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Pesquisa : D08.811.682.690.416.330 [Categoria DeCS]
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[PMID]:28128559
[Au] Autor:Santucci A; Bernardini G; Braconi D; Petricci E; Manetti F
[Ad] Endereço:Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena , via A. Moro 2, I-53100 Siena, Italy.
[Ti] Título:4-Hydroxyphenylpyruvate Dioxygenase and Its Inhibition in Plants and Animals: Small Molecules as Herbicides and Agents for the Treatment of Human Inherited Diseases.
[So] Source:J Med Chem;60(10):4101-4125, 2017 May 25.
[Is] ISSN:1520-4804
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:This review mainly focuses on the physiological function of 4-hydroxyphenylpyruvate dioxygenase (HPPD), as well as on the development and application of HPPD inhibitors of several structural classes. Among them, one illustrative example is represented by compounds belonging to the class of triketone compounds. They were discovered by serendipitous observations on weed growth and were developed as bleaching herbicides. Informed reasoning on nitisinone (NTBC, 14), a triketone that failed to reach the final steps of the herbicidal design and development process, allowed it to become a curative agent for type I tyrosinemia (T1T) and to enter clinical trials for alkaptonuria. These results boosted the research of new compounds able to interfere with HPPD activity to be used for the treatment of the tyrosine metabolism-related diseases.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Descoberta de Drogas
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Herbicidas/química
Bibliotecas de Moléculas Pequenas/química
Bibliotecas de Moléculas Pequenas/farmacologia
Controle de Plantas Daninhas
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Alcaptonúria/tratamento farmacológico
Alcaptonúria/enzimologia
Animais
Descoberta de Drogas/métodos
Inibidores Enzimáticos/farmacocinética
Inibidores Enzimáticos/uso terapêutico
Herbicidas/metabolismo
Seres Humanos
Modelos Moleculares
Plantas/efeitos dos fármacos
Plantas/enzimologia
Bibliotecas de Moléculas Pequenas/farmacocinética
Bibliotecas de Moléculas Pequenas/uso terapêutico
Tirosinemias/tratamento farmacológico
Tirosinemias/enzimologia
Controle de Plantas Daninhas/métodos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Herbicides); 0 (Small Molecule Libraries); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase)
[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
[do] DOI:10.1021/acs.jmedchem.6b01395


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[PMID]:27305933
[Au] Autor:Ward JP; Dunster JL; Derks G; Mistry P; Salazar JD
[Ad] Endereço:Department of Mathematical Sciences, Loughborough University, Loughborough LE11 3TU, UK.
[Ti] Título:Predicting tyrosinaemia: a mathematical model of 4-hydroxyphenylpyruvate dioxygenase inhibition by nitisinone in rats.
[So] Source:Math Med Biol;34(3):335-390, 2017 Sep 01.
[Is] ISSN:1477-8602
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nitisinone or 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione is a reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme important in tyrosine catabolism. Today, nitisinone is successfully used to treat Hereditary Tyrosinaemia type 1, although its original expected role was as a herbicide. In laboratory animals, treatment with nitisinone leads to the elevation of plasma tyrosine (tyrosinaemia). In rats and Beagle dogs, repeat low-dose exposure to nitisinone leads to corneal opacities whilst similar studies in the mouse and Rhesus monkey showed no comparable toxicities or other treatment related findings. The differences in toxicological sensitivities have been related to the upper limit of the concentration of tyrosine that accumulates in plasma, which is driven by the amount/activity of tyrosine aminotransferase. A physiologically based, pharmacodynamics ordinary differential equation model of HPPD inhibition to bolus exposure of nitisinone in vivo is presented. Going beyond traditional approaches, asymptotic analysis is used to separate the different timescales of events involved in HPPD inhibition and tyrosinaemia. This analysis elucidates, in terms of the model parameters, a critical inhibitor concentration (at which tyrosine concentration starts to rise) and highlights the contribution of in vitro measured parameters to events in an in vivo system. Furthermore, using parameter-fitting methods, a systematically derived reduced model is shown to fit well to rat data, making explicit how the parameters are informed by such data. This model in combination with in vitro descriptors has potential as a surrogate for animal experimentation to predict tyrosinaemia, and further development can extend its application to other related medical scenarios.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Cicloexanonas/efeitos adversos
Modelos Biológicos
Nitrobenzoatos/efeitos adversos
Tirosinemias/etiologia
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Animais
Simulação por Computador
Cicloexanonas/administração & dosagem
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Cinética
Fígado/efeitos dos fármacos
Fígado/metabolismo
Conceitos Matemáticos
Modelos Animais
Nitrobenzoatos/administração & dosagem
Ratos
Tirosina/metabolismo
Tirosinemias/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Nitrobenzoates); 42HK56048U (Tyrosine); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); K5BN214699 (nitisinone)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160617
[St] Status:MEDLINE
[do] DOI:10.1093/imammb/dqw006


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[PMID]:27933872
[Au] Autor:Wang DW; Lin HY; He B; Wu FX; Chen T; Chen Q; Yang WC; Yang GF
[Ad] Endereço:Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University , Wuhan 430079, People's Republic of China.
