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  1 / 3194 MEDLINE  
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[PMID]:29372683
[Au] Autor:Sopková J; Vidomanová E; Strnádel J; Skovierová H; Halasová E
[Ad] Endereço:Department of Medical Biochemistry, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia. evablahovcova@yahoo.com.
[Ti] Título:The role of statins as therapeutic agents in cancer.
[So] Source:Gen Physiol Biophys;36(5):501-511, 2017 Dec.
[Is] ISSN:0231-5882
[Cp] País de publicação:Slovakia
[La] Idioma:eng
[Ab] Resumo:Statins are the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This enzyme catalyzes conversion of HMG-CoA to mevalonate, which are the intermediates in cholesterol biosynthetic pathway. Statins also play an important role in carcinogenesis, because they are able to affect the cancer cell metabolism. Their effect has been observed in several cellular processes, such as angiogenesis, metastasis, apoptosis and cell proliferation. However, these effects are highly dependent on type of cancer and individual statins vary in their antitumor potential. This review summarizes the recent epidemiological evidence and preclinical studies that showed effects of all clinically used statins in vitro and in vivo. We also consider the results of different observational and retrospective studies focused on association among statins and cancer risk which are still under open discussion.
[Mh] Termos MeSH primário: Carcinogênese/efeitos dos fármacos
Carcinogênese/metabolismo
Colesterol/metabolismo
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
Ácido Mevalônico/metabolismo
Neoplasias/tratamento farmacológico
Neoplasias/metabolismo
[Mh] Termos MeSH secundário: Carcinogênese/patologia
Relação Dose-Resposta a Droga
Medicina Baseada em Evidências
Feminino
Seres Humanos
Masculino
Modelos Biológicos
Neoplasias/patologia
Resultado do Tratamento
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 97C5T2UQ7J (Cholesterol); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180127
[St] Status:MEDLINE
[do] DOI:10.4149/gpb_2017045


  2 / 3194 MEDLINE  
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[PMID]:28882874
[Au] Autor:Loregger A; Raaben M; Tan J; Scheij S; Moeton M; van den Berg M; Gelberg-Etel H; Stickel E; Roitelman J; Brummelkamp T; Zelcer N
[Ad] Endereço:From the Department of Medical Biochemistry, Academic Medical Center of the University of Amsterdam, The Netherlands (A.L., J.T., S.S., M.M., M.v.d.B., N.Z.); Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam (M.R., E.S., T.B.); CeMM Research Center for Molecular Medicine of the
[Ti] Título:Haploid Mammalian Genetic Screen Identifies UBXD8 as a Key Determinant of HMGCR Degradation and Cholesterol Biosynthesis.
[So] Source:Arterioscler Thromb Vasc Biol;37(11):2064-2074, 2017 Nov.
[Is] ISSN:1524-4636
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: The cellular demand for cholesterol requires control of its biosynthesis by the mevalonate pathway. Regulation of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), a rate-limiting enzyme in this pathway and the target of statins, is a key control point herein. Accordingly, HMGCR is subject to negative and positive regulation. In particular, the ability of oxysterols and intermediates of the mevalonate pathway to stimulate its proteasomal degradation is an exquisite example of metabolically controlled feedback regulation. To define the genetic determinants that govern this process, we conducted an unbiased haploid mammalian genetic screen. APPROACH AND RESULTS: We generated human haploid cells with mNeon fused to endogenous HMGCR using CRISPR/Cas9 and used these cells to interrogate regulation of HMGCR abundance in live cells. This resulted in identification of known and new regulators of HMGCR, and among the latter, UBXD8 (ubiquitin regulatory X domain-containing protein 8), a gene that has not been previously implicated in this process. We demonstrate that UBXD8 is an essential determinant of metabolically stimulated degradation of HMGCR and of cholesterol biosynthesis in multiple cell types. Accordingly, UBXD8 ablation leads to aberrant cholesterol synthesis due to loss of feedback control. Mechanistically, we show that UBXD8 is necessary for sterol-stimulated dislocation of ubiquitylated HMGCR from the endoplasmic reticulum membrane en route to proteasomal degradation, a function dependent on its UBX domain. CONCLUSIONS: We establish UBXD8 as a previously unrecognized determinant that couples flux across the mevalonate pathway to control of cholesterol synthesis and demonstrate the feasibility of applying mammalian haploid genetics to study metabolic traits.
