Base de dados : MEDLINE
Pesquisa : G02.111.385 [Categoria DeCS]
Referências encontradas : 11850 [refinar]
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[PMID]:28461575
[Au] Autor:Phuc NM; Wu Z; O Y; Lee JH; Oh S; Song GY; Liu KH
[Ad] Endereço:BK21 Plus KNU Multi-Omics-Based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Korea (N.M.P., Z.W., K.-H.L.); College of Pharmacy, Chungnam National University, Daejeon, Korea (Y.O., J.-H.L., G.-Y.S.); and Dep
[Ti] Título:LKY-047: First Selective Inhibitor of Cytochrome P450 2J2.
[So] Source:Drug Metab Dispos;45(7):765-769, 2017 Jul.
[Is] ISSN:1521-009X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7 )-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro- -pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole -demethylase and terfenadine hydroxylase activity, with values of 0.96 and 2.61 M, respectively. It also acted as an uncompetitive inhibitor of CYP2J2-mediated ebastine hydroxylation with a value of 3.61 M. Preincubation of LKY-047 with HLMs and NADPH did not alter inhibition potency, indicating that it is not a mechanism-based inhibitor. LKY-047 was found to be a selective CYP2J2 inhibitor with no inhibitory effect on other human P450s, such as CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A (IC > 50 M). These in vitro data support the use of LKY-047 as a selective CYP2J2 inhibitor with potential application in the identification of P450 isoforms responsible for drug metabolism in reaction phenotyping assays.
[Mh] Termos MeSH primário: Inibidores das Enzimas do Citocromo P-450/farmacologia
Sistema Enzimático do Citocromo P-450/metabolismo
[Mh] Termos MeSH secundário: Seres Humanos
Hidroxilação/efeitos dos fármacos
Inativação Metabólica/efeitos dos fármacos
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/metabolismo
NADP/metabolismo
Isoformas de Proteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Protein Isoforms); 53-59-8 (NADP); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.14.1 (arachidonate epoxygenase)
[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:170503
[St] Status:MEDLINE
[do] DOI:10.1124/dmd.117.075036


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[PMID]:29336152
[Au] Autor:Fu B; Xu T; Cui Z; Ng HL; Wang K; Li J; Li QX
[Ad] Endereço:Beijing Key Laboratory of Biodiversity and Organic Farming, College of Resources and Environmental Sciences, China Agricultural University , 2 Yuanmingyuan West Road, Beijing 100193, China.
[Ti] Título:Mutation of Phenylalanine-223 to Leucine Enhances Transformation of Benzo[a]pyrene by Ring-Hydroxylating Dioxygenase of Sphingobium sp. FB3 by increasing Accessibility of the Catalytic Site.
[So] Source:J Agric Food Chem;66(5):1206-1213, 2018 Feb 07.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Burning of agricultural biomass generates polycyclic aromatic hydrocarbons (PAHs) including the carcinogen benzo[a]pyrene, of which the catabolism is primarily initiated by a ring-hydroxylating dioxygenase (RHD). This study explores catalytic site accessibility and its role in preferential catabolism of some PAHs over others. The genes flnA1f, flnA2f, flnA3, and flnA4, encoding the oxygenase α and ß subunits, ferredoxin, and ferredoxin reductase, respectively, of the RHD enzyme complex (FlnA) were cloned from Sphingobium sp. FB3 and coexpressed in E. coli BL21. The FlnA effectively transformed fluoranthene but not benzo[a]pyrene. Substitution of the bulky phenylalanine-223 by leucine reduces the steric constraint in the substrate entrance to make the catalytic site of FlnA more accessible to large substrates, as visualized by 3D modeling, and allows the FlnA mutant to efficiently transform benzo[a]pyrene. Accessibility of the catalytic site to PAHs is a mechanism of RHD substrate specificity. The results shed light on why some PAHs are more recalcitrant than others.
