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[PMID]:28196402
[Au] Autor:Manandhar M; Cronan JE
[Ad] Endereço:Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
[Ti] Título:Pimelic acid, the first precursor of the Bacillus subtilis biotin synthesis pathway, exists as the free acid and is assembled by fatty acid synthesis.
[So] Source:Mol Microbiol;104(4):595-607, 2017 05.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Biotin synthetic pathways are readily separated into two stages, synthesis of the seven carbon α, ω-dicarboxylic acid pimelate moiety and assembly of the fused heterocyclic rings. The biotin pathway genes responsible for pimelate moiety synthesis vary widely among bacteria whereas the ring synthesis genes are highly conserved. Bacillus subtilis seems to have redundant genes, bioI and bioW, for generation of the pimelate intermediate. Largely consistent with previous genetic studies it was found that deletion of bioW caused a biotin auxotrophic phenotype whereas deletion of bioI did not. BioW is a pimeloyl-CoA synthetase that converts pimelic acid to pimeloyl-CoA. The essentiality of BioW for biotin synthesis indicates that the free form of pimelic acid is an intermediate in biotin synthesis although this is not the case in E. coli. Since the origin of pimelic acid in Bacillus subtilis is unknown, C-NMR studies were carried out to decipher the pathway for its generation. The data provided evidence for the role of free pimelate in biotin synthesis and the involvement of fatty acid synthesis in pimelate production. Cerulenin, an inhibitor of the key fatty acid elongation enzyme, FabF, markedly decreased biotin production by B. subtilis resting cells whereas a strain having a cerulenin-resistant FabF mutant produced more biotin. In addition, supplementation with pimelic acid fully restored biotin production in cerulenin-treated cells. These results indicate that pimelic acid originating from fatty acid synthesis pathway is a bona fide precursor of biotin in B. subtilis.
[Mh] Termos MeSH primário: Biotina/biossíntese
Ácidos Pimélicos/metabolismo
[Mh] Termos MeSH secundário: Proteína de Transporte de Acila/metabolismo
Acil Coenzima A/genética
Acil Coenzima A/metabolismo
Bacillus subtilis/genética
Bacillus subtilis/metabolismo
Vias Biossintéticas
Biotina/metabolismo
Clonagem Molecular
Coenzima A Ligases/genética
Coenzima A Ligases/metabolismo
Ácidos Graxos/metabolismo
Ácidos Pimélicos/química
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Acyl Carrier Protein); 0 (Acyl Coenzyme A); 0 (Fatty Acids); 0 (Pimelic Acids); 18907-20-5 (pimeloyl-coenzyme A); 6SO6U10H04 (Biotin); EC 6.2.1.- (Coenzyme A Ligases); EC 6.2.1.- (pimeloyl-CoA synthetase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170215
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13648


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[PMID]:27933801
[Au] Autor:Shi J; Cao X; Chen Y; Cronan JE; Guo Z
[Ad] Endereço:Department of Chemistry and State Key Lab for Molecular Neuroscience, The Hong Kong University of Science and Technology , Clear Water Bay, Kowloon, Hong Kong SAR, China.
[Ti] Título:An Atypical α/ß-Hydrolase Fold Revealed in the Crystal Structure of Pimeloyl-Acyl Carrier Protein Methyl Esterase BioG from Haemophilus influenzae.
