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  1 / 8213 MEDLINE  
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[PMID]:28463568
[Au] Autor:Salinas G; Gao W; Wang Y; Bonilla M; Yu L; Novikov A; Virginio VG; Ferreira HB; Vieites M; Gladyshev VN; Gambino D; Dai S
[Ad] Endereço:1 Worm Biology Lab, Institut Pasteur de Montevideo , Montevideo, Uruguay .
[Ti] Título:The Enzymatic and Structural Basis for Inhibition of Echinococcus granulosus Thioredoxin Glutathione Reductase by Gold(I).
[So] Source:Antioxid Redox Signal;27(18):1491-1504, 2017 Dec 20.
[Is] ISSN:1557-7716
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIMS: New drugs are needed to treat flatworm infections that cause severe human diseases such as schistosomiasis. The unique flatworm enzyme thioredoxin glutathione reductase (TGR), structurally different from the human enzyme, is a key drug target. Structural studies of the flatworm Echinococcus granulosus TGR, free and complexed with Au -MPO, a novel gold inhibitor, together with inhibition assays were performed. RESULTS: Au -MPO is a potent TGR inhibitor that achieves 75% inhibition at a 1:1 TGR:Au ratio and efficiently kills E. granulosus in vitro. The structures revealed salient insights: (i) unique monomer-monomer interactions, (ii) distinct binding sites for thioredoxin and the glutaredoxin (Grx) domain, (iii) a single glutathione disulfide reduction site in the Grx domain, (iv) rotation of the Grx domain toward the Sec-containing redox active site, and (v) a single gold atom bound to Cys and Cys in the Au -TGR complex. Structural modeling suggests that these residues are involved in the stabilization of the Sec-containing C-terminus. Consistently, Cys→Ser mutations in these residues decreased TGR activities. Mass spectroscopy confirmed these cysteines are the primary binding site. INNOVATION: The identification of a primary site for gold binding and the structural model provide a basis for gold compound optimization through scaffold adjustments. CONCLUSIONS: The structural study revealed that TGR functions are achieved not only through a mobile Sec-containing redox center but also by rotation of the Grx domain and distinct binding sites for Grx domain and thioredoxin. The conserved Cys and Cys residues targeted by gold assist catalysis through stabilization of the Sec-containing redox center. Antioxid. Redox Signal. 27, 1491-1504.
[Mh] Termos MeSH primário: Echinococcus granulosus/enzimologia
Complexos Multienzimáticos/química
Complexos Multienzimáticos/metabolismo
NADH NADPH Oxirredutases/química
NADH NADPH Oxirredutases/metabolismo
Compostos Organoáuricos/farmacologia
[Mh] Termos MeSH secundário: Animais
Sítios de Ligação/efeitos dos fármacos
Cisteína/metabolismo
Echinococcus granulosus/química
Echinococcus granulosus/genética
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacocinética
Glutarredoxinas/metabolismo
Proteínas de Helminto/química
Proteínas de Helminto/genética
Proteínas de Helminto/metabolismo
Modelos Moleculares
Complexos Multienzimáticos/genética
Mutação
NADH NADPH Oxirredutases/genética
Compostos Organoáuricos/química
Ligação Proteica
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Glutaredoxins); 0 (Helminth Proteins); 0 (Multienzyme Complexes); 0 (Organogold Compounds); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.4.- (thioredoxin glutathione reductase); K848JZ4886 (Cysteine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1089/ars.2016.6816


  2 / 8213 MEDLINE  
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[PMID]:29176870
[Au] Autor:Negi B; Salvi P; Bhatt D; Majee M; Arora S
[Ad] Endereço:Department of Molecular Biology and Genetic Engineering, College of Basic Sciences and Humanities, G. B. Pant University of Agriculture and Technology, Pantnagar, Uttarakhand, India.
[Ti] Título:Molecular cloning, in-silico characterization and functional validation of monodehydroascorbate reductase gene in Eleusine coracana.