[Mh] Termos MeSH primário: Benzo(a)pireno/metabolismo
Domínio Catalítico/fisiologia
Dioxigenases/metabolismo
Leucina/genética
Mutação
Fenilalanina/genética
[Mh] Termos MeSH secundário: Biodegradação Ambiental
Clonagem Molecular
Dioxigenases/genética
Escherichia coli/genética
Fluorenos/metabolismo
Expressão Gênica
Hidroxilação
Leucina/química
Fenilalanina/química
Hidrocarbonetos Aromáticos Policíclicos/metabolismo
Proteobactérias/enzimologia
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fluorenes); 0 (Polycyclic Aromatic Hydrocarbons); 3417WMA06D (Benzo(a)pyrene); 360UOL779Z (fluoranthene); 47E5O17Y3R (Phenylalanine); EC 1.13.11.- (Dioxygenases); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b05018


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[PMID]:29203276
[Au] Autor:Lazarska KE; Dekker SJ; Vermeulen NPE; Commandeur JNM
[Ad] Endereço:AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical sciences, Vrije Universiteit, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
[Ti] Título:Effect of UGT2B7*2 and CYP2C8*4 polymorphisms on diclofenac metabolism.
[So] Source:Toxicol Lett;284:70-78, 2018 Mar 01.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The use of diclofenac is associated with rare but severe drug-induced liver injury (DILI) in a very small number of patients. The factors which predispose susceptible patients to hepatotoxicity of diclofenac are still incompletely understood. Formation of protein-reactive metabolites by UDP-glucuronosyl transferases and cytochromes P450 is commonly considered to play an important role, as indicated by the detection of covalent protein adducts and antibodies in the serum of patients suffering from diclofenac-induced liver injury. Since no associations have been found with HLA-alleles, polymorphisms of genes encoding for proteins involved in the disposition of diclofenac may be important. Previous association studies showed that possession of the UGT2B7*2 and CYP2C8*4 alleles is more common in cases of diclofenac-induced DILI. In the present study, the metabolism of diclofenac by UGT2B7*2 and CYP2C8*4 was compared with their corresponding wild-type enzymes. Enzyme kinetic analysis revealed that recombinant UGT2B7*2 showed an almost 6-fold lower intrinsic clearance of diclofenac glucuronidation compared to UGT2B7*1. The mutant CYP2C8*4 showed approximately 35% reduced activity in the 4'-hydroxylation of diclofenac acyl glucuronide. Therefore, a decreased hepatic exposure to diclofenac acyl glucuronide is expected in patients with the UGT2B7*2 genotype. The increased risk for hepatotoxicity, therefore, might be the result from a shift to oxidative bioactivation to cytotoxic quinoneimines.
[Mh] Termos MeSH primário: Anti-Inflamatórios não Esteroides/metabolismo
Citocromo P-450 CYP2C8/genética
Diclofenaco/metabolismo
Glucuronosiltransferase/genética
Polimorfismo Genético
[Mh] Termos MeSH secundário: Animais
Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Escherichia coli/genética
Glucuronídeos/metabolismo
Hidroxilação
Cinética
Mutação
Oxirredução
Proteínas Recombinantes
Células Sf9
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents, Non-Steroidal); 0 (Glucuronides); 0 (Recombinant Proteins); 144O8QL0L1 (Diclofenac); EC 1.14.14.1 (CYP2C8 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP2C8); EC 2.4.1.- (UGT2B7 protein, human); EC 2.4.1.17 (Glucuronosyltransferase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE


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[PMID]:28467386
[Au] Autor:Legradi J; Pomeren MV; Dahlberg AK; Legler J
[Ad] Endereço:Environment and Health, VU University, 1081 HV Amsterdam, The Netherlands. Jessica.legradi@vu.nl.
[Ti] Título:Effects of Hydroxylated Polybrominated Diphenyl Ethers in Developing Zebrafish Are Indicative of Disruption of Oxidative Phosphorylation.