[Ti] Título:An Efficient One-Pot Synthesis of 2-(Aryloxyacetyl)cyclohexane-1,3-diones as Herbicidal 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.
[So] Source:J Agric Food Chem;64(47):8986-8993, 2016 Nov 30.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is an important target for new bleaching herbicides discovery. As a continuous work to discover novel crop selective HPPD inhibitor, a series of 2-(aryloxyacetyl)cyclohexane-1,3-diones were rationally designed and synthesized by an efficient one-pot procedure using N,N'-carbonyldiimidazole (CDI), triethylamine, and acetone cyanohydrin in CH Cl . A total of 58 triketone compounds were synthesized in good to excellent yields. Some of the triketones displayed potent in vitro Arabidopsis thaliana HPPD (AtHPPD) inhibitory activity. 2-(2-((1-Bromonaphthalen-2-yl)oxy)acetyl)-3-hydroxycyclohex-2-en-1-one, II-13, displayed high, broad-spectrum, and postemergent herbicidal activity at the dosage of 37.5-150 g ai/ha, nearly as potent as mesotrione against some weeds. Furthermore, II-13 showed good crop safety against maize and canola at the rate of 150 g ai/ha, indicating that II-13 might have potential as a herbicide for weed control in maize and canola fields. II-13 is the first HPPD inhibitor showing good crop safety toward canola.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Cicloexanonas/síntese química
Inibidores Enzimáticos/síntese química
Herbicidas/síntese química
Naftalenos/síntese química
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Arabidopsis/efeitos dos fármacos
Brassica rapa/efeitos dos fármacos
Cicloexanonas/química
Relação Dose-Resposta a Droga
Etilaminas/química
Imidazóis/química
Estrutura Molecular
Nitrilos/química
Plantas Daninhas/efeitos dos fármacos
Relação Estrutura-Atividade
Controle de Plantas Daninhas
Zea mays/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2-((1-bromonaphthalen-2-yl)oxy)acetyl)-3-hydroxycyclohex-2-en-1-one); 0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Ethylamines); 0 (Herbicides); 0 (Imidazoles); 0 (Naphthalenes); 0 (Nitriles); 48TR68G21T (mesotrione); 63A10X1FSP (N,N-carbonyldiimidazole); CO1YOV1KFI (acetone cyanohydrin); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); VOU728O6AY (triethylamine)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170502
[Lr] Data última revisão:
170502
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE


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[PMID]:27701365
[Ti] Título:In brief: Nitisinone (Orfadin) for hereditary tyrosinemia.
[So] Source:Med Lett Drugs Ther;58(1505):e132, 2016 Oct 10.