[So] Source:PLoS One;12(11):e0187793, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ascorbic acid is a ubiquitous water soluble antioxidant that plays a critical role in plant growth and environmental stress tolerance. It acts as a free radical scavenger as well as a source of reducing power for several cellular processes. Because of its pivotal role in regulating plant growth under optimal as well as sub-optimal conditions, it becomes obligatory for plants to maintain a pool of reduced ascorbic acid. Several cellular processes help in maintaining the reduced ascorbic acid pool, by regulating its synthesis and regeneration processes. Current study demonstrates that monodehydroascorbate reductase is an important enzyme responsible for maintaining the reduced ascorbate pool, by optimizing the recycling of oxidized ascorbate. Cloning and functional characterization of this important stress inducible gene is of great significance for its imperative use in plant stress management. Therefore, we have cloned and functionally validated the role of monodehydroascorbate reductase gene (mdar) from a drought tolerant variety of Eleusine coracana. The cloned Ecmdar gene comprises of 1437bp CDS, encoding a 478 amino acid long polypeptide. The active site analysis showed presence of conserved Tyr348 residue, facilitating the catalytic activity in electron transfer mechanism. qPCR expression profiling of Ecmdar under stress indicated that it is an early responsive gene. The analysis of Ecmdar overexpressing Arabidopsis transgenic lines suggests that monodehydroascorbate reductase acts as a key stress regulator by modulating the activity of antioxidant enzymes to strengthen the ROS scavenging ability and maintains ROS homeostasis. Thus, it is evident that Ecmdar is an important gene for cellular homeostasis and its over-expression could be successfully used to strengthen stress tolerance in crop plants.
[Mh] Termos MeSH primário: Simulação por Computador
Eleusine/enzimologia
Eleusine/genética
Genes de Plantas
NADH NADPH Oxirredutases/genética
NADH NADPH Oxirredutases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Arabidopsis/genética
Sequência de Bases
Domínio Catalítico
Clonagem Molecular
Sequência Conservada
DNA Complementar/genética
Escherichia coli/metabolismo
Regulação da Expressão Gênica de Plantas
Modelos Moleculares
Anotação de Sequência Molecular
NADH NADPH Oxirredutases/química
NADH NADPH Oxirredutases/isolamento & purificação
Fenótipo
Filogenia
Proteínas de Plantas/química
Proteínas de Plantas/genética
Proteínas de Plantas/isolamento & purificação
Proteínas de Plantas/metabolismo
Prolina/metabolismo
Regiões Promotoras Genéticas/genética
Ligação Proteica
Domínios Proteicos
Processamento de Proteína Pós-Traducional
Reprodutibilidade dos Testes
Alinhamento de Sequência
Homologia de Sequência do Ácido Nucleico
Estresse Fisiológico/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Complementary); 0 (Plant Proteins); 9DLQ4CIU6V (Proline); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.5.4 (monodehydroascorbate reductase (NADH))
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0187793


  3 / 8213 MEDLINE  
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Steindel, Mário
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[PMID]:28926763
[Au] Autor:Hartmann AP; de Carvalho MR; Bernardes LSC; Moraes MH; de Melo EB; Lopes CD; Steindel M; da Silva JS; Carvalho I
[Ad] Endereço:School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. Café s/n, Ribeirão Preto, SP 14040-930, Brazil.
[Ti] Título:Synthesis and 2D-QSAR studies of neolignan-based diaryl-tetrahydrofuran and -furan analogues with remarkable activity against Trypanosoma cruzi and assessment of the trypanothione reductase activity.
[So] Source:Eur J Med Chem;140:187-199, 2017 Nov 10.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Two series of diaryl-tetrahydrofuran and -furan were synthesised and screened for anti-trypanosomal activity against trypomastigote and amastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. Based on evidence that modification of a natural product may result in a more effective drug than the natural product itself, and using known neolignan inhibitors veraguensin 1 and grandisin 2 as templates to synthesise simpler analogues, remarkable anti-trypanosomal activity and selectivity were found for 3,5-dimethoxylated diaryl-furan 5c and 2,4-dimethoxylated diaryl-tetrahydrofuran 4e analogues with EC 0.01 µM and EC 0.75 µM, respectively, the former being 260-fold more potent than veraguensin 1 and 150-fold better than benznidazole, the current available drugs for Chagas disease treatment. The ability of the most potent anti-trypanosomal compounds to penetrate LLC-MK2 cells infected with T. cruzi amastigotes parasite was tested, which revealed 4e and 5e analogues as the most effective, causing no damage to mammalian cells. In particular, the majority of the derivatives were non-toxic against mice spleen cells. 2D-QSAR studies show the rigid central core and the position of dimethoxy-aryl substituents dramatically affect the anti-trypanosomal activity. The mode of action of the most active anti-trypanosomal derivatives was investigated by exploring the anti-oxidant functions of Trypanothione reductase (TR). As a result, diarylfuran series displayed the strongest inhibition, highlighting compounds 5d-e (IC 19.2 and 17.7 µM) and 5f-g (IC 8.9 and 7.4 µM), respectively, with similar or 2-fold higher than the reference inhibitor clomipramine (IC 15.2 µM).
