both mutants showed a defect in oligomerisation. In addition, we observed an increased calcium influx in KCl-depolarised cells expressing mutated hippocalcin, mostly driven by N-type voltage-gated calcium channels. Our data demonstrate that the dystonia-causing mutations strongly affect hippocalcin cellular functions which suggest a central role for perturbed calcium signalling in DYT2 dystonia.
[Mh] Termos MeSH primário: Distonia/genética
Hipocalcina/genética
Hipocalcina/metabolismo
[Mh] Termos MeSH secundário: Cálcio/metabolismo
Canais de Cálcio/metabolismo
Sinalização do Cálcio
Proteínas de Ligação ao Cálcio/genética
Técnicas de Cultura de Células
Membrana Celular/metabolismo
Distúrbios Distônicos
Hipocalcina/fisiologia
Seres Humanos
Mutação
Ácido Mirístico/metabolismo
Proteínas do Tecido Nervoso/genética
Neurônios/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Calcium Channels); 0 (Calcium-Binding Proteins); 0 (HPCA protein, human); 0 (Nerve Tissue Proteins); 0I3V7S25AW (Myristic Acid); 149223-81-4 (Hippocalcin); SY7Q814VUP (Calcium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170412
[St] Status:MEDLINE
[do] DOI:10.1093/hmg/ddx133


  9 / 1541 MEDLINE  
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[PMID]:28342136
[Au] Autor:Du J; Liu L; Guo LZ; Yao XJ; Yang JM
[Ad] Endereço:Key Lab of Applied Mycology, College of Life Science, Qingdao Agricultural University, Qingdao, 266109, China.
[Ti] Título:Molecular basis of P450 OleT : an investigation of substrate binding mechanism and major pathways.
[So] Source:J Comput Aided Mol Des;31(5):483-495, 2017 May.
[Is] ISSN:1573-4951
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 OleT has attracted much attention for its ability to catalyze the decarboxylation of long chain fatty acids to generate alkenes, which are not only biofuel molecule, but also can be used broadly for making lubricants, polymers and detergents. In this study, the molecular basis of the binding mechanism of P450 OleT for arachidic acid, myristic acid, and caprylic acid was investigated by utilizing conventional molecular dynamics simulation and binding free energy calculations. Moreover, random acceleration molecular dynamics (RAMD) simulations were performed to uncover the most probable access/egress channels for different fatty acids. The predicted binding free energy shows an order of arachidic acid < myristic acid < caprylic acid. Key residues interacting with three substrates and residues specifically binding to one of them were identified. The RAMD results suggest the most likely channel for arachidic acid, myristic acid, and caprylic acid are 2e/2b, 2a and 2f/2a, respectively. It is suggested that the reaction is easier to carry out in myristic acid bound system than those in arachidic acid and caprylic acid bound system based on the distance of Hß atom of substrate relative to P450 OleT Compound I states. This study provided novel insight to understand the substrate preference mechanism of P450 OleT and valuable information for rational enzyme design for short chain fatty acid decarboxylation.
[Mh] Termos MeSH primário: Caprilatos/química
Sistema Enzimático do Citocromo P-450/química
Ácidos Eicosanoicos/química
Ácido Mirístico/química
[Mh] Termos MeSH secundário: Catálise
Cinética
Simulação de Dinâmica Molecular
Oxirredução
Ligação Proteica
Conformação Proteica
Transdução de Sinais
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Caprylates); 0 (Eicosanoic Acids); 0I3V7S25AW (Myristic Acid); 9035-51-2 (Cytochrome P-450 Enzyme System); OBL58JN025 (octanoic acid); PQB8MJD4RB (arachidic acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170326
[St] Status:MEDLINE
[do] DOI:10.1007/s10822-017-0013-x


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[PMID]:28287417
[Au] Autor:Yu M; Jia HM; Cui FX; Yang Y; Zhao Y; Yang MH; Zou ZM
[Ad] Endereço:Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China. yumeng.5555@163.com.
[Ti] Título:The Effect of Chinese Herbal Medicine Formula mKG on Allergic Asthma by Regulating Lung and Plasma Metabolic Alternations.
[So] Source:Int J Mol Sci;18(3), 2017 Mar 10.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Asthma is a chronic inflammatory disorder of the airway and is characterized by airway remodeling, hyperresponsiveness, and shortness of breath. Modified Kushen Gancao Formula (mKG), derived from traditional Chinese herbal medicines (TCM), has been demonstrated to have good therapeutic effects on experimental allergic asthma. However, its anti-asthma mechanism remains currently unknown. In the present work, metabolomics studies of biochemical changes in the lung tissue and plasma of ovalbumin (OVA)-induced allergic asthma mice with mKG treatment were performed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation induced by OVA was reduced after mKG treatment. A total of twenty-four metabolites involved in seven metabolic pathways were identified as potential biomarkers in the development of allergic asthma. Among them, myristic acid ( or ), sphinganine ( or ), and lysoPC(15:0) ( or ) were detected both in lung tissue and plasma. Additionally, l-acetylcarnitine ( ), thromboxane B2 ( ), 10-HDoHE ( ), and 5-HETE ( ) were first reported to be potential biomarkers associated with allergic asthma. The treatment of mKG mediated all of those potential biomarkers except lysoPC(15:0) ( ). The anti-asthma mechanism of mKG can be achieved through the comprehensive regulation of multiple perturbed biomarkers and metabolic pathways.
[Mh] Termos MeSH primário: Asma/metabolismo
Medicamentos de Ervas Chinesas/farmacologia
Hipersensibilidade/metabolismo
Pulmão/efeitos dos fármacos
Metaboloma/efeitos dos fármacos
[Mh] Termos MeSH secundário: Acetilcarnitina/sangue
Acetilcarnitina/metabolismo
Animais
Asma/etiologia
Biomarcadores/sangue
Biomarcadores/metabolismo
Feminino
Hipersensibilidade/complicações
Pulmão/metabolismo
Camundongos
Camundongos Endogâmicos BALB C
Ácido Mirístico/sangue
Ácido Mirístico/metabolismo
Esfingosina/análogos & derivados
Esfingosina/sangue
Esfingosina/metabolismo
Tromboxano B2/sangue
Tromboxano B2/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Drugs, Chinese Herbal); 0I3V7S25AW (Myristic Acid); 54397-85-2 (Thromboxane B2); 6DH1W9VH8Q (Acetylcarnitine); NGZ37HRE42 (Sphingosine); OWA98U788S (safingol)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170314
[St] Status:MEDLINE



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