[Is] ISSN:1523-2859
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Cicloexanonas/uso terapêutico
Inibidores Enzimáticos/uso terapêutico
Nitrobenzoatos/uso terapêutico
Tirosinemias/tratamento farmacológico
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Administração Oral
Cápsulas
Cicloexanonas/administração & dosagem
Cicloexanonas/efeitos adversos
Esquema de Medicação
Inibidores Enzimáticos/administração & dosagem
Inibidores Enzimáticos/efeitos adversos
Seres Humanos
Nitrobenzoatos/administração & dosagem
Nitrobenzoatos/efeitos adversos
Soluções Farmacêuticas
Resultado do Tratamento
Tirosinemias/diagnóstico
Tirosinemias/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Capsules); 0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Nitrobenzoates); 0 (Pharmaceutical Solutions); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); K5BN214699 (nitisinone)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:161005
[St] Status:MEDLINE


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[PMID]:27660165
[Au] Autor:Stacey MG; Cahoon RE; Nguyen HT; Cui Y; Sato S; Nguyen CT; Phoka N; Clark KM; Liang Y; Forrester J; Batek J; Do PT; Sleper DA; Clemente TE; Cahoon EB; Stacey G
[Ad] Endereço:Division of Plant Sciences (M.G.S., Y.C., C.T.N., K.M.C., Y.L., J.B., P.T.D., D.A.S., G.S.), Division of Biochemistry (G.S.), and DNA Core Facility (J.F.), University of Missouri, Columbia, Missouri 65211; and staceym@missouri.edu.
[Ti] Título:Identification of Homogentisate Dioxygenase as a Target for Vitamin E Biofortification in Oilseeds.
[So] Source:Plant Physiol;172(3):1506-1518, 2016 Nov.
[Is] ISSN:1532-2548
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Soybean (Glycine max) is a major plant source of protein and oil and produces important secondary metabolites beneficial for human health. As a tool for gene function discovery and improvement of this important crop, a mutant population was generated using fast neutron irradiation. Visual screening of mutagenized seeds identified a mutant line, designated MO12, which produced brown seeds as opposed to the yellow seeds produced by the unmodified Williams 82 parental cultivar. Using forward genetic methods combined with comparative genome hybridization analysis, we were able to establish that deletion of the GmHGO1 gene is the genetic basis of the brown seeded phenotype exhibited by the MO12 mutant line. GmHGO1 encodes a homogentisate dioxygenase (HGO), which catalyzes the committed enzymatic step in homogentisate catabolism. This report describes to our knowledge the first functional characterization of a plant HGO gene, defects of which are linked to the human genetic disease alkaptonuria. We show that reduced homogentisate catabolism in a soybean HGO mutant is an effective strategy for enhancing the production of lipid-soluble antioxidants such as vitamin E, as well as tolerance to herbicides that target pathways associated with homogentisate metabolism. Furthermore, this work demonstrates the utility of fast neutron mutagenesis in identifying novel genes that contribute to soybean agronomic traits.
[Mh] Termos MeSH primário: Biofortificação
Homogentisato 1,2-Dioxigenase/metabolismo
Óleos Vegetais/metabolismo
Sementes/enzimologia
Feijão de Soja/enzimologia
Vitamina E/metabolismo
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Adaptação Fisiológica/efeitos dos fármacos
Arabidopsis/genética
Inibidores Enzimáticos/toxicidade
Deleção de Genes
Genoma de Planta
Herbicidas/toxicidade
Ácido Homogentísico/metabolismo
Isoenzimas/metabolismo
Redes e Vias Metabólicas/efeitos dos fármacos
Mutação/genética
Fenótipo
Células Vegetais/efeitos dos fármacos
Células Vegetais/metabolismo
Feijão de Soja/efeitos dos fármacos
Feijão de Soja/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Herbicides); 0 (Isoenzymes); 0 (Plant Oils); 1406-18-4 (Vitamin E); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); EC 1.13.11.5 (Homogentisate 1,2-Dioxygenase); NP8UE6VF08 (Homogentisic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171003
[Lr] Data última revisão:
171003
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160924
[St] Status:MEDLINE


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[PMID]:27073170
[Au] Autor:Shreeram S; Ramesh S; Puthan JK; Balakrishnan G; Subramanian R; Reddy MT; Pereira SL
[Ad] Endereço:Abbott Nutrition Research and Development, 20 Biopolis Way, Singapore 138668. Electronic address: shreeram.sathya@abbott.com.
[Ti] Título:Age associated decline in the conversion of leucine to ß-Hydroxy-ß-Methylbutyrate in rats.
[So] Source:Exp Gerontol;80:6-11, 2016 Jul.
