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[PMID]:28750088
[Au] Autor:Foti A; Dorendorf F; Leimkühler S
[Ad] Endereço:Department of Molecular Enzymology, Institute of Biochemistry and Biology, University of Potsdam, Potsdam, Germany.
[Ti] Título:A single nucleotide polymorphism causes enhanced radical oxygen species production by human aldehyde oxidase.
[So] Source:PLoS One;12(7):e0182061, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. The enzymes use oxygen as the terminal electron acceptor and produce reduced oxygen species during turnover. The physiological function of mammalian AOX isoenzymes is still unclear, however, human AOX (hAOX1) is an emerging enzyme in phase-I drug metabolism. Indeed, the number of xenobiotics acting as hAOX1 substrates is increasing. Further, numerous single-nucleotide polymorphisms (SNPs) have been identified within the hAOX1 gene. SNPs are a major source of inter-individual variability in the human population, and SNP-based amino acid exchanges in hAOX1 reportedly modulate the catalytic function of the enzyme in either a positive or negative fashion. In this report we selected ten novel SNPs resulting in amino acid exchanges in proximity to the FAD site of hAOX1 and characterized the purified enzymes after heterologous expression in Escherichia coli. The hAOX1 variants were characterized carefully by quantitative differences in their ability to produce superoxide radical. ROS represent prominent key molecules in physiological and pathological conditions in the cell. Our data reveal significant alterations in superoxide anion production among the variants. In particular the SNP-based amino acid exchange L438V in proximity to the isoalloxanzine ring of the FAD cofactor resulted in increased rate of superoxide radical production of 75%. Considering the high toxicity of the superoxide in the cell, the hAOX1-L438V SNP variant is an eventual candidate for critical or pathological roles of this natural variant within the human population.
[Mh] Termos MeSH primário: Aldeído Oxidase/genética
Polimorfismo de Nucleotídeo Único/genética
Espécies Reativas de Oxigênio/metabolismo
[Mh] Termos MeSH secundário: Aldeído Oxidase/química
Aldeído Oxidase/isolamento & purificação
Aminoácidos/genética
Anaerobiose
Domínio Catalítico
Coenzimas/metabolismo
Transporte de Elétrons
Flavina-Adenina Dinucleotídeo/metabolismo
Seres Humanos
Ferro/metabolismo
Cinética
Modelos Moleculares
Molibdênio/metabolismo
Proteínas Mutantes/isolamento & purificação
NAD/metabolismo
Oniocompostos/metabolismo
Multimerização Proteica
Espectrofotometria Ultravioleta
Superóxidos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids); 0 (Coenzymes); 0 (Mutant Proteins); 0 (Onium Compounds); 0 (Reactive Oxygen Species); 0U46U6E8UK (NAD); 11062-77-4 (Superoxides); 146-14-5 (Flavin-Adenine Dinucleotide); 6HJ411TU98 (diphenyleneiodonium); 81AH48963U (Molybdenum); E1UOL152H7 (Iron); EC 1.2.3.1 (AOX1 protein, human); EC 1.2.3.1 (Aldehyde Oxidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171004
[Lr] Data última revisão:
171004
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170728
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182061


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[PMID]:28645573
[Au] Autor:Maiti K; Sultana Z; Aitken RJ; Morris J; Park F; Andrew B; Riley SC; Smith R
[Ad] Endereço:Mothers and Babies Research Center, Hunter Medical Research Institute, Newcastle, Australia; Priority Research Center in Reproductive Science, Faculty of Health, University of Newcastle, Newcastle, Australia.
[Ti] Título:Evidence that fetal death is associated with placental aging.
[So] Source:Am J Obstet Gynecol;217(4):441.e1-441.e14, 2017 Oct.
