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Pesquisa : D08.811.464.259.200 [Categoria DeCS]
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  1 / 174 MEDLINE  
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[PMID]:28827112
[Au] Autor:Wang X; Ahn YM; Lentscher AG; Lister JS; Brothers RC; Kneen MM; Gerratana B; Boshoff HI; Dowd CS
[Ad] Endereço:Department of Chemistry, George Washington University, Washington DC 20052, United States.
[Ti] Título:Design, synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD ) synthetase inhibitors as potential antitubercular agents.
[So] Source:Bioorg Med Chem Lett;27(18):4426-4430, 2017 09 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Nicotinamide adenine dinucleotide (NAD ) synthetase catalyzes the last step in NAD biosynthesis. Depletion of NAD is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD synthetase (NadE) from Mtb, we expect to eliminate NAD production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure-activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC =1000µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC value of 90µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19-100µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target.
[Mh] Termos MeSH primário: Amida Sintases/antagonistas & inibidores
Antituberculosos/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Mycobacterium tuberculosis/efeitos dos fármacos
[Mh] Termos MeSH secundário: Amida Sintases/metabolismo
Antituberculosos/síntese química
Antituberculosos/química
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Seres Humanos
Testes de Sensibilidade Microbiana
Estrutura Molecular
Mycobacterium tuberculosis/crescimento & desenvolvimento
Mycobacterium tuberculosis/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antitubercular Agents); 0 (Enzyme Inhibitors); EC 6.3.1.- (Amide Synthases); EC 6.3.1.5 (NAD+ synthase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170823
[St] Status:MEDLINE


  2 / 174 MEDLINE  
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[PMID]:28796499
[Au] Autor:Cheng S; Fu X; Wang X; Liao Y; Zeng L; Dong F; Yang Z
[Ad] Endereço:Key Laboratory of South China Agricultural Plant Molecular Analysis and Genetic Improvement & Guangdong Provincial Key Laboratory of Applied Botany, South China Botanical Garden, Chinese Academy of Sciences , Xingke Road 723, Tianhe District, Guangzhou 510650, China.
[Ti] Título:Studies on the Biochemical Formation Pathway of the Amino Acid l-Theanine in Tea (Camellia sinensis) and Other Plants.
[So] Source:J Agric Food Chem;65(33):7210-7216, 2017 Aug 23.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Tea (Camellia sinensis) is the most widely consumed beverage aside from water. The flavor of tea is conferred by certain metabolites, especially l-theanine, in C. sinensis. To determine why more l-theanine accumulates in C. sinensis than in other plants, we compare l-theanine contents between C. sinensis and other plant species (Camellia nitidissima, Camellia japonica, Zea mays, Arabidopsis thaliana, and Solanum lycopersicum) and use a stable isotope labeling approach to elucidate its biosynthetic route. We quantify relevant intermediates and metabolites by mass spectrometry. l-Glutamic acid, a precursor of l-theanine, is present in most plants, while ethylamine, another precursor of l-theanine, specifically accumulates in Camellia species, especially C. sinensis. Most plants contain the enzyme/gene catalyzing the conversion of ethylamine and l-glutamic acid to l-theanine. After supplementation with [ H ]ethylamine, all the plants produce [ H ]l-theanine, which suggests that ethylamine availability is the reason for the difference in l-theanine accumulation between C. sinensis and other plants.