[So] Source:Int J Mol Sci;18(5), 2017 May 03.
[Is] ISSN:1422-0067
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) have been detected in humans and wildlife. Using in vitro models, we recently showed that OH-PBDEs disrupt oxidative phosphorylation (OXPHOS), an essential process in energy metabolism. The goal of the current study was to determine the in vivo effects of OH-PBDE reported in marine wildlife. To this end, we exposed zebrafish larvae to 17 OH-PBDEs from fertilisation to 6 days of age, and determined developmental toxicity as well as OXPHOS disruption potential with a newly developed assay of oxygen consumption in living embryos. We show here that all OH-PBDEs tested, both individually and as mixtures, resulted in a concentration-dependant delay in development in zebrafish embryos. The most potent substances were 6-OH-BDE47 and 6'-OH-BDE49 (No-Effect-Concentration: 0.1 and 0.05 µM). The first 24 h of development were the most sensitive, resulting in significant and irreversible developmental delay. All substances increased oxygen consumption, an effect indicative of OXPHOS disruption. Our results suggest that the induced developmental delay may be caused by disruption of OXPHOS. Though further studies are needed, our findings suggest that the environmental concentrations of some OH-PBDEs found in Baltic Sea wildlife in the Baltic Sea may be of toxicological concern.
[Mh] Termos MeSH primário: Embrião não Mamífero/efeitos dos fármacos
Éteres Difenil Halogenados/toxicidade
Fosforilação Oxidativa/efeitos dos fármacos
Consumo de Oxigênio/efeitos dos fármacos
Poluentes Químicos da Água/toxicidade
Peixe-Zebra/embriologia
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Monitoramento Ambiental
Seres Humanos
Hidroxilação
Modelos Lineares
Oceanos e Mares
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Halogenated Diphenyl Ethers); 0 (Water Pollutants, Chemical)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180221
[Lr] Data última revisão:
180221
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE


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[PMID]:28821467
[Au] Autor:Kim J; Lee PG; Jung EO; Kim BG
[Ad] Endereço:Department of Chemical and Biological Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
[Ti] Título:In vitro characterization of CYP102G4 from Streptomyces cattleya: A self-sufficient P450 naturally producing indigo.
[So] Source:Biochim Biophys Acta;1866(1):60-67, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Self-sufficient CYP102As possess outstanding hydroxylating activity to fatty acids such as myristic acid. Other CYP102 subfamily members share substrate specificity of CYP102As, but, occasionally, unusual characteristics of its own subfamily have been found. In this study, only one self-sufficient cytochrome P450 from Streptomyces cattleya was renamed from CYP102A_scat to CYP102G4, purified and characterized. UV-Vis spectrometry pattern, FAD/FMN analysis, and protein sequence comparison among CYP102s have shown that CYP102 from Streptomyces cattleya belongs to CYP102G subfamily. It showed hydroxylation activity toward fatty acids generating ω-1, ω-2, and ω-3-hydroxyfatty acids, which is similar to the general substrate specificity of CYP102 family. Unexpectedly, however, expression of CYP102G4 showed indigo production in LB medium batch flask culture, and high catalytic activity (k /K ) for indole was measured as 6.14±0.10min mM . Besides indole, CYP102G4 was able to hydroxylate aromatic compounds such as flavone, benzophenone, and chloroindoles. Homology model has shown such ability to accept aromatic compounds is due to its bigger active site cavity. Unlike other CYP102s, CYP102G4 did not have biased cofactor dependency, which was possibly determined by difference in NAD(P)H binding residues (Ala984, Val990, and Tyr1064) compared to CYP102A1 (Arg966, Lys972 and Trp1046). Overall, a self-sufficient CYP within CYP102G subfamily was characterized using purified enzymes, which appears to possess unique properties such as an only prokaryotic CYP naturally producing indigo.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Ácidos Graxos/metabolismo
Índigo Carmim/metabolismo
NADPH-Ferri-Hemoproteína Redutase/metabolismo
Streptomyces/enzimologia
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Benzofenonas/metabolismo
Domínio Catalítico
Clonagem Molecular
Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/genética
Escherichia coli/genética
Escherichia coli/metabolismo
Ácidos Graxos/química
Flavonas/metabolismo
Expressão Gênica
Hidroxilação
Indóis/metabolismo