[Is] ISSN:1097-6868
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The risk of unexplained fetal death or stillbirth increases late in pregnancy, suggesting that placental aging is an etiological factor. Aging is associated with oxidative damage to DNA, RNA, and lipids. We hypothesized that placentas at >41 completed weeks of gestation (late-term) would show changes consistent with aging that would also be present in placentas associated with stillbirths. OBJECTIVE: We sought to determine whether placentas from late-term pregnancies and unexplained stillbirth show oxidative damage and other biochemical signs of aging. We also aimed to develop an in vitro term placental explant culture model to test the aging pathways. STUDY DESIGN: We collected placentas from women at 37-39 weeks' gestation (early-term and term), late-term, and with unexplained stillbirth. We used immunohistochemistry to compare the 3 groups for: DNA/RNA oxidation (8-hydroxy-deoxyguanosine), lysosomal distribution (lysosome-associated membrane protein 2), lipid oxidation (4-hydroxynonenal), and autophagosome size (microtubule-associated proteins 1A/1B light chain 3B, LC3B). The expression of aldehyde oxidase 1 was measured by real-time polymerase chain reaction. Using a placental explant culture model, we tested the hypothesis that aldehyde oxidase 1 mediates oxidative damage to lipids in the placenta. RESULTS: Placentas from late-term pregnancies show increased aldehyde oxidase 1 expression, oxidation of DNA/RNA and lipid, perinuclear location of lysosomes, and larger autophagosomes compared to placentas from women delivered at 37-39 weeks. Stillbirth-associated placentas showed similar changes in oxidation of DNA/RNA and lipid, lysosomal location, and autophagosome size to placentas from late-term. Placental explants from term deliveries cultured in serum-free medium also showed evidence of oxidation of lipid, perinuclear lysosomes, and larger autophagosomes, changes that were blocked by the G-protein-coupled estrogen receptor 1 agonist G1, while the oxidation of lipid was blocked by the aldehyde oxidase 1 inhibitor raloxifene. CONCLUSION: Our data are consistent with a role for aldehyde oxidase 1 and G-protein-coupled estrogen receptor 1 in mediating aging of the placenta that may contribute to stillbirth. The placenta is a tractable model of aging in human tissue.
[Mh] Termos MeSH primário: Envelhecimento/fisiologia
Morte Fetal
Placenta/metabolismo
Natimorto
[Mh] Termos MeSH secundário: Aldeído Oxidase/metabolismo
Autofagossomos/metabolismo
DNA/química
Desoxiguanosina/análogos & derivados
Desoxiguanosina/metabolismo
Feminino
Idade Gestacional
Seres Humanos
Lipídeos/química
Lisossomos/metabolismo
Oxirredução
Gravidez
RNA/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lipids); 63231-63-0 (RNA); 88847-89-6 (8-oxo-7-hydrodeoxyguanosine); 9007-49-2 (DNA); EC 1.2.3.1 (AOX1 protein, human); EC 1.2.3.1 (Aldehyde Oxidase); G9481N71RO (Deoxyguanosine)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170625
[St] Status:MEDLINE


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[PMID]:28606603
[Au] Autor:Konishi K; Fukami T; Gotoh S; Nakajima M
[Ad] Endereço:Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan.
[Ti] Título:Identification of enzymes responsible for nitrazepam metabolism and toxicity in human.
[So] Source:Biochem Pharmacol;140:150-160, 2017 Sep 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nitrazepam (NZP) is a hypnotic agent that rarely causes liver injuries in humans and teratogenicity in rodents. In humans, NZP is primarily metabolized to 7-aminonitrazepam (ANZP) by reduction and subsequently to 7-acetylamino nitrazepam (AANZP) by acetylation. ANZP can be regenerated from AANZP by hydrolysis in rodents, but it is still unclear whether this reaction occurs in humans. In rodents, AANZP may be associated with teratogenicity, while in humans, it is known that drug-induced liver injuries may be caused by NZP reactive metabolite(s). In this study, we attempted to identify the enzymes responsible for NZP metabolism to obtain a basic understanding of this process and the associated metabolite toxicities. We found that the NZP reductase activity in human liver cytosol (HLC) was higher than that in human liver microsomes (HLM). We purified the responsible enzyme(s) from HLC and found that the NZP reductase was aldehyde oxidase 1 (AOX1). The role of AOX1 was confirmed by an observed increase in the NZP reductase activity upon addition of N -methylnicotinamide, an electron donor of AOX1, as well as inhibition of this activity in HLC in the presence of AOX1 inhibitors. ANZP was acetylated to form AANZP by N-acetyltransferase (NAT) 2. An experiment using recombinant esterases in an inhibition study using HLM revealed that AANZP is hydrolyzed by arylacetamide deacetylase (AADAC) in the human liver. N-Hydroxylamino NZP, which is suspected to be a reactive metabolite, was detected as a conjugate with N-acetyl-l-cysteine through NZP reduction and ANZP hydroxylation reactions. In the latter reaction, the conjugate was readily formed by recombinant CYP3A4 among the various P450 isoforms tested. In sum, we found that AOX1, NAT2, AADAC, and CYP3A4 are the determinants for the pharmacokinetics of NZP and that they confer interindividual variability in sensitivity to NZP side effects.