[Mh] Termos MeSH primário: Camellia sinensis/metabolismo
Glutamatos/biossíntese
[Mh] Termos MeSH secundário: Amida Sintases/genética
Amida Sintases/metabolismo
Vias Biossintéticas
Camellia sinensis/enzimologia
Camellia sinensis/genética
Glutamato-Amônia Ligase/genética
Glutamato-Amônia Ligase/metabolismo
Ácido Glutâmico/metabolismo
Proteínas de Plantas/genética
Proteínas de Plantas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Glutamates); 0 (Plant Proteins); 3KX376GY7L (Glutamic Acid); 8021PR16QO (theanine); EC 6.3.1.- (Amide Synthases); EC 6.3.1.2 (Glutamate-Ammonia Ligase); EC 6.3.1.6 (theanine synthetase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170914
[Lr] Data última revisão:
170914
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170811
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jafc.7b02437


  3 / 174 MEDLINE  
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[PMID]:28618168
[Au] Autor:Booth WT; Morris TL; Mysona DP; Shah MJ; Taylor LK; Karlin TW; Clary K; Majorek KA; Offermann LR; Chruszcz M
[Ad] Endereço:Department of Chemistry and Biochemistry, University of South Carolina, Columbia, SC, USA.
[Ti] Título:Streptococcus pyogenes quinolinate-salvage pathway-structural and functional studies of quinolinate phosphoribosyl transferase and NH -dependent NAD synthetase.
[So] Source:FEBS J;284(15):2425-2441, 2017 Aug.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Streptococcus pyogenes, also known as Group A Strep (GAS), is an obligate human pathogen that is responsible for millions of infections and numerous deaths per year. Infection manifestations can range from simple, acute pharyngitis to more complex, necrotizing fasciitis. To date, most treatments for GAS infections involve the use of common antibiotics including tetracycline and clindamycin. Unfortunately, new strains have been identified that are resistant to these drugs, therefore, new targets must be identified to treat drug-resistant strains. This work is focused on the structural and functional characterization of three proteins: spNadC, spNadD, and spNadE. These enzymes are involved in the biosynthesis of nicotinamide adenine dinucleotide (NAD ). The structures of spNadC and spNadE were determined. SpNadC is suggested to play a role in GAS virulence, while spNadE, functions as an NAD synthetase and is considered to be a new drug target. Determination of the spNadE structure uncovered a putative, NH channel, which may provide insight into the mechanistic details of NH -dependent NAD synthetases in prokaryotes. ENZYMES: Quinolinate phosphoribosyltransferase: EC2.4.2.19 and NAD synthetase: EC6.3.1.5. DATABASE: Protein structures for spNadC, spNadC , and spNadE are deposited into Protein Data Bank under the accession codes 5HUL, 5HUO & 5HUP, and 5HUH & 5HUJ, respectively.
[Mh] Termos MeSH primário: Amida Sintases/metabolismo
Proteínas de Bactérias/metabolismo
Modelos Moleculares
Nicotinamida-Nucleotídeo Adenililtransferase/metabolismo
Pentosiltransferases/metabolismo
Ácido Quinolínico/metabolismo
Streptococcus pyogenes/metabolismo
[Mh] Termos MeSH secundário: Trifosfato de Adenosina/química
Trifosfato de Adenosina/metabolismo
Amida Sintases/química
Amida Sintases/genética
Apoenzimas/química
Apoenzimas/genética
Apoenzimas/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Sítios de Ligação
Domínio Catalítico
Análise por Conglomerados
Biologia Computacional
Cristalografia por Raios X
Dimerização
Deleção de Genes
Nicotinamida-Nucleotídeo Adenililtransferase/química
Nicotinamida-Nucleotídeo Adenililtransferase/genética
Pentosiltransferases/química
Pentosiltransferases/genética
Conformação Proteica
Domínios e Motivos de Interação entre Proteínas
Multimerização Proteica
Estrutura Quaternária de Proteína
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Homologia Estrutural de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Apoenzymes); 0 (Bacterial Proteins); 0 (Recombinant Proteins); 8L70Q75FXE (Adenosine Triphosphate); EC 2.4.2.- (Pentosyltransferases); EC 2.4.2.19 (nicotinate-nucleotide diphosphorylase (carboxylating)); EC 2.7.7.1 (Nicotinamide-Nucleotide Adenylyltransferase); EC 2.7.7.18 (nicotinic acid mononucleotide adenylyltransferase); EC 6.3.1.- (Amide Synthases); EC 6.3.1.5 (NAD+ synthase); F6F0HK1URN (Quinolinic Acid)
[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:170616
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14136


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[PMID]:27590711
[Au] Autor:Hashida SN; Itami T; Takahara K; Hirabayashi T; Uchimiya H; Kawai-Yamada M
[Ad] Endereço:Institute of Molecular and Cellular Biosciences (IMCB), The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan shashida@criepi.denken.or.jp.