[Mh] Termos MeSH primário: Proteínas Sanguíneas/metabolismo
Colesterol/biossíntese
Haploidia
Hidroximetilglutaril-CoA Redutases/metabolismo
Proteínas de Membrana/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteínas Sanguíneas/genética
Sistemas CRISPR-Cas
Retículo Endoplasmático/enzimologia
Estabilidade Enzimática
Retroalimentação Fisiológica
Regulação Enzimológica da Expressão Gênica
Células Hep G2
Hepatócitos/enzimologia
Seres Humanos
Hidroximetilglutaril-CoA Redutases/genética
Proteínas de Membrana/genética
Ácido Mevalônico/metabolismo
Microscopia Confocal
Complexo de Endopeptidases do Proteassoma/metabolismo
Transporte Proteico
Proteólise
Ratos
Proteínas Recombinantes de Fusão/metabolismo
Transfecção
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (Blood Proteins); 0 (ETEA protein, human); 0 (Membrane Proteins); 0 (Recombinant Fusion Proteins); 97C5T2UQ7J (Cholesterol); EC 1.1.1.- (HMGCR protein, human); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases); EC 3.4.25.1 (Proteasome Endopeptidase Complex); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171123
[Lr] Data última revisão:
171123
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1161/ATVBAHA.117.310002


  3 / 3194 MEDLINE  
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[PMID]:28729418
[Au] Autor:Wang X; Huang Z; Wu Q; Prager BC; Mack SC; Yang K; Kim LJY; Gimple RC; Shi Y; Lai S; Xie Q; Miller TE; Hubert CG; Song A; Dong Z; Zhou W; Fang X; Zhu Z; Mahadev V; Bao S; Rich JN
[Ad] Endereço:Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio.
[Ti] Título:MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells.
[So] Source:Cancer Res;77(18):4947-4960, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Metabolic dysregulation drives tumor initiation in a subset of glioblastomas harboring isocitrate dehydrogenase (IDH) mutations, but metabolic alterations in glioblastomas with wild-type IDH are poorly understood. MYC promotes metabolic reprogramming in cancer, but targeting MYC has proven notoriously challenging. Here, we link metabolic dysregulation in patient-derived brain tumor-initiating cells (BTIC) to a nexus between MYC and mevalonate signaling, which can be inhibited by statin or 6-fluoromevalonate treatment. BTICs preferentially express mevalonate pathway enzymes, which we find regulated by novel MYC-binding sites, validating an additional transcriptional activation role of MYC in cancer metabolism. Targeting mevalonate activity attenuated RAS-ERK-dependent BTIC growth and self-renewal. In turn, mevalonate created a positive feed-forward loop to activate MYC signaling via induction of miR-33b. Collectively, our results argue that MYC mediates its oncogenic effects in part by altering mevalonate metabolism in glioma cells, suggesting a therapeutic strategy in this setting. .
[Mh] Termos MeSH primário: Neoplasias Encefálicas/patologia
Transformação Celular Neoplásica/patologia
Glioblastoma/patologia
Ácido Mevalônico/metabolismo
Células-Tronco Neoplásicas/patologia
Proteínas Proto-Oncogênicas c-myc/metabolismo
[Mh] Termos MeSH secundário: Animais
Apoptose
Biomarcadores Tumorais/genética
Biomarcadores Tumorais/metabolismo
Neoplasias Encefálicas/genética
Neoplasias Encefálicas/metabolismo
Proliferação Celular
Transformação Celular Neoplásica/metabolismo
Glioblastoma/genética
Glioblastoma/metabolismo
Seres Humanos
Isocitrato Desidrogenase/metabolismo
Camundongos
Camundongos Endogâmicos NOD
Camundongos SCID
MicroRNAs/genética
Células-Tronco Neoplásicas/metabolismo
Transdução de Sinais/efeitos dos fármacos
Células Tumorais Cultivadas
Ensaios Antitumorais Modelo de Xenoenxerto
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (MIRN33 microRNA, human); 0 (MicroRNAs); 0 (Proto-Oncogene Proteins c-myc); EC 1.1.1.41 (Isocitrate Dehydrogenase); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-17-0114


  4 / 3194 MEDLINE  
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[PMID]:28672185
[Au] Autor:You S; Yin Q; Zhang J; Zhang C; Qi W; Gao L; Tao Z; Su R; He Z
[Ad] Endereço:Chemical Engineering Research Center, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China.