[Mh] Termos MeSH primário: Inibidores Enzimáticos/farmacologia
Furanos/farmacologia
Lignanas/farmacologia
NADH NADPH Oxirredutases/antagonistas & inibidores
Tripanossomicidas/farmacologia
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Furanos/síntese química
Furanos/química
Lignanas/química
Macaca mulatta
Camundongos
Camundongos Endogâmicos C57BL
Estrutura Molecular
NADH NADPH Oxirredutases/metabolismo
Testes de Sensibilidade Parasitária
Relação Quantitativa Estrutura-Atividade
Tripanossomicidas/síntese química
Tripanossomicidas/química
Trypanosoma cruzi/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Furans); 0 (Lignans); 0 (Trypanocidal Agents); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.8.1.12 (trypanothione reductase)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE


  4 / 8213 MEDLINE  
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Vassallo, Dalton Valentim
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[PMID]:28826906
[Au] Autor:Martinez CS; Piagette JT; Escobar AG; Martín Á; Palacios R; Peçanha FM; Vassallo DV; Exley C; Alonso MJ; Miguel M; Salaices M; Wiggers GA
[Ad] Endereço:Postgraduate Program in Biochemistry, Universidade Federal do Pampa, BR 472 - Km 592 - PO box 118, Zip Code: 97500-970, Uruguaiana, Rio Grande do Sul, Brazil.
[Ti] Título:Aluminum exposure at human dietary levels promotes vascular dysfunction and increases blood pressure in rats: A concerted action of NAD(P)H oxidase and COX-2.
[So] Source:Toxicology;390:10-21, 2017 Sep 01.
[Is] ISSN:1879-3185
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Aluminum (Al) is a non-essential metal and a significant environmental contaminant and is associated with a number of human diseases including cardiovascular disease. We investigated the effects of Al exposure at doses similar to human dietary levels on the cardiovascular system over a 60day period. Wistar male rats were divided into two major groups and received orally: 1) Low aluminum level - rats were subdivided and treated for 60days as follows: a) Untreated - ultrapure water; b) AlCl at a dose of 8.3mg/kg bw for 60days, representing human Al exposure by diet; and 2) High aluminum level - rats were subdivided and treated for 42days as follows: C) Untreated - ultrapure water; d) AlCl at 100mg/kg bw for 42days, representing a high level of human exposure to Al. Effects on systolic blood pressure (SBP) and vascular function of aortic and mesenteric resistance arteries (MRA) were studied. Endothelium and smooth muscle integrity were evaluated by concentration-response curves to acetylcholine (ACh) and sodium nitroprusside. Vasoconstrictor responses to phenylephrine (Phe) in the presence and absence of endothelium and in the presence of the NOS inhibitor L-NAME, the potassium channels blocker TEA, the NAD(P)H oxidase inhibitor apocynin, superoxide dismutase (SOD), the non-selective COX inhibitor indomethacin and the selective COX-2 inhibitor NS 398 were analyzed. Vascular reactive oxygen species (ROS), lipid peroxidation and total antioxidant capacity, were measured. The mRNA expressions of eNOS, NAD(P)H oxidase 1 and 2, SOD1, COX-2 and thromboxane A2 receptor (TXA-2 R) were also investigated. Al exposure at human dietary levels impaired the cardiovascular system and these effects were almost the same as Al exposure at much higher levels. Al increased SBP, decreased ACh-induced relaxation, increased response to Phe, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide (NO), the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric arteries. Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Our results point to an excess of ROS mainly from NAD(P)H oxidase after Al exposure and the increased vascular prostanoids from COX-2 acting in concert to decrease NO bioavailability, thus inducing vascular dysfunction and increasing blood pressure. Therefore, 60-day chronic exposure to Al, which reflects common human dietary Al intake, appears to pose a risk for the cardiovascular system.