[Is] ISSN:1873-6815
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The loss of muscle mass is considered to be a major factor contributing to strength decline during aging. ß-Hydroxy-ß-Methylbutyrate (HMB), a metabolite of leucine has been shown to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. However, the production and regulation of endogenous levels of HMB over the lifespan have not been investigated. OBJECTIVE: The objective of the present study was to do a cross-sectional analysis of the basal plasma levels of HMB in male Sprague-Dawley rats of different ages and to compare the efficiency of conversion of leucine to HMB in young versus older rats. METHODS: Plasma levels of HMB and α-ketoisocaproate (KIC) were analyzed in rats of different age groups (3, 9, 12 and 24months old, n=10 per group). Levels of 4-HPPD, the enzyme involved in the conversion of KIC to HMB in the liver were determined by ELISA. The conversion efficiency of leucine to HMB was compared between 3 and 24month rats after an oral bolus dose of leucine. RESULTS: Endogenous circulating levels of HMB were significantly reduced in older age rats compared to young rats (100±3.7 vs 156±10 (mean±SEM), ng/mL, p<0.001). A significant negative correlation was seen between HMB levels and age. The liver levels of 4-HPPD were found to be significantly lower in old versus young rats. Consistent with this, the conversion efficiency of leucine to HMB was significantly lower in the aged versus young cohorts. CONCLUSIONS: In summary, this study depicts for the first time that the basal levels of HMB, a metabolite of amino acid leucine, declines with age, and that this decline is due to perturbations in the key enzyme 4-HPPD which catalyzes the conversion of KIC to HMB. As a consequence, the efficiency of conversion of leucine to HMB is diminished in older rats compared to younger rats.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Envelhecimento/fisiologia
Cetoácidos/sangue
Leucina/metabolismo
Valeratos/sangue
[Mh] Termos MeSH secundário: Animais
Suplementos Nutricionais
Seres Humanos
Fígado/metabolismo
Masculino
Músculo Esquelético/metabolismo
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Keto Acids); 0 (Valerates); 3F752311CD (beta-hydroxyisovaleric acid); 816-66-0 (alpha-ketoisocaproic acid); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); GMW67QNF9C (Leucine)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170928
[Lr] Data última revisão:
170928
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160414
[St] Status:MEDLINE


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[PMID]:26947423
[Au] Autor:Laschi M; Bernardini G; Dreassi E; Millucci L; Geminiani M; Braconi D; Marzocchi B; Botta M; Manetti F; Santucci A
[Ad] Endereço:Department of Biotechnology, Chemistry and Pharmacy, Università degli Studi di Siena, Via Aldo Moro 2, 53100, Siena, Italy.
[Ti] Título:Inhibition of para-Hydroxyphenylpyruvate Dioxygenase by Analogues of the Herbicide Nitisinone As a Strategy to Decrease Homogentisic Acid Levels, the Causative Agent of Alkaptonuria.
[So] Source:ChemMedChem;11(7):674-8, 2016 Apr 05.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Alkaptonuria (AKU) is a rare multisystem metabolic disease caused by deficient activity of homogentisate 1,2-dioxygenase (HGD), which leads to the accumulation of homogentisic acid (HGA). Currently, there is no treatment for AKU. The sole drug with some beneficial effects is the herbicide nitisinone (1), an inhibitor of p-hydroxyphenylpyruvate dioxygenase (4-HPPD). 1 has been used as a life-saving drug in infants with type I tyrosinemia despite severe side effects due to the buildup of tyrosine. Four clinical trials of nitisinone to treat AKU have shown that 1 consistently decreases HGA levels, but also caused the accumulation of tyrosine in blood serum. Moreover, the human preclinical toxicological data for 1 are incomplete. In this work, we performed pharmacodynamics and toxicological evaluations of 1, providing the first report of LD50 values in human cells. Intracellular tyrosinemia was also evaluated. Three additional 4-HPPD inhibitors with a more favorable profile than that of 1 in terms of IC50, LD50, and tyrosine accumulation were also identified among commercially available compounds. These may be promising starting points for the development of new therapeutic strategies for the treatment of AKU.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Alcaptonúria/tratamento farmacológico
Cicloexanonas/química
Cicloexanonas/farmacologia
Herbicidas/química
Herbicidas/farmacologia
Ácido Homogentísico/metabolismo
Nitrobenzoatos/química
Nitrobenzoatos/farmacologia
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/metabolismo
Alcaptonúria/metabolismo
Animais
Sobrevivência Celular/efeitos dos fármacos
Cicloexanonas/síntese química
Relação Dose-Resposta a Droga
Herbicidas/síntese química
Seres Humanos
Masculino
Estrutura Molecular
Nitrobenzoatos/síntese química
Ratos
Ratos Wistar
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (Herbicides); 0 (Nitrobenzoates); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase); K5BN214699 (nitisinone); NP8UE6VF08 (Homogentisic Acid)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160308
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201500578


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[PMID]:26936969
[Au] Autor:Huang CW; Liu HC; Shen CP; Chen YT; Lee SJ; Lloyd MD; Lee HJ
[Ad] Endereço:Pharmacy Division, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
[Ti] Título:The different catalytic roles of the metal-binding ligands in human 4-hydroxyphenylpyruvate dioxygenase.