Cinética
Modelos Moleculares
NADP/química
NADP/metabolismo
NADPH-Ferri-Hemoproteína Redutase/química
NADPH-Ferri-Hemoproteína Redutase/genética
Ligação Proteica
Domínios e Motivos de Interação entre Proteínas
Estrutura Secundária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Streptomyces/genética
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 (Bacterial Proteins); 0 (Benzophenones); 0 (Fatty Acids); 0 (Flavones); 0 (Indoles); 0 (Recombinant Proteins); 53-59-8 (NADP); 701M4TTV9O (benzophenone); 8724FJW4M5 (indole); 9035-51-2 (Cytochrome P-450 Enzyme System); D3741U8K7L (Indigo Carmine); EC 1.6.2.4 (NADPH-Ferrihemoprotein Reductase); EC 1.6.2.4 (flavocytochrome P450 BM3 monoxygenases); S2V45N7G3B (flavone)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170820
[St] Status:MEDLINE


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[PMID]:28780179
[Au] Autor:Schmitz D; Janocha S; Kiss FM; Bernhardt R
[Ad] Endereço:Department of Biochemistry, Saarland University, Campus B2.2, 66123 Saarbruecken, Germany.
[Ti] Título:CYP106A2-A versatile biocatalyst with high potential for biotechnological production of selectively hydroxylated steroid and terpenoid compounds.
[So] Source:Biochim Biophys Acta;1866(1):11-22, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:CYP106A2 from Bacillus megaterium ATCC13368, was identified in the 1970s as one of the first bacterial steroid hydroxylases responsible for the conversion of progesterone to 15ß-hydroxyprogesterone. Later on it has been proven to be a potent hydroxylase of numerous 3-oxo-Δ as well as 3-hydroxy-Δ -steroids and has recently also been characterized as a regioselective allylic bacterial diterpene hydroxylase. The main hydroxylation position of CYP106A2 is thought to be influenced by the functional groups at C3 position in the steroid core leading to a favored 15ß-hydroxylation of 3-oxo-Δ -steroids and 7ß-hydroxylation of 3-hydroxy-Δ -steroids. However, in some cases the hydroxylation is not strictly selective, resulting in the formation of undesired side-products. To overcome the unspecific hydroxylations or, on the contrary, to gain more of these products in case they are of industrial interest, rational protein design and directed evolution have been successfully performed to shift the stereoselectivity of hydroxylation by CYP106A2. The subsequently obtained hydroxylated steroid and terpene derivatives are especially useful as drug metabolites and drug precursors for the pharmaceutical industry, due to their diverse biological properties and hardship of their chemical synthesis. As a soluble prokaryotic P450 with broad substrate spectrum and hydroxylating capacity, CYP106A2 is an outstanding candidate to establish bioconversion processes. It has been expressed with respectable yields in Escherichia coli and Bacillus megaterium and was applied for the preparative hydroxylation of several steroids and terpenes. Recently, the application of the enzyme was assessed under process conditions as well, depicting a successfully optimized process development and getting us closer to industrial scale process requirements and a future large scale application. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Bacillus megaterium/enzimologia
Proteínas de Bactérias/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
Diterpenos/síntese química
Engenharia de Proteínas/métodos
Esteroides/síntese química
Terpenos/síntese química
[Mh] Termos MeSH secundário: Bacillus megaterium/genética
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Biocatálise
Biotecnologia/métodos
Sistema Enzimático do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/genética
Evolução Molecular Direcionada
Escherichia coli/enzimologia
Escherichia coli/genética
Expressão Gênica
Hidroxilação
Modelos Moleculares
Estrutura Secundária de Proteína
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Diterpenes); 0 (Steroids); 0 (Terpenes); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.14.- (15beta-hydroxylase CYP106A2, Bacillus megaterium)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170807
[St] Status:MEDLINE


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[PMID]:28734978
[Au] Autor:Kranz-Finger S; Mahmoud O; Ricklefs E; Ditz N; Bakkes PJ; Urlacher VB
[Ad] Endereço:Institute of Biochemistry, Heinrich-Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany; Cluster of Excellence on Plant Sciences, Heinrich-Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
[Ti] Título:Insights into the functional properties of the marneral oxidase CYP71A16 from Arabidopsis thaliana.