[So] Source:Biochemistry;55(48):6705-6717, 2016 Dec 06.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Pimeloyl-acyl carrier protein (ACP) methyl esterase is an α/ß-hydrolase that catalyzes the last biosynthetic step of pimeloyl-ACP, a key intermediate in biotin biosynthesis. Intriguingly, multiple nonhomologous isofunctional forms of this enzyme that lack significant sequence identity are present in diverse bacteria. One such esterase, Escherichia coli BioH, has been shown to be a typical α/ß-hydrolase fold enzyme. To gain further insights into the role of this step in biotin biosynthesis, we have determined the crystal structure of another widely distributed pimeloyl-ACP methyl esterase, Haemophilus influenzae BioG, at 1.26 Å. The BioG structure is similar to the BioH structure and is composed of an α-helical lid domain and a core domain that contains a central seven-stranded ß-pleated sheet. However, four of the six α-helices that flank both sides of the BioH core ß-sheet are replaced with long loops in BioG, thus forming an unusual α/ß-hydrolase fold. This structural variation results in a significantly decreased thermal stability of the enzyme. Nevertheless, the lid domain and the residues at the lid-core interface are well conserved between BioH and BioG, in which an analogous hydrophobic pocket for pimelate binding as well as similar ionic interactions with the ACP moiety are retained. Biochemical characterization of site-directed mutants of the residues hypothesized to interact with the ACP moiety supports a similar substrate interaction mode for the two enzymes. Consequently, these enzymes package the identical catalytic function under a considerably different protein surface.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Esterases/metabolismo
Haemophilus influenzae/enzimologia
Hidrolases/metabolismo
[Mh] Termos MeSH secundário: Proteína de Transporte de Acila/química
Proteína de Transporte de Acila/metabolismo
Sequência de Aminoácidos
Proteínas de Bactérias/química
Proteínas de Bactérias/genética
Vias Biossintéticas/genética
Biotina/biossíntese
Biotina/química
Dicroísmo Circular
Cristalografia por Raios X
Eletroforese em Gel de Poliacrilamida
Proteínas de Escherichia coli/química
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Esterases/química
Esterases/genética
Haemophilus influenzae/genética
Haemophilus influenzae/metabolismo
Hidrolases/química
Hidrolases/genética
Modelos Moleculares
Estrutura Molecular
Mutação
Ácidos Pimélicos/química
Ácidos Pimélicos/metabolismo
Domínios Proteicos
Dobramento de Proteína
Estrutura Secundária de Proteína
Homologia de Sequência de Aminoácidos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acyl Carrier Protein); 0 (Bacterial Proteins); 0 (Escherichia coli Proteins); 0 (Pimelic Acids); 124544-49-6 (bioH protein, E coli); 6SO6U10H04 (Biotin); EC 3.- (Hydrolases); EC 3.1.- (Esterases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170529
[Lr] Data última revisão:
170529
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161210
[St] Status:MEDLINE


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[PMID]:27737547
[Au] Autor:Tan ET; Yong KW; Wong SH; D'Arcy BR; Al Jassim R; De Voss JJ; Fletcher MT
[Ad] Endereço:Queensland Alliance for Agriculture and Food Innovation (QAAFI), The University of Queensland , Health and Food Sciences Precinct, Coopers Plains, Queensland 4108, Australia.
[Ti] Título:Thermo-alkaline Treatment as a Practical Degradation Strategy To Reduce Indospicine Contamination in Camel Meat.
[So] Source:J Agric Food Chem;64(44):8447-8453, 2016 Nov 09.
[Is] ISSN:1520-5118
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Ingestion of indospicine-contaminated camel and horse meat has caused fatal liver injury to dogs in Australia, and it is currently not known if such contaminated meat may pose a human health risk upon dietary exposure. To date, indospicine-related research has tended to focus on analytical aspects, with little information on post-harvest management of indospicine-contaminated meat. In this study, indospicine degradation was investigated in both aqueous solution and also contaminated meat, under a range of conditions. Aqueous solutions of indospicine and indospicine-contaminated camel meat were microwaved (180 °C) or autoclaved (121 °C) with the addition of food-grade additives [0.05% (v/v) acetic acid or 0.05% (w/v) sodium bicarbonate] for 0, 15, 30, and 60 min. An aqueous sodium bicarbonate solution demonstrated the greatest efficacy in degrading indospicine, with complete degradation after 15 min of heating in a microwave or autoclave; concomitant formation of indospicine degradation products, namely, 2-aminopimelamic and 2-aminopimelic acids, was observed. Similar treatment of indospicine-contaminated camel meat with aqueous sodium bicarbonate resulted in 50% degradation after 15 min of heating in an autoclave and 100% degradation after 15 min of heating in a microwave. The results suggest that thermo-alkaline aqueous treatment has potential as a pragmatic post-harvest handling technique in reducing indospicine levels in indospicine-contaminated meat.