[Mh] Termos MeSH primário: Compostos de Alumínio/toxicidade
Pressão Sanguínea/efeitos dos fármacos
Cloretos/toxicidade
Ciclo-Oxigenase 2/metabolismo
Dieta
Endotélio Vascular/efeitos dos fármacos
Hipertensão/induzido quimicamente
NADH NADPH Oxirredutases/metabolismo
Vasoconstrição/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Inibidores de Ciclo-Oxigenase 2/farmacologia
Relação Dose-Resposta a Droga
Endotélio Vascular/enzimologia
Endotélio Vascular/fisiopatologia
Seres Humanos
Hipertensão/enzimologia
Hipertensão/genética
Hipertensão/fisiopatologia
Peroxidação de Lipídeos/efeitos dos fármacos
Masculino
NADH NADPH Oxirredutases/antagonistas & inibidores
NADH NADPH Oxirredutases/genética
NADPH Oxidase 1
Óxido Nítrico/metabolismo
Óxido Nítrico Sintase Tipo III/metabolismo
Estresse Oxidativo/efeitos dos fármacos
Ratos Wistar
Receptores de Tromboxano A2 e Prostaglandina H2/efeitos dos fármacos
Receptores de Tromboxano A2 e Prostaglandina H2/genética
Receptores de Tromboxano A2 e Prostaglandina H2/metabolismo
Medição de Risco
Transdução de Sinais/efeitos dos fármacos
Superóxido Dismutase-1/genética
Superóxido Dismutase-1/metabolismo
Fatores de Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aluminum Compounds); 0 (Chlorides); 0 (Cyclooxygenase 2 Inhibitors); 0 (Receptors, Thromboxane A2, Prostaglandin H2); 31C4KY9ESH (Nitric Oxide); 3CYT62D3GA (aluminum chloride); EC 1.14.13.39 (Nitric Oxide Synthase Type III); EC 1.14.13.39 (Nos3 protein, rat); EC 1.14.99.1 (Cyclooxygenase 2); EC 1.14.99.1 (Ptgs2 protein, rat); EC 1.15.1.1 (Sod1 protein, rat); EC 1.15.1.1 (Superoxide Dismutase-1); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


  5 / 8213 MEDLINE  
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[PMID]:28805804
[Au] Autor:Cracan V; Titov DV; Shen H; Grabarek Z; Mootha VK
[Ad] Endereço:Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.
[Ti] Título:A genetically encoded tool for manipulation of NADP /NADPH in living cells.
[So] Source:Nat Chem Biol;13(10):1088-1095, 2017 Oct.
[Is] ISSN:1552-4469
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The redox coenzymes NADH and NADPH are broadly required for energy metabolism, biosynthesis and detoxification. Despite detailed knowledge of specific enzymes and pathways that utilize these coenzymes, a holistic understanding of the regulation and compartmentalization of NADH- and NADPH-dependent pathways is lacking, partly because of a lack of tools with which to investigate these processes in living cells. We have previously reported the use of the naturally occurring Lactobacillus brevis H O-forming NADH oxidase (LbNOX) as a genetic tool for manipulation of the NAD /NADH ratio in human cells. Here, we present triphosphopyridine nucleotide oxidase (TPNOX), a rationally designed and engineered mutant of LbNOX that is strictly specific to NADPH. We characterized the effects of TPNOX expression on cellular metabolism and used it in combination with LbNOX to show how the redox states of mitochondrial NADPH and NADH pools are connected.
[Mh] Termos MeSH primário: NADH NADPH Oxirredutases/genética
NADH NADPH Oxirredutases/metabolismo
NADP/metabolismo
Engenharia de Proteínas
[Mh] Termos MeSH secundário: Células HeLa
Seres Humanos
NADH NADPH Oxirredutases/química
NADP/química
Oxirredução
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
53-59-8 (NADP); EC 1.6.- (NADH, NADPH Oxidoreductases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE
[do] DOI:10.1038/nchembio.2454


  6 / 8213 MEDLINE  
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[PMID]:28782186
[Au] Autor:Sowaileh MF; Hazlitt RA; Colby DA
[Ad] Endereço:Department of BioMolecular Sciences, University of Mississippi, University, MS, 38677, USA.
[Ti] Título:Application of the Pentafluorosulfanyl Group as a Bioisosteric Replacement.