[Ti] Título:Increased Rate of NAD Metabolism Shortens Plant Longevity by Accelerating Developmental Senescence in Arabidopsis.
[So] Source:Plant Cell Physiol;57(11):2427-2439, 2016 Nov.
[Is] ISSN:1471-9053
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:NAD is a well-known co-enzyme that mediates hundreds of redox reactions and is the basis of various processes regulating cell responses to different environmental and developmental cues. The regulatory mechanism that determines the amount of cellular NAD and the rate of NAD metabolism remains unclear. We created Arabidopsis thaliana plants overexpressing the NAD synthase (NADS) gene that participates in the final step of NAD biosynthesis. NADS overexpression enhanced the activity of NAD biosynthesis but not the amounts of NAD , NADH, NADP or NADPH. However, the amounts of some intermediates were elevated, suggesting that NAD metabolism increased. The NAD redox state was greatly facilitated by an imbalance between NAD generation and degradation in response to bolting. Metabolite profiling and transcriptional analysis revealed that the drastic modulation of NAD redox homeostasis increased tricarboxylic acid flux, causing the ectopic generation of reactive oxygen species. Vascular bundles suffered from oxidative stress, leading to a malfunction in amino acid and organic acid transportation that caused early wilting of the flower stalk and shortened plant longevity, probably due to malnutrition. We concluded that the mechanism regulating the balance between NAD synthesis and degradation is important in the systemic plant response to developmental cues during the growth-phase transition.
[Mh] Termos MeSH primário: Arabidopsis/metabolismo
Arabidopsis/fisiologia
Longevidade
NAD/metabolismo
Desenvolvimento Vegetal
[Mh] Termos MeSH secundário: Amida Sintases/metabolismo
Arabidopsis/genética
Arabidopsis/crescimento & desenvolvimento
Proteínas de Arabidopsis/metabolismo
Vias Biossintéticas
Coenzimas/metabolismo
Regulação da Expressão Gênica de Plantas
Homeostase
Peróxido de Hidrogênio/metabolismo
Metabolômica
Modelos Biológicos
Oxirredução
Folhas de Planta/metabolismo
Plantas Geneticamente Modificadas
Reprodução
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Arabidopsis Proteins); 0 (Coenzymes); 0U46U6E8UK (NAD); BBX060AN9V (Hydrogen Peroxide); EC 6.3.1.- (Amide Synthases); EC 6.3.1.5 (NAD+ synthase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170327
[Lr] Data última revisão:
170327
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160904
[St] Status:MEDLINE


  5 / 174 MEDLINE  
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[PMID]:27349574
[Au] Autor:Orban OC; Korn RS; Benítez D; Medeiros A; Preu L; Loaëc N; Meijer L; Koch O; Comini MA; Kunick C
[Ad] Endereço:Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany.
[Ti] Título:5-Substituted 3-chlorokenpaullone derivatives are potent inhibitors of Trypanosoma brucei bloodstream forms.
[So] Source:Bioorg Med Chem;24(16):3790-800, 2016 Aug 15.