[Ti] Título:Utilization of biodiesel by-product as substrate for high-production of ß-farnesene via relatively balanced mevalonate pathway in Escherichia coli.
[So] Source:Bioresour Technol;243:228-236, 2017 Nov.
[Is] ISSN:1873-2976
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Farnesene has been identified as suitable jet fuel substitutes and metabolic engineering for microbial production of farnesene is an alternative and attractive route. In this study, due to accumulation of toxic intermediate isopentenyl pyrophosphate (IPP), an engineered Escherichia coli strain harboring heterologous mevalonate pathway produced only 4.11mg/L ß-farnesene. Through higher-level expression of isopentenyl diphosphate isomerase and farnesyl diphosphate synthase to minimize the accumulated IPP, another engineered strain with relatively balanced mevalonate pathway was constructed and had the highest production of ß-farnesene to date (8.74g/L) by Escherichia coli in a lab bioreactor. Furthermore, this is the first report on utilization of biodiesel by-product (simple purification) as substrate for high-production of ß-farnesene by the engineered strain optimized and ß-farnesene concentration reached 2.83g/L in a lab bioreactor. Therefore, the engineered strain optimized could be used as a platform host for high-production of other terpenoids using biodiesel by-product as substrate.
[Mh] Termos MeSH primário: Biocombustíveis
Escherichia coli
Ácido Mevalônico
[Mh] Termos MeSH secundário: Sesquiterpenos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biofuels); 0 (Sesquiterpenes); 18794-84-8 (beta-farnesene); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171023
[Lr] Data última revisão:
171023
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170704
[St] Status:MEDLINE


  5 / 3194 MEDLINE  
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[PMID]:28668359
[Au] Autor:Ahmadi Y; Ghorbanihaghjo A; Argani H
[Ad] Endereço:Tabriz University of Medical Sciences, Student Research Committee, Tabriz, Iran; Tabriz University of Medical Sciences, Biotechnology Research Center, Tabriz, Iran. Electronic address: ahmadi.bchemistry@yahoo.com.
[Ti] Título:The balance between induction and inhibition of mevalonate pathway regulates cancer suppression by statins: A review of molecular mechanisms.
[So] Source:Chem Biol Interact;273:273-285, 2017 Aug 01.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Statins are widely used drugs for their role in decreasing cholesterol in hypercholesterolemic patients. Statins through inhibition of Hydroxy Methyl Glutaryl-CoA Reductase (HMGCR), the main enzyme of the cholesterol biosynthesis pathway, inhibit mevalonate pathway that provides isoprenoids for prenylation of different proteins such as Ras superfamily which has an essential role in cancer developing. Inhibition of the mevalonate/isoprenoid pathway is the cause of the cholesterol independent effects of statins or pleotropic effects. Depending on their penetrance into the extra-hepatic cells, statins have different effects on mevalonate/isoprenoid pathway. Lipophilic statins diffuse into all cells and hydrophilic ones use a variety of membrane transporters to gain access to cells other than hepatocytes. It has been suggested that the lower accessibility of statins for extra-hepatic tissues may result in the compensatory induction of mevalonate/isoprenoid pathway and so cancer developing. However, most of the population-based studies have demonstrated that statins have no effect on cancer developing, even decrease the risk of different types of cancer. In this review we focus on the cancer developing "potentials" and the anti-cancer "activities" of statins regarding the effects of statins on mevalonate/isoprenoid pathway in the liver and extra-hepatic tissues.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Neoplasias Hepáticas/tratamento farmacológico
Ácido Mevalônico/metabolismo
Terpenos/metabolismo
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Proliferação Celular/efeitos dos fármacos
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/metabolismo
Neoplasias Hepáticas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Terpenes); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171002
[Lr] Data última revisão:
171002
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170703
[St] Status:MEDLINE


  6 / 3194 MEDLINE  
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[PMID]:28603204
[Au] Autor:Yamashita Y; Matsumoto S; Hiramoto R; Komori I; Tanaka T; Nishikomori R; Heike T; Umetsu S; Inui A
[Ad] Endereço:Department of Pediatrics, Matsudo City Hospital Children's Medical Centre.
[Ti] Título:A 6-year-old girl diagnosed with mevalonate kinase deficiency who had hydrops fetalis and neonatal-onset cholestasis.
[So] Source:Nihon Rinsho Meneki Gakkai Kaishi;40(2):131-137, 2017.