[So] Source:Biochim Biophys Acta;1866(1):2-10, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:The Arabidopsis thaliana gene encoding CYP71A16 is part of the gene cluster for the biosynthesis and modification of the triterpenoid marneral. Previous investigations of A. thaliana have revealed that CYP71A16 catalyzes marneral oxidation, while it also can accept marnerol as substrate. The aim of the present study was to investigate functional properties of CYP71A16 in vitro. For this purpose, heterologous expression of a N-terminally modified version of CYP71A16 was established in Escherichia coli, which yielded up to 50mgL recombinant enzyme. The enzyme was purified and activity was reconstituted in vitro with different redox partners. A heterologous bacterial redox partner system consisting of the flavodoxin YkuN from Bacillus subtilis and the flavodoxin reductase Fpr from E. coli clearly outperformed the cytochrome P450 reductase ATR2 from A. thaliana in supporting the CYP71A16-mediated hydroxylation of marnerol. Substrate binding experiments with CYP71A16 revealed a dissociation constant K of 225µM for marnerol. CYP71A16 catalyzed the hydroxylation of marnerol to 23-hydroxymarnerol with a K of 142µM and a k of 3.9min . Furthermore, GC/MS analysis revealed an as of yet unidentified overoxidation product of this in vitro reaction. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Proteínas de Arabidopsis/metabolismo
Arabidopsis/enzimologia
Bacillus subtilis/enzimologia
Sistema Enzimático do Citocromo P-450/metabolismo
Proteínas de Escherichia coli/metabolismo
Ferredoxina-NADP Redutase/metabolismo
Flavodoxina/metabolismo
Triterpenos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arabidopsis/química
Proteínas de Arabidopsis/genética
Bacillus subtilis/química
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Clonagem Molecular
Sistema Enzimático do Citocromo P-450/genética
Escherichia coli/genética
Escherichia coli/metabolismo
Proteínas de Escherichia coli/genética
Ferredoxina-NADP Redutase/genética
Flavodoxina/genética
Expressão Gênica
Vetores Genéticos/química
Vetores Genéticos/metabolismo
Hidroxilação
Cinética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ATR2 protein, Arabidopsis); 0 (Arabidopsis Proteins); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Escherichia coli Proteins); 0 (Flavodoxin); 0 (Recombinant Proteins); 0 (Triterpenes); 0 (marneral); 117385-73-6 (fpr protein, E coli); 9035-51-2 (Cytochrome P-450 Enzyme System); EC 1.- (CYP71A16 protein, Arabidopsis); EC 1.18.1.2 (Ferredoxin-NADP Reductase)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170724
[St] Status:MEDLINE


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[PMID]:28583351
[Au] Autor:Yasuda K; Sugimoto H; Hayashi K; Takita T; Yasukawa K; Ohta M; Kamakura M; Ikushiro S; Shiro Y; Sakaki T
[Ad] Endereço:Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan; Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
[Ti] Título:Protein engineering of CYP105s for their industrial uses.