[Is] ISSN:1464-3391
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Trypanothione synthetase is an essential enzyme for kinetoplastid parasites which cause highly disabling and fatal diseases in humans and animals. Inspired by the observation that N(5)-substituted paullones inhibit the trypanothione synthetase from the related parasite Leishmania infantum, we designed and synthesized a series of new derivatives. Although none of the new compounds displayed strong inhibition of Trypanosoma brucei trypanothione synthetase, several of them caused a remarkable growth inhibition of cultivated Trypanosoma brucei bloodstream forms. The most potent congener 3a showed antitrypanosomal activity in double digit nanomolar concentrations and a selectivity index of three orders of magnitude versus murine macrophage cells.
[Mh] Termos MeSH primário: Antiprotozoários/farmacologia
Benzazepinas/farmacologia
Indóis/farmacologia
Trypanosoma brucei brucei/efeitos dos fármacos
[Mh] Termos MeSH secundário: Amida Sintases/antagonistas & inibidores
Animais
Antiprotozoários/química
Benzazepinas/química
Seres Humanos
Indóis/química
Análise Espectral/métodos
Trypanosoma brucei brucei/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Benzazepines); 0 (Indoles); 0 (N-benzyl-2-(9-bromo-3-chloro-6-oxo-5,6,7,12-tetrahydrobenzo(2,3)azepino(4,5-b)indole-5-yl)acetamide); EC 6.3.1.- (Amide Synthases); EC 6.3.1.9 (trypanothione synthetase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170808
[Lr] Data última revisão:
170808
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160629
[St] Status:MEDLINE


  6 / 174 MEDLINE  
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[PMID]:27070550
[Au] Autor:Benítez D; Medeiros A; Fiestas L; Panozzo-Zenere EA; Maiwald F; Prousis KC; Roussaki M; Calogeropoulou T; Detsi A; Jaeger T; Sarlauskas J; Peterlin Masic L; Kunick C; Labadie GR; Flohé L; Comini MA
[Ad] Endereço:Laboratory Redox Biology of Trypanosomes, Institut Pasteur de Montevideo, Montevideo, Uruguay.
[Ti] Título:Identification of Novel Chemical Scaffolds Inhibiting Trypanothione Synthetase from Pathogenic Trypanosomatids.
[So] Source:PLoS Negl Trop Dis;10(4):e0004617, 2016 Apr.
[Is] ISSN:1935-2735
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: The search for novel chemical entities targeting essential and parasite-specific pathways is considered a priority for neglected diseases such as trypanosomiasis and leishmaniasis. The thiol-dependent redox metabolism of trypanosomatids relies on bis-glutathionylspermidine [trypanothione, T(SH)2], a low molecular mass cosubstrate absent in the host. In pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Thus, TryS qualifies as an attractive drug target candidate. METHODOLOGY/PRINCIPAL FINDING: A library composed of 144 compounds from 7 different families and several singletons was screened against TryS from three major pathogen species (Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum). The screening conditions were adjusted to the TryS´ kinetic parameters and intracellular concentration of substrates corresponding to each trypanosomatid species, and/or to avoid assay interference. The screening assay yielded suitable Z' and signal to noise values (≥0.85 and ~3.5, respectively), and high intra-assay reproducibility. Several novel chemical scaffolds were identified as low µM and selective tri-tryp TryS inhibitors. Compounds displaying multi-TryS inhibition (N,N'-bis(3,4-substituted-benzyl) diamine derivatives) and an N5-substituted paullone (MOL2008) halted the proliferation of infective Trypanosoma brucei (EC50 in the nM range) and Leishmania infantum promastigotes (EC50 = 12 µM), respectively. A bis-benzyl diamine derivative and MOL2008 depleted intracellular trypanothione in treated parasites, which confirmed the on-target activity of these compounds. CONCLUSIONS/SIGNIFICANCE: Novel molecular scaffolds with on-target mode of action were identified as hit candidates for TryS inhibition. Due to the remarkable species-specificity exhibited by tri-tryp TryS towards the compounds, future optimization and screening campaigns should aim at designing and detecting, respectively, more potent and broad-range TryS inhibitors.