[Is] ISSN:1349-7413
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo:We experienced a 6-year-old girl diagnosed with mevalonate kinase deficiency (MKD) who had cholestasis, anemia, and elevated inflammatory markers in neonatal period. She was admitted to our hospital because of fever and elevated inflammatory markers at 5 years 11months of age. Without using antibiotics, the fever and the inflammatory markers were spontaneously resolved. MKD was suspected from elevated serum IgD level and the recurrent febrile attacks. The genetic test revealed heterozygous mutation of p.Leu51Phe known as causative gene of MKD and p.Met 282Thr which is the novel mutation. In addition, urinary mevalonate levels increased both in afebrile and febrile periods, and mevalonate kinase activity level was very low. Prednisolone was administered on each attack, and her febrile attack has been controlled well since she was diagnosed with MKD. Fetal edema, cholestasis, anemia, elevation of inflammatory markers in her neonatal period are considered to be complications of MKD. Recurrent fever attacks compromise quality of life in patients with MKD. Children with unexplained cholestasis and anemia in neonatal period, or recurrent fever attacks with elevated inflammatory markers should be examined for MKD.
[Mh] Termos MeSH primário: Colestase/etiologia
Edema/etiologia
Deficiência de Mevalonato Quinase/complicações
Deficiência de Mevalonato Quinase/diagnóstico
[Mh] Termos MeSH secundário: Anemia/etiologia
Biomarcadores/sangue
Biomarcadores/urina
Criança
Feminino
Testes Genéticos
Seres Humanos
Imunoglobulina D/sangue
Deficiência de Mevalonato Quinase/tratamento farmacológico
Deficiência de Mevalonato Quinase/genética
Ácido Mevalônico/urina
Mutação
Fosfotransferases (Aceptor do Grupo Álcool)/genética
Prednisolona/administração & dosagem
Febre Recorrente/etiologia
Resultado do Tratamento
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers); 0 (Immunoglobulin D); 9PHQ9Y1OLM (Prednisolone); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.36 (mevalonate kinase); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171015
[Lr] Data última revisão:
171015
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170613
[St] Status:MEDLINE
[do] DOI:10.2177/jsci.40.131


  7 / 3194 MEDLINE  
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[PMID]:28524155
[Au] Autor:Gray RT; Loughrey MB; Bankhead P; Cardwell CR; McQuaid S; O'Neill RF; Arthur K; Bingham V; McGready C; Gavin AT; James JA; Hamilton PW; Salto-Tellez M; Murray LJ; Coleman HG
[Ad] Endereço:Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK.
[Ti] Título:Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study.
[So] Source:Br J Cancer;116(12):1652-1659, 2017 Jun 06.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Statin use after colorectal cancer diagnosis may improve survival but evidence from observational studies is conflicting. The anti-cancer effect of statins may be restricted to certain molecular subgroups. In this population-based cohort study, the interaction between p53 and 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) expression, KRAS mutations, and the association between statin use and colon cancer survival was assessed. METHODS: The cohort consisted of 740 stage II and III colon cancer patients diagnosed between 2004 and 2008. Statin use was determined through clinical note review. Tissue blocks were retrieved to determine immunohistochemical expression of p53 and HMGCR in tissue microarrays and the presence of KRAS mutations in extracted DNA. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for colorectal cancer-specific and overall survival. RESULTS: Statin use was not associated with improved cancer-specific survival in this cohort (HR=0.91, 95% CI 0.64-1.28). Statin use was also not associated with improved survival when the analyses were stratified by tumour p53 (wild-type HR=1.31, 95% CI 0.67-2.56 vs aberrant HR=0.80, 95% CI 0.52-1.24), HMGCR (HMGCR-high HR=0.69, 95% CI 0.40-1.18 vs HMGCR-low HR=1.10, 95% CI 0.66-1.84), and KRAS (wild-type HR=0.73, 95% CI 0.44-1.19 vs mutant HR=1.21, 95% CI 0.70-2.21) status. CONCLUSIONS: Statin use was not associated with improved survival either independently or when stratified by potential mevalonate pathway biomarkers in this population-based cohort of colon cancer patients.