[So] Source:Biochim Biophys Acta;1866(1):23-31, 2018 01.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cytochrome P450 enzymes belonging to the CYP105 family are predominantly found in bacteria belonging to the phylum Actinobacteria and the order Actinomycetales. In this review, we focused on the protein engineering of P450s belonging to the CYP105 family for industrial use. Two Arg substitutions to Ala of CYP105A1 enhanced its vitamin D 25- and 1α-hydroxylation activities by 400 and 100-fold, respectively. The coupling efficiency between product formation and NADPH oxidation was largely improved by the R84A mutation. The quintuple mutant Q87W/T115A/H132L/R194W/G294D of CYP105AB3 showed a 20-fold higher activity than the wild-type enzyme. Amino acids at positions 87 and 191 were located at the substrate entrance channel, and that at position 294 was located close to the heme group. Semi-rational engineering of CYP105A3 selected the best performing mutant, T85F/T119S/V194N/N363Y, for producing pravastatin. The T119S and N363Y mutations synergistically had remarkable effects on the interaction between CYP105A3 and putidaredoxin. Although wild-type CYP105AS1 hydroxylated compactin to 6-epi-pravastatin, the quintuple mutant I95T/Q127R/A180V/L236I/A265N converted almost all compactin to pravastatin. Five amino acid substitutions by two rounds of mutagenesis almost completely changed the stereo-selectivity of CYP105AS1. These results strongly suggest that the protein engineering of CYP105 enzymes greatly increase their industrial utility. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone.
[Mh] Termos MeSH primário: Actinobacteria/genética
Substituição de Aminoácidos
Proteínas de Bactérias/química
Sistema Enzimático do Citocromo P-450/química
Mutação
Engenharia de Proteínas/métodos
[Mh] Termos MeSH secundário: Actinobacteria/enzimologia
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Colecalciferol/metabolismo
Sequência Conservada
Sistema Enzimático do Citocromo P-450/genética
Sistema Enzimático do Citocromo P-450/metabolismo
Ferredoxinas/metabolismo
Expressão Gênica
Hidroxilação
Isoenzimas
Lovastatina/análogos & derivados
Lovastatina/metabolismo
Simulação de Acoplamento Molecular
Pravastatina/biossíntese
Streptomyces/enzimologia
Streptomyces/genética
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Ferredoxins); 0 (Isoenzymes); 1C6V77QF41 (Cholecalciferol); 1UQM1K0W9X (mevastatin); 57087-75-9 (putidaredoxin); 9035-51-2 (Cytochrome P-450 Enzyme System); 9LHU78OQFD (Lovastatin); EC 1.14.- (P450SU1 protein, Streptomyces griseolus); KXO2KT9N0G (Pravastatin)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180208
[Lr] Data última revisão:
180208
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170607
[St] Status:MEDLINE


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[PMID]:29205036
[Au] Autor:Yang S; Zhang H; Sun F; De Ruyck K; Zhang J; Jin Y; Li Y; Wang Z; Zhang S; De Saeger S; Zhou J; Li Y; De Boevre M
[Ad] Endereço:Institute of Apicultural Research, Chinese Academy of Agricultural Sciences , Key Laboratory of Bee Products for Quality and Safety Control, Laboratory of Risk Assessment for Quality and Safety of Bee Products, Bee Product Quality Supervision and Testing Center, Ministry of Agriculture, Beijing 1000
[Ti] Título:Metabolic Profile of Zearalenone in Liver Microsomes from Different Species and Its in Vivo Metabolism in Rats and Chickens Using Ultra High-Pressure Liquid Chromatography-Quadrupole/Time-of-Flight Mass Spectrometry.