[So] Source:ChemMedChem;12(18):1481-1490, 2017 Sep 21.
[Is] ISSN:1860-7187
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The success of fluorinated molecules in drug design has led medicinal chemists to search for new fluorine-containing substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiological conditions and displays unique physical and chemical properties. There are currently few synthetic methods to install the SF group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF group has been used as a replacement for trifluoromethyl, tert-butyl, halogen, or nitro groups. In this review, the use of the SF group as a bioisosteric replacement for each of these three functionalities is compared and contrasted across various groups of biologically active molecules. The organization and presentation of these data should be instructive to medicinal chemists considering to design synthetic strategies to access SF -substituted molecules.
[Mh] Termos MeSH primário: Sulfetos/química
Compostos de Enxofre/química
[Mh] Termos MeSH secundário: Antiprotozoários/química
Antiprotozoários/farmacologia
Desenho de Drogas
Ácido Flufenâmico/análogos & derivados
Ácido Flufenâmico/farmacologia
Halogenação
NADH NADPH Oxirredutases/antagonistas & inibidores
NADH NADPH Oxirredutases/metabolismo
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/metabolismo
Plasmodium falciparum/efeitos dos fármacos
Plasmodium falciparum/enzimologia
Ligação Proteica
Receptores de Canabinoides/química
Receptores de Canabinoides/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Receptors, Cannabinoid); 0 (Sulfides); 0 (Sulfur Compounds); 60GCX7Y6BH (Flufenamic Acid); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.5.2 (dihydroorotate dehydrogenase); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.8.1.12 (trypanothione reductase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170808
[St] Status:MEDLINE
[do] DOI:10.1002/cmdc.201700356


  7 / 8213 MEDLINE  
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[PMID]:28752634
[Au] Autor:Nowak C; Pick A; Csepei LI; Sieber V
[Ad] Endereço:Technical University of Munich, Department of Life Science Engineering, Straubing Center of Science, Schulgasse 16, 94315, Straubing, Germany.
[Ti] Título:Characterization of Biomimetic Cofactors According to Stability, Redox Potentials, and Enzymatic Conversion by NADH Oxidase from Lactobacillus pentosus.
[So] Source:Chembiochem;18(19):1944-1949, 2017 Oct 05.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Oxidoreductases are attractive biocatalysts that convert achiral substrates into products of higher value, but they are also for the most part dependent on nicotinamide cofactors. Recently, biomimetic nicotinamide derivatives have received attention as less costly alternatives to natural cofactors. However, recycling of biomimetics is still challenging because there are only limited opportunities. Here, we have characterized various biomimetic cofactors with regard to stability and redox potentials to find the best alternative to natural cofactors. Further, the cofactor spectrum of NADH oxidase from Lactobacillus pentosus (LpNox) could be expanded, and the enzymatic activity was also compared to activities with different small-molecule catalysts. As a result, we succeeded in identifying several strategies for regeneration of oxidized biomimetics.
[Mh] Termos MeSH primário: Materiais Biomiméticos/metabolismo
Lactobacillus pentosus/enzimologia
Complexos Multienzimáticos/metabolismo
NADH NADPH Oxirredutases/metabolismo
Niacinamida/metabolismo
[Mh] Termos MeSH secundário: Materiais Biomiméticos/síntese química
Materiais Biomiméticos/química
Concentração de Íons de Hidrogênio
Estrutura Molecular
Niacinamida/síntese química
Niacinamida/química
Oxirredução
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Multienzyme Complexes); 25X51I8RD4 (Niacinamide); EC 1.6.- (NADH oxidase); EC 1.6.- (NADH, NADPH Oxidoreductases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170729
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700258


  8 / 8213 MEDLINE  
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[PMID]:28715469
[Au] Autor:Jayachandran C; Palanisamy Athiyaman B; Sankaranarayanan M
[Ad] Endereço:Centre for Biotechnology, Anna University, Chennai, India.
[Ti] Título:Cofactor engineering improved CALB production in Pichia pastoris through heterologous expression of NADH oxidase and adenylate kinase.