[Mh] Termos MeSH primário: Camelus
Contaminação de Alimentos
Carne
Norleucina/análogos & derivados
[Mh] Termos MeSH secundário: Aminoácidos Neutros/análise
Animais
Cromatografia Líquida/métodos
Hidrólise
Espectrometria de Massas/métodos
Norleucina/análise
Norleucina/química
Ácidos Pimélicos/análise
Bicarbonato de Sódio/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-aminopimelamic acid); 0 (Amino Acids, Neutral); 0 (Pimelic Acids); 3721-85-5 (alpha-aminopimelic acid); 832C8OV84S (Norleucine); 8MDF5V39QO (Sodium Bicarbonate); X29Q4D9671 (indospicine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170621
[Lr] Data última revisão:
170621
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161015
[St] Status:MEDLINE


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[PMID]:26511532
[Au] Autor:Turk SC; Kloosterman WP; Ninaber DK; Kolen KP; Knutova J; Suir E; Schürmann M; Raemakers-Franken PC; Müller M; de Wildeman SM; Raamsdonk LM; van der Pol R; Wu L; Temudo MF; van der Hoeven RA; Akeroyd M; van der Stoel RE; Noorman HJ; Bovenberg RA; Trefzer AC
[Ad] Endereço:DSM Biotechnology Center , PO Box 1, 2600 MA Delft, The Netherlands.
[Ti] Título:Metabolic Engineering toward Sustainable Production of Nylon-6.
[So] Source:ACS Synth Biol;5(1):65-73, 2016 Jan 15.
[Is] ISSN:2161-5063
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nylon-6 is a bulk polymer used for many applications. It consists of the non-natural building block 6-aminocaproic acid, the linear form of caprolactam. Via a retro-synthetic approach, two synthetic pathways were identified for the fermentative production of 6-aminocaproic acid. Both pathways require yet unreported novel biocatalytic steps. We demonstrated proof of these bioconversions by in vitro enzyme assays with a set of selected candidate proteins expressed in Escherichia coli. One of the biosynthetic pathways starts with 2-oxoglutarate and contains bioconversions of the ketoacid elongation pathway known from methanogenic archaea. This pathway was selected for implementation in E. coli and yielded 6-aminocaproic acid at levels up to 160 mg/L in lab-scale batch fermentations. The total amount of 6-aminocaproic acid and related intermediates generated by this pathway exceeded 2 g/L in lab-scale fed-batch fermentations, indicating its potential for further optimization toward large-scale sustainable production of nylon-6.
[Mh] Termos MeSH primário: Caprolactama/análogos & derivados
Engenharia Metabólica/métodos
Polímeros/síntese química
[Mh] Termos MeSH secundário: Adipatos/metabolismo
Ácido Aminocaproico/metabolismo
Técnicas de Cultura Celular por Lotes
Caprolactama/síntese química
Cromatografia Líquida
Escherichia coli/genética
Escherichia coli/metabolismo
Fermentação
Metaboloma
Ácidos Pimélicos/metabolismo
Proteômica
Espectrometria de Massas em Tandem
Ácidos Tricarboxílicos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adipates); 0 (Pimelic Acids); 0 (Polymers); 0 (Tricarboxylic Acids); 25038-54-4 (nylon 6); 3562-74-1 (homocitric acid); 6879X594Z8 (Caprolactam); 76A0JE0FKJ (adipic acid); U6F3787206 (Aminocaproic Acid)
[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:151030
[St] Status:MEDLINE
[do] DOI:10.1021/acssynbio.5b00129


  5 / 404 MEDLINE  
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[PMID]:26394696
[Au] Autor:Huang L; Hu H; Tang H; Liu Y; Xu P; Shi J; Lin K; Luo Q; Cui C
[Ad] Endereço:State Environmental Protection Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resources and Environmental Engineering, East China University of Science and Technology, Shanghai 200237, People's Republic of China.
[Ti] Título:Identification and Characterization of a Novel Gentisate 1,2-Dioxygenase Gene from a Halophilic Martelella Strain.
[So] Source:Sci Rep;5:14307, 2015 Sep 23.