[Mh] Termos MeSH primário: Amida Sintases/antagonistas & inibidores
Antiprotozoários/isolamento & purificação
Inibidores Enzimáticos/isolamento & purificação
Leishmania infantum/efeitos dos fármacos
Trypanosoma brucei brucei/efeitos dos fármacos
Trypanosoma cruzi/efeitos dos fármacos
[Mh] Termos MeSH secundário: Antiprotozoários/metabolismo
Avaliação Pré-Clínica de Medicamentos
Inibidores Enzimáticos/metabolismo
Leishmania infantum/enzimologia
Trypanosoma brucei brucei/enzimologia
Trypanosoma cruzi/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Enzyme Inhibitors); EC 6.3.1.- (Amide Synthases); EC 6.3.1.9 (trypanothione synthetase)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160413
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pntd.0004617


  7 / 174 MEDLINE  
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[PMID]:26891837
[Au] Autor:Alberca LN; Sbaraglini ML; Balcazar D; Fraccaroli L; Carrillo C; Medeiros A; Benitez D; Comini M; Talevi A
[Ad] Endereço:Laboratory of Bioactive Compounds Research and Development (LIDeB), Medicinal Chemistry, Department of Biological Science, Exact Sciences College, National University of La Plata (UNLP), Argentina, 47 & 115, B1900AJI, La Plata, Buenos Aires, Argentina.
[Ti] Título:Discovery of novel polyamine analogs with anti-protozoal activity by computer guided drug repositioning.
[So] Source:J Comput Aided Mol Des;30(4):305-21, 2016 Apr.
[Is] ISSN:1573-4951
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids (T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.
[Mh] Termos MeSH primário: Amida Sintases/antagonistas & inibidores
Doença de Chagas/tratamento farmacológico
Reposicionamento de Medicamentos
Poliaminas/química
[Mh] Termos MeSH secundário: Amida Sintases/química
Antiprotozoários/química
Doença de Chagas/parasitologia
Simulação por Computador
Glutationa/análogos & derivados
Glutationa/química
Glutationa/uso terapêutico
Seres Humanos
Imidazóis/química
Imidazóis/uso terapêutico
Nitroimidazóis/química
Nitroimidazóis/uso terapêutico
Poliaminas/uso terapêutico
Espermidina/análogos & derivados
Espermidina/química
Espermidina/uso terapêutico
Tiofenos/química
Tiofenos/uso terapêutico
Trypanosoma cruzi/efeitos dos fármacos
Trypanosoma cruzi/patogenicidade
Interface Usuário-Computador
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Imidazoles); 0 (Nitroimidazoles); 0 (Polyamines); 0 (Thiophenes); 33932-35-3 (glutathionylspermidine); 72W71I16EG (sertaconazole); 96304-42-6 (trypanothione); EC 6.3.1.- (Amide Synthases); EC 6.3.1.9 (trypanothione synthetase); GAN16C9B8O (Glutathione); U87FK77H25 (Spermidine); YC42NRJ1ZD (benzonidazole)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:171021
[Lr] Data última revisão:
171021
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160220
[St] Status:MEDLINE
[do] DOI:10.1007/s10822-016-9903-6


  8 / 174 MEDLINE  
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[PMID]:26802007
[Au] Autor:Laskoski K; Santos AR; Bonatto AC; Pedrosa FO; Souza EM; Huergo LF
[Ad] Endereço:Departamento de Bioquímica e Biologia Molecular, Curitiba, Brazil.
[Ti] Título:In vitro characterization of the NAD+ synthetase NadE1 from Herbaspirillum seropedicae.
[So] Source:Arch Microbiol;198(4):307-13, 2016 May.