[Mh] Termos MeSH primário: Aldeído Oxidase/metabolismo
Arilamina N-Acetiltransferase/metabolismo
Hidrolases de Éster Carboxílico/metabolismo
Citocromo P-450 CYP3A/metabolismo
Hepatócitos/metabolismo
Hipnóticos e Sedativos/metabolismo
Nitrazepam/metabolismo
[Mh] Termos MeSH secundário: Acetilação
Aldeído Oxidase/antagonistas & inibidores
Aldeído Oxidase/química
Aldeído Oxidase/isolamento & purificação
Arilamina N-Acetiltransferase/genética
Biotransformação
Hidrolases de Éster Carboxílico/genética
Citocromo P-450 CYP3A/genética
Citosol/enzimologia
Citosol/metabolismo
Inibidores Enzimáticos/farmacologia
Hepatócitos/enzimologia
Seres Humanos
Hidrólise/efeitos dos fármacos
Hidroxilação
Hipnóticos e Sedativos/efeitos adversos
Cinética
Microssomos Hepáticos/enzimologia
Microssomos Hepáticos/metabolismo
Nitrazepam/efeitos adversos
Nitrazepam/análogos & derivados
Oxirredução
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Hypnotics and Sedatives); 0 (Recombinant Proteins); 1A49O337AZ (7-aminonitrazepam); 4928-03-4 (7-acetamidonitrazepam); 9CLV70W7HS (Nitrazepam); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); EC 1.2.3.1 (AOX1 protein, human); EC 1.2.3.1 (Aldehyde Oxidase); EC 2.3.1.5 (Arylamine N-Acetyltransferase); EC 2.3.1.5 (NAT2 protein, human); EC 3.1.1.- (AADAC protein, human); EC 3.1.1.- (Carboxylic Ester Hydrolases)
[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:170614
[St] Status:MEDLINE


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[PMID]:28263602
[Au] Autor:Xu Y; Li L; Wang Y; Xing J; Zhou L; Zhong D; Luo X; Jiang H; Chen K; Zheng M; Deng P; Chen X
[Ad] Endereço:Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
[Ti] Título:Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study.
[So] Source:J Med Chem;60(7):2973-2982, 2017 Apr 13.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified. In addition, the proposed strategy was used to evaluate the metabolism of newly designed c-Met inhibitors, and a success switch-off of AOX metabolism was observed. Overall, this study provide useful information to guide lead optimization and drug discovery based on AOX-mediated metabolism.
[Mh] Termos MeSH primário: Aldeído Oxidase/metabolismo
Preparações Farmacêuticas/metabolismo
[Mh] Termos MeSH secundário: Descoberta de Drogas
Seres Humanos
Cinética
Modelos Biológicos
Preparações Farmacêuticas/química
Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); EC 1.2.3.1 (Aldehyde Oxidase); EC 2.7.10.1 (Proto-Oncogene Proteins c-met)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170424
[Lr] Data última revisão:
170424
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170307
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jmedchem.7b00019


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[PMID]:28242415
[Au] Autor:Serova TA; Tikhonovich IA; Tsyganov VE
[Ad] Endereço:All-Russia Research Institute for Agricultural Microbiology, Laboratory of Molecular and Cellular Biology, Podbelsky chaussee 3, 196608, Pushkin 8, Saint-Petersburg, Russia.
[Ti] Título:Analysis of nodule senescence in pea (Pisum sativum L.) using laser microdissection, real-time PCR, and ACC immunolocalization.
[So] Source:J Plant Physiol;212:29-44, 2017 May.