[Is] ISSN:2045-2322
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Halophilic Martelella strain AD-3, isolated from highly saline petroleum-contaminated soil, can efficiently degrade polycyclic aromatic hydrocarbons (PAHs), such as phenanthrene and anthracene, in 3-5% salinity. Gentisic acid is a key intermediate in the microbial degradation of PAH compounds. However, there is little information on PAH degradation by moderately halophilic bacteria. In this study, a 1,077-bp long gene encoding gentisate 1,2-dioxygenase (GDO) from a halophilic Martelella strain AD-3 was cloned, sequenced, and expressed in Escherichia coli. The recombinant enzyme GDO was purified and characterized in detail. By using the (18)O isotope experiment and LC-MS analysis, the sources of the two oxygen atoms added onto maleylpyruvate were identified as H2O and O2, respectively. The Km and kcat values for gentisic acid were determined to be 26.64 µM and 161.29 s(-1), respectively. In addition, optimal GDO activity was observed at 30 °C, pH 7.0, and at 12% salinity. Site-directed mutagenesis demonstrated the importance of four highly conserved His residues at positions 155, 157, 167, and 169 for enzyme activity. This finding provides new insights into mechanism and variety of gentisate 1,2-dioxygenase for PAH degradation in high saline conditions.
[Mh] Termos MeSH primário: Alphaproteobacteria/enzimologia
Alphaproteobacteria/genética
Antracenos/metabolismo
Dioxigenases/genética
Fenantrenos/metabolismo
Salinidade
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência de Bases
Biodegradação Ambiental
Clonagem Molecular
Escherichia coli/genética
Poluição por Petróleo
Ácidos Pimélicos/química
Alinhamento de Sequência
Análise de Sequência de DNA
Cloreto de Sódio/química
Solo/química
Microbiologia do Solo
Poluentes do Solo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anthracenes); 0 (Phenanthrenes); 0 (Pimelic Acids); 0 (Soil); 0 (Soil Pollutants); 0 (maleylpyruvic acid); 448J8E5BST (phenanthrene); 451W47IQ8X (Sodium Chloride); EC 1.13.11.- (Dioxygenases); EC 1.13.11.4 (gentisate 1,2-dioxygenase); EH46A1TLD7 (anthracene)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150924
[St] Status:MEDLINE
[do] DOI:10.1038/srep14307


  6 / 404 MEDLINE  
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[PMID]:26328874
[Au] Autor:Tian JS; Liu CC; Xiang H; Zheng XF; Peng GJ; Zhang X; Du GH; Qin XM
[Ad] Endereço:Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, P. R. China. qinxm@sxu.edu.cn.
[Ti] Título:Investigation on the antidepressant effect of sea buckthorn seed oil through the GC-MS-based metabolomics approach coupled with multivariate analysis.
[So] Source:Food Funct;6(11):3585-92, 2015 Nov.
[Is] ISSN:2042-650X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Depression is one of the prevalent and serious mental disorders and the number of depressed patients has been on the rise globally during the recent decades. Sea buckthorn seed oil from traditional Chinese medicine (TCM) is edible and has been widely used for treatment of different diseases for a long time. However, there are few published reports on the antidepressant effect of sea buckthorn seed oil. With the objective of finding potential biomarkers of the therapeutic response of sea buckthorn seed oil in chronic unpredictable mild stress (CUMS) rats, urine metabolomics based on gas chromatography-mass spectrometry (GC-MS) coupled with multivariate analysis was applied. In this study, we discovered a higher level of pimelic acid as well as palmitic acid and a lower level of suberic acid, citrate, phthalic acid, cinnamic acid and Sumiki's acid in urine of rats exposed to CUMS procedures after sea buckthorn seed oil was administered. These changes of metabolites are involved in energy metabolism, fatty acid metabolism and other metabolic pathways as well as in the synthesis of neurotransmitters and it is helpful to facilitate the efficacy evaluation and mechanism elucidating the effect of sea buckthorn seed oil for depression management.