[Is] ISSN:1432-072X
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Nicotinamide adenine dinucleotide synthetase enzyme (NadE) catalyzes the amination of nicotinic acid adenine dinucleotide (NaAD) to form NAD(+). This reaction represents the last step in the majority of the NAD(+) biosynthetic routes described to date. NadE enzymes typically use either glutamine or ammonium as amine nitrogen donor, and the reaction is energetically driven by ATP hydrolysis. Given the key role of NAD(+) in bacterial metabolism, NadE has attracted considerable interest as a potential target for the development of novel antibiotics. The plant-associative nitrogen-fixing bacteria Herbaspirillum seropedicae encodes two putative NadE, namely nadE1 and nadE2. The nadE1 gene is linked to glnB encoding the signal transduction protein GlnB. Here we report the purification and in vitro characterization of H. seropedicae NadE1. Gel filtration chromatography analysis suggests that NadE1 is an octamer. The NadE1 activity was assayed in vitro, and the Michaelis-Menten constants for substrates NaAD, ATP, glutamine and ammonium were determined. Enzyme kinetic and in vitro substrate competition assays indicate that H. seropedicae NadE1 uses glutamine as a preferential nitrogen donor.
[Mh] Termos MeSH primário: Amida Sintases/isolamento & purificação
Amida Sintases/metabolismo
Herbaspirillum/enzimologia
[Mh] Termos MeSH secundário: Cromatografia em Gel
Glutamina/metabolismo
Cinética
NAD/análogos & derivados
NAD/biossíntese
NAD/metabolismo
Nitrogênio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0RH81L854J (Glutamine); 0U46U6E8UK (NAD); 6450-77-7 (nicotinic acid adenine dinucleotide); EC 6.3.1.- (Amide Synthases); EC 6.3.1.5 (NAD+ synthase); N762921K75 (Nitrogen)
[Em] Mês de entrada:1609
[Cu] Atualização por classe:160418
[Lr] Data última revisão:
160418
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160124
[St] Status:MEDLINE
[do] DOI:10.1007/s00203-016-1190-z


  9 / 174 MEDLINE  
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[PMID]:26617065
[Au] Autor:Gemperlein K; Zipf G; Bernauer HS; Müller R; Wenzel SC
[Ad] Endereço:Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, D-66123 Saarbrücken, Germany.
[Ti] Título:Metabolic engineering of Pseudomonas putida for production of docosahexaenoic acid based on a myxobacterial PUFA synthase.
[So] Source:Metab Eng;33:98-108, 2016 Jan.
[Is] ISSN:1096-7184
[Cp] País de publicação:Belgium
[La] Idioma:eng
[Ab] Resumo:Long-chain polyunsaturated fatty acids (LC-PUFAs) can be produced de novo via polyketide synthase-like enzymes known as PUFA synthases, which are encoded by pfa biosynthetic gene clusters originally discovered from marine microorganisms. Recently similar gene clusters were detected and characterized in terrestrial myxobacteria revealing several striking differences. As the identified myxobacterial producers are difficult to handle genetically and grow very slowly we aimed to establish heterologous expression platforms for myxobacterial PUFA synthases. Here we report the heterologous expression of the pfa gene cluster from Aetherobacter fasciculatus (SBSr002) in the phylogenetically distant model host bacteria Escherichia coli and Pseudomonas putida. The latter host turned out to be the more promising PUFA producer revealing higher production rates of n-6 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). After several rounds of genetic engineering of expression plasmids combined with metabolic engineering of P. putida, DHA production yields were eventually increased more than threefold. Additionally, we applied synthetic biology approaches to redesign and construct artificial versions of the A. fasciculatus pfa gene cluster, which to the best of our knowledge represents the first example of a polyketide-like biosynthetic gene cluster modulated and synthesized for P. putida. Combination with the engineering efforts described above led to a further increase in LC-PUFA production yields. The established production platform based on synthetic DNA now sets the stage for flexible engineering of the complex PUFA synthase.