[Is] ISSN:1618-1328
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:A delay in the senescence of symbiotic nodules could prolong active nitrogen fixation, resulting in improved crop yield and a reduced need for chemical fertilizers. The molecular genetic mechanisms underlying nodule senescence have not been extensively studied with a view to breeding varieties with delayed nodule senescence. In such studies, plant mutants with the phenotype of premature degradation of symbiotic structures are useful models to elucidate the genetic basis of nodule senescence. Using a dataset from transcriptome analysis of Medicago truncatula Gaertn. nodules and previous studies on pea (Pisum sativum L.) nodules, we developed a set of molecular markers based on genes that are known to be activated during nodule senescence. These genes encode cysteine proteases, a thiol protease, a bZIP transcription factor, enzymes involved in the biosynthesis of ethylene (ACS2 for ACC synthase and ACO1 for ACC oxidase) and ABA (AO3 for aldehyde oxidase), and an enzyme involved in catabolism of gibberellins (GA 2-oxidase). We analyzed the transcript levels of these genes in the nodules of two pea wild-types (cv. Sparkle and line Sprint-2) and two mutant lines, one showing premature nodule senescence (E135F (sym13)) and one showing no morphological signs of symbiotic structure degradation (Sprint-2Fix (sym31)). Real-time PCR analyses revealed that all of the selected genes showed increased transcript levels during nodule aging in all phenotypes. Remarkably, at 4 weeks after inoculation (WAI), the transcript levels of all analyzed genes were significantly higher in the early senescent nodules of the mutant line E135F (sym13) and in nodules of the mutant Sprint-2Fix (sym31) than in the active nitrogen-fixing nodules of wild-types. In contrast, the transcript levels of the same genes of both wild-types were significantly increased only at 6 WAI. We evaluated the expression of selected markers in the different histological nodule zones of pea cv. Sparkle and its mutant line E135F (sym13) by laser capture microdissection analysis. Finally, we analyzed ACC by immunolocalization in the nodules of both wild-type pea and their mutants. Together, the results indicate that nodule senescence is a general plant response to nodule ineffectiveness.
[Mh] Termos MeSH primário: Envelhecimento/genética
Marcadores Genéticos/genética
Microdissecção/métodos
Ervilhas/genética
Proteínas de Plantas/genética
Reação em Cadeia da Polimerase em Tempo Real/métodos
Nódulos Radiculares de Plantas/genética
[Mh] Termos MeSH secundário: Ácido Abscísico/metabolismo
Aldeído Oxidase/genética
Aminoácido Oxirredutases/genética
Aminoácidos Cíclicos/análise
Cisteína Proteases/genética
DNA de Plantas/genética
Etilenos/biossíntese
Perfilação da Expressão Gênica/métodos
Regulação da Expressão Gênica de Plantas
Genes de Plantas/genética
Giberelinas/genética
Liases/genética
Medicago truncatula/microbiologia
Oxigenases de Função Mista/genética
Mutação
Fixação de Nitrogênio/genética
Ervilhas/microbiologia
Peptídeo Hidrolases/genética
Fenótipo
Reguladores de Crescimento de Planta/análise
Reguladores de Crescimento de Planta/genética
Raízes de Plantas/metabolismo
RNA Mensageiro/análise
RNA de Plantas
Rhizobium/genética
Nódulos Radiculares de Plantas/citologia
Nódulos Radiculares de Plantas/metabolismo
Simbiose/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amino Acids, Cyclic); 0 (DNA, Plant); 0 (Ethylenes); 0 (Genetic Markers); 0 (Gibberellins); 0 (Plant Growth Regulators); 0 (Plant Proteins); 0 (RNA, Messenger); 0 (RNA, Plant); 3K9EJ633GL (1-aminocyclopropane-1-carboxylic acid); 72S9A8J5GW (Abscisic Acid); 91GW059KN7 (ethylene); EC 1.- (Mixed Function Oxygenases); EC 1.14.11.13 (gibberellin 2-dioxygenase); EC 1.2.3.1 (Aldehyde Oxidase); EC 1.4.- (Amino Acid Oxidoreductases); EC 1.4.3.- (1-aminocyclopropane-1-carboxylic acid oxidase); EC 3.4.- (Cysteine Proteases); EC 3.4.- (Peptide Hydrolases); EC 4.- (Lyases); EC 4.4.1.14 (1-aminocyclopropanecarboxylate synthase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170301
[St] Status:MEDLINE


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[PMID]:28188272
[Au] Autor:Srivastava S; Brychkova G; Yarmolinsky D; Soltabayeva A; Samani T; Sagi M
[Ad] Endereço:Jacob Blaustein Institutes for Desert Research, Albert Katz Department of Dryland Biotechnologies, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
[Ti] Título:Aldehyde Oxidase 4 Plays a Critical Role in Delaying Silique Senescence by Catalyzing Aldehyde Detoxification.