[So] Source:Biochem J;473(9):1179-89, 2016 May 01.
[Is] ISSN:1470-8728
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a non-haem iron(II)-dependent oxygenase that catalyses the conversion of 4-hydroxyphenylpyruvate (HPP) to homogentisate (HG). In the active site, a strictly conserved 2-His-1-Glu facial triad co-ordinates the iron ready for catalysis. Substitution of these residues resulted in about a 10-fold decrease in the metal binding affinity, as measured by isothermal titration calorimetry, and a large reduction in enzyme catalytic efficiencies. The present study revealed the vital role of the ligand Glu(349) in enzyme function. Replacing this residue with alanine resulted in loss of activity. The E349G variant retained 5% activity for the coupled reaction, suggesting that co-ordinating water may be able to support activation of the trans-bound dioxygen upon substrate binding. The reaction catalysed by the H183A variant was fully uncoupled. H183A variant catalytic activity resulted in protein cleavage between Ile(267) and Ala(268) and the production of an N-terminal fragment. The H266A variant was able to produce 4-hydroxyphenylacetate (HPA), demonstrating that decarboxylation had occurred but that there was no subsequent product formation. Structural modelling of the variant enzyme with bound dioxygen revealed the rearrangement of the co-ordination environment and the dynamic behaviour of bound dioxygen in the H266A and H183A variants respectively. These models suggest that the residues regulate the geometry of the reactive oxygen intermediate during the oxidation reaction. The mutagenesis and structural simulation studies demonstrate the critical and unique role of each ligand in the function of HPPD, and which correlates with their respective co-ordination position.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/química
Ferro/química
Modelos Moleculares
Mutação de Sentido Incorreto
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/genética
Substituição de Aminoácidos
Seres Humanos
Ferro/metabolismo
Ligantes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Ligands); E1UOL152H7 (Iron); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170608
[Lr] Data última revisão:
170608
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160304
[St] Status:MEDLINE
[do] DOI:10.1042/BCJ20160146


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[PMID]:26731565
[Au] Autor:Killeen DP; Larsen L; Dayan FE; Gordon KC; Perry NB; van Klink JW
[Ti] Título:Nortriketones: Antimicrobial Trimethylated Acylphloroglucinols from MaÌ…nuka (Leptospermum scoparium).
[So] Source:J Nat Prod;79(3):564-9, 2016 Mar 25.
[Is] ISSN:1520-6025
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Four trimethylated acylphloroglucinols (5-8) have been isolated from maÌ…nuka (Leptospermum scoparium) foliage. Apart from myrigalone A (8), which has previously been isolated from European bog myrtle (Myrica gale), these compounds have not been characterized before. The nortriketones are structurally similar to the bioactive tetramethylated ß-triketones from maÌ…nuka, but have one less ring methyl group. Two oxidized trimethylated compounds, 9 and 10, were also isolated, but these are likely isolation artifacts. When evaluated for antibacterial activity against Gram-positive bacteria, myrigalone A (8) was slightly less potent (MIC 64 µg/mL) than the corresponding tetramethylated compound, grandiflorone (4) (MIC 16-32 µg/mL). Unlike their tetramethylated analogues, the nortriketones were inactive against the herbicide target enzyme p-hydroxyphenylpyruvate dioxygenase. The Raman spectra of leaf oil glands in different maÌ…nuka varieties can be used to distinguish plants that contain nortriketones from those that accumulate triketones.