[Mh] Termos MeSH primário: Amida Sintases/metabolismo
Ácidos Docosa-Hexaenoicos/biossíntese
Ácidos Graxos Insaturados/metabolismo
Engenharia Metabólica/métodos
Myxococcales/enzimologia
Pseudomonas putida/enzimologia
[Mh] Termos MeSH secundário: Amida Sintases/genética
Clonagem Molecular/métodos
Ácidos Docosa-Hexaenoicos/genética
Ácidos Docosa-Hexaenoicos/isolamento & purificação
Ácidos Graxos Insaturados/genética
Myxococcales/genética
Pseudomonas putida/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Fatty Acids, Unsaturated); 0 (Recombinant Proteins); 25167-62-8 (Docosahexaenoic Acids); EC 6.3.1.- (Amide Synthases)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151201
[St] Status:MEDLINE


  10 / 174 MEDLINE  
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[PMID]:26592324
[Au] Autor:Leroux AE; Krauth-Siegel RL
[Ad] Endereço:Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany. Electronic address: alejandro.leroux@bzh.uni-heidelberg.de.
[Ti] Título:Thiol redox biology of trypanosomatids and potential targets for chemotherapy.
[So] Source:Mol Biochem Parasitol;206(1-2):67-74, 2016 Mar-Apr.
[Is] ISSN:1872-9428
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different forms of leishmaniasis. This family of protozoan parasite possesses a trypanothione-based redox metabolism that provides the reducing equivalents for various vital processes such as the biosynthesis of DNA precursors and the detoxification of hydroperoxides. Almost all enzymes of the redox pathway proved to be essential and therefore fulfil one crucial prerequisite for a putative drug target. Trypanothione synthetase and trypanothione reductase are present in all trypanosomatids but absent from the mammalian host which, in addition to the essentiality, renders them highly specific. The chemotherapy research on both enzymes is further supported by the availability of high-throughput screening techniques and crystal structures. In this review we focus on the recent advances and limitations in the development of lead compounds targeting trypanothione synthetase and trypanothione reductase. We present an overview of the available inhibitors and discuss future perspectives including other components of the parasite-specific redox pathway.
[Mh] Termos MeSH primário: Amida Sintases/antagonistas & inibidores
Antiprotozoários/farmacologia
Inibidores Enzimáticos/farmacologia
NADH NADPH Oxirredutases/antagonistas & inibidores
Proteínas de Protozoários/antagonistas & inibidores
[Mh] Termos MeSH secundário: Amida Sintases/genética
Amida Sintases/metabolismo
Animais
Antiprotozoários/síntese química
Doença de Chagas/tratamento farmacológico
Doença de Chagas/parasitologia
Inibidores Enzimáticos/síntese química
Expressão Gênica
Ensaios de Triagem em Larga Escala
Leishmania/efeitos dos fármacos
Leishmania/enzimologia
Leishmania/genética
Leishmania/crescimento & desenvolvimento
Leishmaniose/tratamento farmacológico
Leishmaniose/parasitologia
Terapia de Alvo Molecular
NADH NADPH Oxirredutases/genética
NADH NADPH Oxirredutases/metabolismo
Oxirredução
Proteínas de Protozoários/genética
Proteínas de Protozoários/metabolismo
Relação Estrutura-Atividade
Compostos de Sulfidrila/metabolismo
Trypanosoma/efeitos dos fármacos
Trypanosoma/enzimologia
Trypanosoma/genética
Trypanosoma/crescimento & desenvolvimento
Tripanossomíase Africana/tratamento farmacológico
Tripanossomíase Africana/parasitologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiprotozoal Agents); 0 (Enzyme Inhibitors); 0 (Protozoan Proteins); 0 (Sulfhydryl Compounds); EC 1.6.- (NADH, NADPH Oxidoreductases); EC 1.8.1.12 (trypanothione reductase); EC 6.3.1.- (Amide Synthases); EC 6.3.1.9 (trypanothione synthetase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171124
[Lr] Data última revisão:
171124
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151124
[St] Status:MEDLINE



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