[So] Source:Plant Physiol;173(4):1977-1997, 2017 Apr.
[Is] ISSN:1532-2548
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Arabidopsis ( ) aldehyde oxidases are a multigene family of four oxidases (AAO1-AAO4) that oxidize a variety of aldehydes, among them abscisic aldehyde, which is oxidized to the phytohormone abscisic acid. Toxic aldehydes are generated in plants both under normal conditions and in response to stress. The detoxification of such aldehydes by oxidation is attributed to aldehyde dehydrogenases but never to aldehyde oxidases. The feasibility of the detoxification of aldehydes in siliques via oxidation by AAO4 was demonstrated, first, by its ability to efficiently oxidize an array of aromatic and aliphatic aldehydes, including the reactive carbonyl species (RCS) acrolein, hydroxyl-2-nonenal, and malondialdehyde. Next, exogenous application of several aldehydes to siliques in AAO4 knockout (KO) Arabidopsis plants induced severe tissue damage and enhanced malondialdehyde levels and senescence symptoms, but not in wild-type siliques. Furthermore, abiotic stresses such as dark and ultraviolet C irradiation caused an increase in endogenous RCS and higher expression levels of senescence marker genes, leading to premature senescence of KO siliques, whereas RCS and senescence marker levels in wild-type siliques were hardly affected. Finally, in naturally senesced KO siliques, higher endogenous RCS levels were associated with enhanced senescence molecular markers, chlorophyll degradation, and earlier seed shattering compared with the wild type. The aldehyde-dependent differential generation of superoxide and hydrogen peroxide by AAO4 and the induction of AAO4 expression by hydrogen peroxide shown here suggest a self-amplification mechanism for detoxifying additional reactive aldehydes produced during stress. Taken together, our results indicate that AAO4 plays a critical role in delaying senescence in siliques by catalyzing aldehyde detoxification.
[Mh] Termos MeSH primário: Aldeído Oxidase/metabolismo
Aldeídos/metabolismo
Proteínas de Arabidopsis/metabolismo
Arabidopsis/metabolismo
Sementes/metabolismo
[Mh] Termos MeSH secundário: Ácido Abscísico/metabolismo
Aldeído Oxidase/genética
Sequência de Aminoácidos
Arabidopsis/enzimologia
Arabidopsis/genética
Proteínas de Arabidopsis/genética
Sequência de Bases
Benzaldeídos/metabolismo
Biocatálise
Regulação da Expressão Gênica de Plantas/efeitos dos fármacos
Regulação da Expressão Gênica de Plantas/efeitos da radiação
Técnicas de Inativação de Genes
Peróxido de Hidrogênio/metabolismo
Peróxido de Hidrogênio/farmacologia
Concentração de Íons de Hidrogênio
Cinética
Malondialdeído/metabolismo
Oxidantes/metabolismo
Oxidantes/farmacologia
Oxirredução
Plantas Geneticamente Modificadas
Espécies Reativas de Oxigênio/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Sementes/enzimologia
Sementes/genética
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
Fatores de Tempo
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aldehydes); 0 (Arabidopsis Proteins); 0 (Benzaldehydes); 0 (Oxidants); 0 (Reactive Oxygen Species); 4Y8F71G49Q (Malondialdehyde); 72S9A8J5GW (Abscisic Acid); BBX060AN9V (Hydrogen Peroxide); CHI530446X (vanillin); EC 1.2.3.1 (AAO4 protein, Arabidopsis); EC 1.2.3.1 (Aldehyde Oxidase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170212
[St] Status:MEDLINE
[do] DOI:10.1104/pp.16.01939


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[PMID]:28126656
[Au] Autor:Romão MJ; Coelho C; Santos-Silva T; Foti A; Terao M; Garattini E; Leimkühler S
[Ad] Endereço:UCIBIO-Requimte, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, 2829-516 Caparica, Portugal. Electronic address: mjr@fct.unl.pt.