[So] Source:PLoS One;12(7):e0181370, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The cofactor engineering strategy can relieve the metabolic stress induced by expression of recombinant protein in cellular metabolism related to cofactor and energy reactions. To study the effect of cofactor regeneration on recombinant protein expression, NADH oxidase (noxE) was engineered in P. pastoris expressing lipase B (GSCALB). Expression of noxE in P. pastoris (GSCALBNOX) increased NAD+ levels by 85% with a concomitant reduction in NADH/NAD+ ratio of 67% compared to GSCALB. The change in the redox level positively influenced the methanol uptake rate and made 34% augment in CALB activity. The decline in NADH level (44%) by noxE expression had lowered the adenylate energy charge (AEC) and ATP level in GSCALBNOX. In order to regenerate ATP in GSCALBNOX, adenylate kinase (ADK1) gene from S. cerevisiae S288c was co-expressed. Expression of ADK1 showed a remarkable increase in AEC and co-expression of both the genes synergistically improved CALB activity. This study shows the importance of maintenance of cellular redox homeostasis and adenylate energy charge during recombinant CALB expression in P. pastoris.
[Mh] Termos MeSH primário: Adenilato Quinase/metabolismo
Proteínas Fúngicas/biossíntese
Lipase/biossíntese
Complexos Multienzimáticos/metabolismo
NADH NADPH Oxirredutases/metabolismo
Pichia/genética
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/metabolismo
Adenilato Quinase/genética
Aldeído Oxirredutases/metabolismo
Proteínas Fúngicas/genética
Expressão Gênica
Engenharia Genética
Homeostase
Lipase/genética
Metanol/metabolismo
Complexos Multienzimáticos/genética
NAD/metabolismo
NADH NADPH Oxirredutases/genética
Oxirredução
Pichia/metabolismo
Reação em Cadeia da Polimerase em Tempo Real
Proteínas Recombinantes/biossíntese
Saccharomyces/enzimologia
Saccharomyces/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Multienzyme Complexes); 0 (Recombinant Proteins); 0U46U6E8UK (NAD); 8L70Q75FXE (Adenosine Triphosphate); EC 1.2.- (Aldehyde Oxidoreductases); EC 1.2.1.46 (formaldehyde dehydrogenase, glutathione-independent); EC 1.6.- (NADH oxidase); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 2.7.4.3 (Adenylate Kinase); EC 3.1.1.3 (Lipase); EC 3.1.1.3 (lipase B, Candida antarctica); Y4S76JWI15 (Methanol)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170718
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0181370


  9 / 8213 MEDLINE  
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[PMID]:28709950
[Au] Autor:Lu J; Risbood P; Kane CT; Hossain MT; Anderson L; Hill K; Monks A; Wu Y; Antony S; Juhasz A; Liu H; Jiang G; Harris E; Roy K; Meitzler JL; Konaté M; Doroshow JH
[Ad] Endereço:Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
[Ti] Título:Characterization of potent and selective iodonium-class inhibitors of NADPH oxidases.
[So] Source:Biochem Pharmacol;143:25-38, 2017 Nov 01.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The NADPH oxidases (NOXs) play a recognized role in the development and progression of inflammation-associated disorders, as well as cancer. To date, several NOX inhibitors have been developed, through either high throughput screening or targeted disruption of NOX interaction partners, although only a few have reached clinical trials. To improve the efficacy and bioavailability of the iodonium class NOX inhibitor diphenylene iodonium (DPI), we synthesized 36 analogs of DPI, focusing on improved solubility and functionalization. The inhibitory activity of the analogs was interrogated through cell viability and clonogenic studies with a colon cancer cell line (HT-29) that depends on NOX for its proliferative potential. Lack of altered cellular respiration at relevant iodonium analog concentrations was also demonstrated. Additionally, inhibition of ROS generation was evaluated with a luminescence assay for superoxide, or by Amplex Red® assay for H O production, in cell models expressing specific NOX isoforms. DPI and four analogs (NSCs 740104, 751140, 734428, 737392) strongly inhibited HT-29 cell growth and ROS production with nanomolar potency in a concentration-dependent manner. NSC 737392 and 734428, which both feature nitro functional groups at the meta position, had >10-fold higher activity against ROS production by cells that overexpress dual oxidase 2 (DUOX2) than the other compounds examined (IC ≈200-400nM). Based on these results, we synthesized and tested NSC 780521 with optimized potency against DUOX2. Iodonium analogs with anticancer activity, including the first generation of targeted agents with improved specificity against DUOX2, may provide a novel therapeutic approach to NOX-driven tumors.