[So] Source:J Agric Food Chem;65(51):11292-11303, 2017 Dec 27.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To explore differences of zearalenone (ZEN) metabolism between various species, phase I and II metabolism by liver microsomes of animals and human were investigated using ultra high-pressure liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF MS). A total of 24 metabolites were identified, among which 12 were reported for the first time. Reduction, hydroxylation, and glucuronidation were the major metabolic pathways of ZEN, and significant differences in various species were also observed. Reduction was the main reaction in swine and human, whereas hydroxylation was predominant in rats, chickens, goats, and cows in in vitro systems. Furthemore, in vivo metabolism of ZEN in rats and chickens was investigated, and 23 and 6 metabolites were identified in each species, respectively. Reduction, hydroxylation, and glucuronidation were the major metabolic pathways in rats, while reduction and sulfation predominated in chickens. These results further enrich the biotransformation profile of ZEN, providing a helpful reference for assessing the risks to animals and humans.
[Mh] Termos MeSH primário: Microssomos Hepáticos/metabolismo
Zearalenona/metabolismo
[Mh] Termos MeSH secundário: Animais
Bovinos
Galinhas
Cromatografia Líquida de Alta Pressão
Cabras
Seres Humanos
Hidroxilação
Espectrometria de Massas
Microssomos Hepáticos/química
Estrutura Molecular
Ratos
Suínos
Zearalenona/química
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
5W827M159J (Zearalenone)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171206
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b04663


  10 / 11850 MEDLINE  
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[PMID]:27770548
[Au] Autor:Arsenault PR; Song D; Bergkamp M; Ravaschiere AM; Navalsky BE; Lieberman PM; Lee FS
[Ad] Endereço:Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 605 Stellar Chance Labs, 422 Curie Blvd, Philadelphia, PA, 19104, USA.
[Ti] Título:Identification of Small-Molecule PHD2 Zinc Finger Inhibitors that Activate Hypoxia Inducible Factor.
[So] Source:Chembiochem;17(24):2316-2323, 2016 Dec 14.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The prolyl hydroxylase domain (PHD) protein:hypoxia inducible factor (HIF) pathway is the main pathway by which changes in oxygen concentration are transduced to changes in gene expression. In mammals, there are three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such as erythropoietin (EPO), which controls red cell mass and hematocrit. PHD2 is distinctive among the three PHDs in that it contains an N-terminal MYND-type zinc finger. We have proposed that this zinc finger binds a Pro-Xaa-Leu-Glu (PXLE) motif found in proteins of the HSP90 pathway to facilitate HIF-α hydroxylation. Targeting this motif could provide a means of specifically inhibiting this PHD isoform. Here, we screened a library of chemical compounds for their capacity to inhibit the zinc finger of PHD2. We identified compounds that, in vitro, can inhibit PHD2 binding to a PXLE-containing peptide and induce activation of HIF. Injection of one of these compounds into mice induces an increase in hematocrit. This study offers proof of principle that inhibition of the zinc finger of PHD2 can provide a means of selectively targeting PHD2 to activate the HIF pathway.
[Mh] Termos MeSH primário: Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo
Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo
[Mh] Termos MeSH secundário: Motivos de Aminoácidos
Animais
Sistemas CRISPR-Cas/genética
Domínio Catalítico
Eritropoetina/sangue
Eritropoetina/genética
Eritropoetina/metabolismo
Técnicas de Introdução de Genes
Proteínas de Choque Térmico HSP90/química
Proteínas de Choque Térmico HSP90/metabolismo
Hematócrito
Seres Humanos
Hidroxilação
Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores
Prolina Dioxigenases do Fator Induzível por Hipóxia/genética
Camundongos
Camundongos Endogâmicos C57BL
Ligação Proteica
RNA Mensageiro/metabolismo
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/isolamento & purificação
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/metabolismo
Dedos de Zinco
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP90 Heat-Shock Proteins); 0 (Hypoxia-Inducible Factor 1, alpha Subunit); 0 (RNA, Messenger); 0 (Recombinant Proteins); 0 (Small Molecule Libraries); 11096-26-7 (Erythropoietin); EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171214
[Lr] Data última revisão:
171214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161023
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201600493



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