[Ti] Título:Structural basis for the role of mammalian aldehyde oxidases in the metabolism of drugs and xenobiotics.
[So] Source:Curr Opin Chem Biol;37:39-47, 2017 Apr.
[Is] ISSN:1879-0402
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Aldehyde oxidases (AOXs) are molybdo-flavoenzymes characterized by broad substrate specificity, oxidizing aromatic/aliphatic aldehydes into the corresponding carboxylic acids and hydroxylating various heteroaromatic rings. Mammals are characterized by a complement of species-specific AOX isoenzymes, that varies from one in humans (AOX1) to four in rodents (AOX1, AOX2, AOX3 and AOX4). The physiological function of mammalian AOX isoenzymes is unknown, although human AOX1 is an emerging enzyme in phase-I drug metabolism. Indeed, the number of therapeutic molecules under development which act as AOX substrates is increasing. The recent crystallization and structure determination of human AOX1 as well as mouse AOX3 has brought new insights into the mechanisms underlying substrate/inhibitor binding as well as the catalytic activity of this class of enzymes.
[Mh] Termos MeSH primário: Aldeído Oxidase/química
Aldeído Oxidase/metabolismo
Mamíferos
Preparações Farmacêuticas/metabolismo
Xenobióticos/metabolismo
[Mh] Termos MeSH secundário: Aldeído Oxidase/antagonistas & inibidores
Aldeído Oxidase/genética
Animais
Inibidores Enzimáticos/metabolismo
Inibidores Enzimáticos/farmacologia
Seres Humanos
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Pharmaceutical Preparations); 0 (Xenobiotics); EC 1.2.3.1 (Aldehyde Oxidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170128
[St] Status:MEDLINE


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[PMID]:28095715
[Au] Autor:Rashidi MR; Soltani S
[Ad] Endereço:a Research Center for Pharmaceutical Nanotechnology , Tabriz University of Medical Sciences , Tabriz , Iran.
[Ti] Título:An overview of aldehyde oxidase: an enzyme of emerging importance in novel drug discovery.
[So] Source:Expert Opin Drug Discov;12(3):305-316, 2017 Mar.
[Is] ISSN:1746-045X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Given the rising trend in medicinal chemistry strategy to reduce cytochrome P450-dependent metabolism, aldehyde oxidase (AOX) has recently gained increased attention in drug discovery programs and the number of drug candidates that are metabolized by AOX is steadily growing. Areas covered: Despite the emerging importance of AOX in drug discovery, there are certain major recognized problems associated with AOX-mediated metabolism of drugs. Intra- and inter-species variations in AOX activity, the lack of reliable and predictive animal models using the common experimental animals, and failure in the predictions of in vivo metabolic activity of AOX using traditional in vitro methods are among these issues that are covered in this article. A comprehensive review of computational human AOX (hAOX) related studies are also provided. Expert opinion: Following the recent progress in the stem cell field, the authors recommend the application of organoids technology as an effective tool to solve the fundamental problems associated with the evaluation of AOX in drug discovery. The recent success in resolving the hAOX crystal structure can too be another valuable data source for the study of AOX-catalyzed metabolism of new drug candidates, using computer-aided drug discovery methods.
[Mh] Termos MeSH primário: Aldeído Oxidase/metabolismo
Desenho de Drogas
Descoberta de Drogas/métodos
[Mh] Termos MeSH secundário: Aldeído Oxidase/química
Animais
Simulação por Computador
Projeto Auxiliado por Computador
Seres Humanos
Preparações Farmacêuticas/metabolismo
Especificidade da Espécie
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Pharmaceutical Preparations); EC 1.2.3.1 (Aldehyde Oxidase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170605
[Lr] Data última revisão:
170605
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170119
[St] Status:MEDLINE
[do] DOI:10.1080/17460441.2017.1284198


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[PMID]:27736754
[Au] Autor:Madelain V; Guedj J; Mentré F; Nguyen TH; Jacquot F; Oestereich L; Kadota T; Yamada K; Taburet AM; de Lamballerie X; Raoul H
[Ad] Endereço:IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France vincent.madelain@inserm.fr.