[Mh] Termos MeSH primário: Proliferação Celular/efeitos dos fármacos
Inibidores Enzimáticos/farmacologia
NADH NADPH Oxirredutases/antagonistas & inibidores
Oniocompostos/farmacologia
Tiofenos/farmacologia
[Mh] Termos MeSH secundário: Sobrevivência Celular/efeitos dos fármacos
Relação Dose-Resposta a Droga
Oxidases Duais
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Células HT29
Seres Humanos
Estrutura Molecular
NADH NADPH Oxirredutases/genética
NADPH Oxidases/antagonistas & inibidores
NADPH Oxidases/genética
Oniocompostos/síntese química
Oniocompostos/química
Consumo de Oxigênio/efeitos dos fármacos
Espécies Reativas de Oxigênio/antagonistas & inibidores
Tiofenos/síntese química
Tiofenos/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Onium Compounds); 0 (Reactive Oxygen Species); 0 (Thiophenes); 45955-43-9 (iodonium thiophene); 6HJ411TU98 (diphenyleneiodonium); EC 1.11.1.- (Dual Oxidases); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.1 (DUOX2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE


  10 / 8213 MEDLINE  
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[PMID]:28684629
[Au] Autor:Thompson JA; Larion S; Mintz JD; Belin de Chantemèle EJ; Fulton DJ; Stepp DW
[Ad] Endereço:From the Vascular Biology Center (J.A.T., S.L., J.D.M., E.J.B.d.C., D.J.F., D.W.S.), Department of Physiology (D.W.S), Department of Pharmacology (D.J.F.), and Department of Medicine (S.L., E.J.B.d.C.), Augusta University, GA.
[Ti] Título:Genetic Deletion of NADPH Oxidase 1 Rescues Microvascular Function in Mice With Metabolic Disease.
[So] Source:Circ Res;121(5):502-511, 2017 Aug 18.
[Is] ISSN:1524-4571
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:RATIONALE: Early vascular changes in metabolic disease that precipitate the development of cardiovascular complications are largely driven by reactive oxygen species accumulation, yet the extent to which excess reactive oxygen species derive from specific NADPH oxidase isoforms remains ill defined. OBJECTIVE: Identify the role of Nox1 in the development of microvascular dysfunction in metabolic disease. METHODS AND RESULTS: Four genotypes were generated by breeding Nox1 knockout mice with mice: lean (H W ), lean Nox1 knockout (H K ), obese (K W ), and obese KK (K K ). The degree of adiposity, insulin resistance, and dyslipidemia in KW mice was not influenced by Nox1 deletion as determined by nuclear magnetic resonance spectroscopy, glucose tolerance tests, and plasma analyses. Endothelium-dependent responses to acetylcholine in pressurized mesenteric arteries were reduced in KW versus HW ( <0.01), whereas deletion of Nox1 in KW mice normalized dilation. Vasodilator responses after inhibition of NO synthase blunted acetylcholine responses in KK and lean controls, but had no impact in KW, attributing recovered dilatory capacity in KK to normalization of NO. Acetylcholine responses were improved ( <0.05) with Tempol, and histochemistry revealed oxidative stress in KW animals, whereas Tempol had no impact and reactive oxygen species staining was negligible in KK. Blunted dilatory responses to an NO donor and loss of myogenic tone in KW animals were also rescued with Nox1 deletion. CONCLUSIONS: Nox1 deletion reduces oxidant load and restores microvascular health in mice without influencing the degree of metabolic dysfunction. Therefore, targeted Nox1 inhibition may be effective in the prevention of vascular complications.
[Mh] Termos MeSH primário: Deleção de Genes
Doenças Metabólicas/genética
Microvasos/fisiologia
Músculo Liso Vascular/fisiologia
NADH NADPH Oxirredutases/deficiência
NADH NADPH Oxirredutases/genética
[Mh] Termos MeSH secundário: Animais
Glicemia/metabolismo
Masculino
Doenças Metabólicas/enzimologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Camundongos Obesos
NADPH Oxidase 1
Estresse Oxidativo/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Blood Glucose); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.6.3.- (NADPH Oxidase 1); EC 1.6.3.- (NOX1 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170708
[St] Status:MEDLINE
[do] DOI:10.1161/CIRCRESAHA.116.309965



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