[Mh] Termos MeSH primário: Anti-Infecciosos/isolamento & purificação
Leptospermum/química
Floroglucinol
[Mh] Termos MeSH secundário: 4-Hidroxifenilpiruvato Dioxigenase/efeitos dos fármacos
Antibacterianos
Anti-Infecciosos/química
Anti-Infecciosos/farmacologia
Chalconas/química
Chalconas/isolamento & purificação
Chalconas/farmacologia
Farmacorresistência Bacteriana/efeitos dos fármacos
Enterococcus faecalis/efeitos dos fármacos
Escherichia coli/efeitos dos fármacos
Cromatografia Gasosa-Espectrometria de Massas
Bactérias Gram-Positivas
Herbicidas
Cetonas/análise
Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Nova Zelândia
Ressonância Magnética Nuclear Biomolecular
Ácidos Fenilpirúvicos
Floroglucinol/análogos & derivados
Floroglucinol/química
Floroglucinol/isolamento & purificação
Floroglucinol/farmacologia
Folhas de Planta/química
Vancomicina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Anti-Infective Agents); 0 (Chalcones); 0 (Herbicides); 0 (Ketones); 0 (Phenylpyruvic Acids); 0 (myrigalone A); 156-39-8 (4-hydroxyphenylpyruvic acid); 6Q205EH1VU (Vancomycin); DHD7FFG6YS (Phloroglucinol); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:160325
[Lr] Data última revisão:
160325
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160106
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jnatprod.5b00968


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[PMID]:26695298
[Au] Autor:Rocaboy-Faquet E; Barthelmebs L; Calas-Blanchard C; Noguer T
[Ad] Endereço:Laboratoire BAE, Université de Perpignan Via Domitia, 52 Avenue Paul Alduy, 66860 Perpignan cedex 9, France.
[Ti] Título:A novel amperometric biosensor for ß-triketone herbicides based on hydroxyphenylpyruvate dioxygenase inhibition: A case study for sulcotrione.
[So] Source:Talanta;146:510-6, 2016.
[Is] ISSN:1873-3573
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:An amperometric biosensor was designed for the determination of sulcotrione, a ß-triketone herbicide, based on inhibition of hydroxyphenylpyruvate dioxygenase (HPPD), an enzyme allowing the oxidation of hydroxyphenylpyruvate (HPP) in homogentisic acid (HGA). HPPD was produced by cloning the hppd gene from Arabidopsis thaliana in E. coli, followed by overexpression and purification by nickel-histidine affinity. The electrochemical detection of HPPD activity was based on the electrochemical oxidation of HGA at +0.1 V vs. Ag/AgCl, using a poly(3,4-ethylenedioxythiophene) polystyrene sulfonate-modified screen-printed electrode. Assays were performed at 25°C in 0.1 M phosphate buffer pH 8 containing 0.1M KCl. The purified HPPD was shown to display a maximum velocity of 0.51 µM(HGA) min(-1), and an apparent K(M) of 22.6 µM for HPP. HPPD inhibition assays in presence of sulcotrione confirmed a competitive inhibition of HPPD, the calculated inhibition constant K(I) was 1.11.10(-8) M. The dynamic range for sulcotrione extended from 5.10(-10) M to 5.10(-6) M and the limit of detection (LOD), estimated as the concentration inducing 20% of inhibition, was 1.4.10(-10) M.
[Mh] Termos MeSH primário: 4-Hidroxifenilpiruvato Dioxigenase/antagonistas & inibidores
Técnicas Biossensoriais/métodos
Cicloexanonas/análise
Inibidores Enzimáticos/análise
Herbicidas/análise
Mesilatos/análise
[Mh] Termos MeSH secundário: Arabidopsis/enzimologia
Calibragem
Cicloexanonas/farmacologia
Eletroquímica
Inibidores Enzimáticos/farmacologia
Herbicidas/farmacologia
Limite de Detecção
Mesilatos/farmacologia
Poliestirenos/química
Tiofenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclohexanones); 0 (Enzyme Inhibitors); 0 (Herbicides); 0 (Mesylates); 0 (Polystyrenes); 0 (Thiophenes); 0 (poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonate)); 5UEH9SXW7V (sulcotrione); EC 1.13.11.27 (4-Hydroxyphenylpyruvate Dioxygenase)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151224
[St] Status:MEDLINE



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