[Mh] Termos MeSH primário: Antidepressivos/farmacologia
Depressão/tratamento farmacológico
Medicamentos de Ervas Chinesas/farmacologia
Hippophae/química
Metabolômica/métodos
Óleos Vegetais/farmacologia
Sementes/química
[Mh] Termos MeSH secundário: Animais
Biomarcadores/urina
Ácidos Carboxílicos/urina
Depressão/urina
Cromatografia Gasosa-Espectrometria de Massas
Masculino
Análise Multivariada
Ácidos Pimélicos/urina
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Biomarkers); 0 (Carboxylic Acids); 0 (Drugs, Chinese Herbal); 0 (Pimelic Acids); 0 (Plant Oils)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:151105
[Lr] Data última revisão:
151105
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150903
[St] Status:MEDLINE
[do] DOI:10.1039/c5fo00695c


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[PMID]:26043797
[Au] Autor:Choi PR; Kang YJ; Sung B; Kim JH; Moon HR; Chung HY; Kim SE; Park MI; Park SJ; Kim ND
[Ad] Endereço:Department of Gastroenterology, Kosin University Gospel Hospital, Busan 602-702, Republic of Korea.
[Ti] Título:MHY218-induced apoptotic cell death is enhanced by the inhibition of autophagy in AGS human gastric cancer cells.
[So] Source:Int J Oncol;47(2):563-72, 2015 Aug.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:We previously reported the anticancer effects of MHY218, which is a hydroxamic acid derivative, in HCT116 human colon cancer cells. In the present study, the involvement of autophagy in the MHY218-induced apoptotic cell death of AGS human gastric cancer cells was investigated. MHY218 treatment induced growth inhibition and apoptotic cell death in a concentration- and time-dependent manner. The induction of apoptosis was confirmed by observations of decreased viability, DNA fragmentation, and an increase in late apoptosis and sub-G1 DNA, which were detected with a flow cytometric analysis. Western blot analyses showed that MHY218 treatment resulted in decreased protein levels of procaspase-8, -9, and -3; cleavage of poly(ADP-ribose) polymerase (PARP); and alterations in the ratio of Bax/Bcl-2 protein expression. Apoptosis induced by MHY218 was involved in the activation of caspase-8, -9, and -3, and it was blocked by the addition of Z-VAD­FMK, a pan-caspase inhibitor. In addition, autophagy-inducing effects of MHY218 were indicated by cytoplasmic vacuolation, the accumulation of acidic vesicular organelles, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate dots, and increased levels of Beclin-1 and LC3-II protein expression. Pretreatment with the autophagy inhibitors LY294002, 3-methyladenine, chloroquine, and bafilomycin A1 enhanced the induction of apoptosis by MHY218, and this was accompanied by an increase in PARP cleavage. Taken together, these results provide new insights into the role of MHY218 as a potential antitumor agent. The combination of MHY218 with an autophagy inhibitor might be a useful candidate for the chemoprevention and/or treatment of gastric cancer.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Autofagia/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Éteres Fenílicos/farmacologia
Ácidos Pimélicos/farmacologia
Neoplasias Gástricas/tratamento farmacológico
[Mh] Termos MeSH secundário: Apoptose
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Cromonas/farmacologia
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Células HCT116
Seres Humanos
Morfolinas/farmacologia
Neoplasias Gástricas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Chromones); 0 (Morpholines); 0 (N1-hydroxy-N8-(4-phenoxyphenyl)octanediamide); 0 (Phenyl Ethers); 0 (Pimelic Acids); 31M2U1DVID (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150606
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2015.3031


  8 / 404 MEDLINE  
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[PMID]:24190633
[Au] Autor:Kim MK; Kang YJ; Kim DH; Hossain MA; Jang JY; Lee SH; Yoon JH; Chun P; Moon HR; Kim HS; Chung HY; Kim ND
[Ad] Endereço:Division of Pharmacy, College of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 609-735, Republic of Korea.
[Ti] Título:A novel hydroxamic acid derivative, MHY218, induces apoptosis and cell cycle arrest through downregulation of NF-κB in HCT116 human colon cancer cells.