[Ti] Título:Favipiravir Pharmacokinetics in Nonhuman Primates and Insights for Future Efficacy Studies of Hemorrhagic Fever Viruses.
[So] Source:Antimicrob Agents Chemother;61(1), 2017 Jan.
[Is] ISSN:1098-6596
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Favipiravir is an RNA polymerase inhibitor that showed strong antiviral efficacy in vitro and in small-animal models of several viruses responsible for hemorrhagic fever (HF), including Ebola virus. The aim of this work was to characterize the complex pharmacokinetics of favipiravir in nonhuman primates (NHPs) in order to guide future efficacy studies of favipiravir in large-animal models. Four different studies were conducted in 30 uninfected cynomolgus macaques of Chinese (n = 17) or Mauritian (n = 13) origin treated with intravenous favipiravir for 7 to 14 days with maintenance doses of 60 to 180 mg/kg of body weight twice a day (BID). A pharmacokinetic model was developed to predict the plasma concentrations obtained with different dosing regimens, and the model predictions were compared to the 50% effective concentration (EC ) of favipiravir against several viruses. Favipiravir pharmacokinetics were described by a model accounting for concentration-dependent aldehyde oxidase inhibition. The enzyme-dependent elimination rate increased over time and was higher in NHPs of Mauritian origin than in those of Chinese origin. Maintenance doses of 100 and 120 mg/kg BID in Chinese and Mauritian NHPs, respectively, are predicted to achieve median trough plasma free concentrations above the EC for Lassa and Marburg viruses until day 7. For Ebola virus, higher doses are required. After day 7, a 20% dose increase is needed to compensate for the increase in drug clearance over time. These results will help rationalize the choice of dosing regimens in future studies evaluating the antiviral effect of favipiravir in NHPs and support its development against a variety of HF viruses.
[Mh] Termos MeSH primário: Amidas/uso terapêutico
Antivirais/uso terapêutico
Febres Hemorrágicas Virais/tratamento farmacológico
Pirazinas/uso terapêutico
[Mh] Termos MeSH secundário: Administração Intravenosa
Aldeído Oxidase/metabolismo
Animais
Cercopithecus aethiops
Ebolavirus/efeitos dos fármacos
Ebolavirus/patogenicidade
Febres Hemorrágicas Virais/virologia
Primatas
Células Vero
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Antiviral Agents); 0 (Pyrazines); EC 1.2.3.1 (Aldehyde Oxidase); EW5GL2X7E0 (favipiravir)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161014
[St] Status:MEDLINE


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[PMID]:27618572
[Au] Autor:Hayes A; Mok NY; Liu M; Thai C; Henley AT; Atrash B; Lanigan RM; Sejberg J; Le Bihan YV; Bavetsias V; Blagg J; Raynaud FI
[Ad] Endereço:a Cancer Research UK Cancer Therapeutics Unit , The Institute of Cancer Research , London , UK.
[Ti] Título:Pyrido[3,4-d]pyrimidin-4(3H)-one metabolism mediated by aldehyde oxidase is blocked by C2-substitution.
[So] Source:Xenobiotica;47(9):771-777, 2017 Sep.
[Is] ISSN:1366-5928
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:1. We have previously described C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as cell permeable inhibitors of the KDM4 and KDM5 subfamilies of JmjC histone lysine demethylases. 2. Although exemplar compound 1 exhibited moderate clearance in mouse liver microsomes, it was highly cleared in vivo due to metabolism by aldehyde oxidase (AO). Similar human and mouse AO-mediated metabolism was observed with the pyrido[3,4-d]pyrimidin-4(3H)-one scaffold and other C8-substituted derivatives. 3. We identified the C2-position as the oxidation site by LC-MS and H-NMR and showed that C2-substituted derivatives are no longer AO substrates. 4. In addition to the experimental data, these observations are supported by molecular modelling studies in the human AO protein crystal structure.
[Mh] Termos MeSH primário: Aldeído Oxidase/antagonistas & inibidores
Pirimidinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Camundongos
Modelos Moleculares
Espectroscopia de Prótons por Ressonância Magnética
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Pyrimidines); EC 1.2.3.1 (Aldehyde Oxidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170929
[Lr] Data última revisão:
170929
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160913
[St] Status:MEDLINE
[do] DOI:10.1080/00498254.2016.1230245



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