[So] Source:Int J Oncol;44(1):256-64, 2014 Jan.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer (CRC) is one of the most common malignant diseases and frequent cause of cancer deaths in the world. In spite of the significant advances in conventional therapeutic approaches to CRC, most patients ultimately die of their disease. There is a need to develop novel preventive approaches for this malignancy. This study was carried out to investigate the anticancer effect of MHY218, a hydroxamic acid derivative, in HCT116 human colon cancer cells. Treatment of cells with MHY218 resulted in growth inhibition and induction of apoptosis in a concentration-dependent manner. MHY218 induced G2/M phase arrest in the cell cycle progression which was observed by flow cytometry analysis, and a decrease in the protein expression of cyclin B1 and its activating partners Cdc25C and Cdc2. MHY218 also caused an increase in the expression levels of p21(WAF1/CIP1), a G2/M phase inhibitor, in a p53-independent pathway. The induction of apoptosis was observed by decreased viability, DNA fragmentation, cleavage of poly(ADP-ribose) polymerase, alteration in the ratio of Bax/Bcl-2 protein expression, and activation of caspase-3, -8 and -9. In addition, MHY218 treatment showed downregulation of the expression levels of the transcription factor nuclear factor-kappa B (NF-κB) in the nucleus, which has been reported to be implicated in the apoptotic cell death of several types of cancer cells, suppression of TNF-α-induced NF-κB activation, inhibition of cyclooxygenase-2 expression, repression of matrix metalloproteinase-9 activation and decrease of 5-lipoxygenase in a concentration-dependent manner. These results suggest that MHY218 may be a useful candidate to be used in the chemoprevention and/or treatment of colon cancer.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Neoplasias do Colo/tratamento farmacológico
NF-kappa B/genética
Éteres Fenílicos/administração & dosagem
Ácidos Pimélicos/administração & dosagem
[Mh] Termos MeSH secundário: Pontos de Checagem do Ciclo Celular/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Neoplasias do Colo/genética
Neoplasias do Colo/patologia
Ciclina B1/biossíntese
Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Células HCT116
Seres Humanos
Ácidos Hidroxâmicos/administração & dosagem
NF-kappa B/metabolismo
Proteínas rho de Ligação ao GTP/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cyclin B1); 0 (Hydroxamic Acids); 0 (N1-hydroxy-N8-(4-phenoxyphenyl)octanediamide); 0 (NF-kappa B); 0 (Phenyl Ethers); 0 (Pimelic Acids); EC 3.6.5.2 (rho GTP-Binding Proteins)
[Em] Mês de entrada:1408
[Cu] Atualização por classe:131122
[Lr] Data última revisão:
131122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131106
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2013.2163


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[PMID]:24168322
[Au] Autor:Sanphui P; Tothadi S; Ganguly S; Desiraju GR
[Ad] Endereço:Solid State and Structural Chemistry Unit, Indian Institute of Science , Bangalore 560 012, India.
[Ti] Título:Salt and cocrystals of sildenafil with dicarboxylic acids: solubility and pharmacokinetic advantage of the glutarate salt.
[So] Source:Mol Pharm;10(12):4687-97, 2013 Dec 02.
[Is] ISSN:1543-8392
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.
[Mh] Termos MeSH primário: Ácidos Dicarboxílicos/química
Ácidos Dicarboxílicos/farmacocinética
Glutaratos/química
Glutaratos/farmacocinética
Piperazinas/química
Piperazinas/farmacocinética
Sais/química
Sulfonas/química
Sulfonas/farmacocinética
[Mh] Termos MeSH secundário: Animais
Área Sob a Curva
Disponibilidade Biológica
Cristalização
Fumaratos/química
Fumaratos/farmacocinética
Masculino
Ácido Oxálico/química
Ácido Oxálico/farmacocinética
Permeabilidade
Ácidos Pimélicos/química
Ácidos Pimélicos/farmacocinética
Purinas/química
Purinas/farmacocinética
Ratos
Ratos Sprague-Dawley
Sais/farmacocinética
Citrato de Sildenafila
Solubilidade
Ácido Succínico/química
Ácido Succínico/farmacocinética
Água/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Dicarboxylic Acids); 0 (Fumarates); 0 (Glutarates); 0 (Pimelic Acids); 0 (Piperazines); 0 (Purines); 0 (Salts); 0 (Sulfones); 059QF0KO0R (Water); 1RTM4PAL0V (piperazine); 88XHZ13131 (fumaric acid); 9E7R5L6H31 (Oxalic Acid); AB6MNQ6J6L (Succinic Acid); BW9B0ZE037 (Sildenafil Citrate); H849F7N00B (glutaric acid)
[Em] Mês de entrada:1407
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:131031
[St] Status:MEDLINE
[do] DOI:10.1021/mp400516b


  10 / 404 MEDLINE  
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[PMID]:23709504
[Au] Autor:Ikeda M; Miyamoto A; Mutoh S; Kitano Y; Tajima M; Shirakura D; Takasaki M; Mitsuhashi S; Takeno S
[Ad] Endereço:Department of Bioscience and Biotechnology, Faculty of Agriculture, Shinshu University, Nagano, Japan. m_ikeda@shinshu-u.ac.jp
[Ti] Título:Development of biotin-prototrophic and -hyperauxotrophic Corynebacterium glutamicum strains.
[So] Source:Appl Environ Microbiol;79(15):4586-94, 2013 Aug.
[Is] ISSN:1098-5336
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:To develop the infrastructure for biotin production through naturally biotin-auxotrophic Corynebacterium glutamicum, we attempted to engineer the organism into a biotin prototroph and a biotin hyperauxotroph. To confer biotin prototrophy on the organism, the cotranscribed bioBF genes of Escherichia coli were introduced into the C. glutamicum genome, which originally lacked the bioF gene. The resulting strain still required biotin for growth, but it could be replaced by exogenous pimelic acid, a source of the biotin precursor pimelate thioester linked to either coenzyme A (CoA) or acyl carrier protein (ACP). To bridge the gap between the pimelate thioester and its dedicated precursor acyl-CoA (or -ACP), the bioI gene of Bacillus subtilis, which encoded a P450 protein that cleaves a carbon-carbon bond of an acyl-ACP to generate pimeloyl-ACP, was further expressed in the engineered strain by using a plasmid system. This resulted in a biotin prototroph that is capable of the de novo synthesis of biotin. On the other hand, the bioY gene responsible for biotin uptake was disrupted in wild-type C. glutamicum. Whereas the wild-type strain required approximately 1 µg of biotin per liter for normal growth, the bioY disruptant (ΔbioY) required approximately 1 mg of biotin per liter, almost 3 orders of magnitude higher than the wild-type level. The ΔbioY strain showed a similar high requirement for the precursor dethiobiotin, a substrate for bioB-encoded biotin synthase. To eliminate the dependency on dethiobiotin, the bioB gene was further disrupted in both the wild-type strain and the ΔbioY strain. By selectively using the resulting two strains (ΔbioB and ΔbioBY) as indicator strains, we developed a practical biotin bioassay system that can quantify biotin in the seven-digit range, from approximately 0.1 µg to 1 g per liter. This bioassay proved that the engineered biotin prototroph of C. glutamicum produced biotin directly from glucose, albeit at a marginally detectable level (approximately 0.3 µg per liter).
[Mh] Termos MeSH primário: Biotina/genética
Corynebacterium glutamicum/genética
Engenharia Genética/métodos
Ácidos Pimélicos/metabolismo
[Mh] Termos MeSH secundário: Proteína de Transporte de Acila/genética
Proteína de Transporte de Acila/metabolismo
Biotina/análogos & derivados
Biotina/biossíntese
Coenzima A/genética
Coenzima A/metabolismo
Corynebacterium glutamicum/metabolismo
Escherichia coli/genética
Processos Fototróficos
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acyl Carrier Protein); 0 (Pimelic Acids); 6SO6U10H04 (Biotin); 71U5JB52KS (desthiobiotin); SAA04E81UX (Coenzyme A)
[Em] Mês de entrada:1310
[Cu] Atualização por classe:170220
[Lr] Data última revisão:
170220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130528
[St] Status:MEDLINE
[do] DOI:10.1128/AEM.00828-13



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