[Mh] Termos MeSH primário: Neoplasias do Colo/química
Neoplasias do Colo/genética
Hidroximetilglutaril-CoA Redutases/análise
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Proteínas Proto-Oncogênicas p21(ras)/genética
Proteína Supressora de Tumor p53/análise
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Biomarcadores Tumorais/análise
Biomarcadores Tumorais/genética
Estudos de Coortes
Feminino
Seres Humanos
Masculino
Redes e Vias Metabólicas
Ácido Mevalônico/metabolismo
Meia-Idade
Taxa de Sobrevida
Proteína Supressora de Tumor p53/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (KRAS protein, human); 0 (Tumor Suppressor Protein p53); EC 1.1.1.- (Hydroxymethylglutaryl CoA Reductases); EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170822
[Lr] Data última revisão:
170822
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2017.139


  8 / 3194 MEDLINE  
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[PMID]:28302121
[Au] Autor:Ye L; He P; Li Q; Zhang X; Bi C
[Ad] Endereço:Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, People's Republic of China.
[Ti] Título:Type IIs restriction based combinatory modulation technique for metabolic pathway optimization.
[So] Source:Microb Cell Fact;16(1):47, 2017 Mar 16.
[Is] ISSN:1475-2859
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: One of the most important research subjects of metabolic engineering is pursuing a balanced metabolic pathway, which is the basis of an efficient cell factory. In this work, we dedicated to develop a simple and efficient technique to modulate expression of multiple genes simultaneously, and select for the optimal regulation pattern. RESULTS: A Type IIs restriction based combinatory modulation (TRCM) technique was designed and established in the research. With this technique, a plasmid library containing variably regulated mvaE, mvaS, mvaK , mvaD and mvaK of the mevalonate (MVA) pathway were obtained and transformed into E. coli DXS37-IDI46 to obtain a ß-carotene producer library. The ratio of successfully assembled plasmids was determined to be 35%, which was increased to 100% when color based pre-screening was applied. Representative strains were sequenced to contain diverse RBSs as designed to regulate expression of MVA pathway genes. A relatively balanced MVA pathway was achieved in E. coli cell factory to increase the ß-carotene yield by two fold. Furthermore, the approximate regulation pattern of this optimal MVA pathway was illustrated. CONCLUSIONS: A TRCM technique for metabolic pathway optimization was designed and established in this research, which can be applied to various applications in terms of metabolic pathway regulation and optimization.
[Mh] Termos MeSH primário: Engenharia Metabólica/métodos
Redes e Vias Metabólicas
[Mh] Termos MeSH secundário: Escherichia coli/genética
Escherichia coli/metabolismo
Biblioteca Gênica
Redes e Vias Metabólicas/genética
Ácido Mevalônico/metabolismo
Plasmídeos
beta Caroteno/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
01YAE03M7J (beta Carotene); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170420
[Lr] Data última revisão:
170420
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170318
[St] Status:MEDLINE
[do] DOI:10.1186/s12934-017-0659-z


  9 / 3194 MEDLINE  
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[PMID]:28300835
[Au] Autor:Agabiti SS; Li J; Wiemer AJ
[Ad] Endereço:Department of Pharmaceutical Sciences, University of Connecticut, School of Pharmacy, Storrs, CT, USA.
[Ti] Título:Geranylgeranyl diphosphate synthase inhibition induces apoptosis that is dependent upon GGPP depletion, ERK phosphorylation and caspase activation.
[So] Source:Cell Death Dis;8(3):e2678, 2017 Mar 16.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Bisphosphonates are diphosphate analogs that inhibit the intermediate enzymes of the mevalonate pathway. Here, we compared the effects of a farnesyl diphosphate synthase inhibitor, zoledronate, and a geranylgeranyl diphosphate synthase (GGDPS) inhibitor, digeranyl bisphosphonate (DGBP), on lymphocytic leukemia cell proliferation and apoptosis. Both zoledronate and DGBP inhibited proliferation with DGBP doing so more potently. DGBP was markedly less toxic than zoledronate toward the viability of healthy human peripheral blood mononuclear cells. Addition of GGPP, but not farnesyl diphosphate (FPP), prevented the anti-proliferative effects of DGBP. Both GGPP and FPP partially rescued the effects of zoledronate. Co-treatment with DGBP and zoledronate was antagonistic. To further assess the effects of the bisphosphonates, we analyzed annexin V and propidium iodide staining via flow cytometry and found that DGBP induced apoptosis more potently than zoledronate. Western blots show that DGBP treatment altered expression and membrane affinity of some but not all geranylgeranylated small GTPases, activated caspases and increased ERK phosphorylation. Importantly, the anti-proliferative effects of DGBP were blocked by treatment with a caspase inhibitor and by treatment with a MEK inhibitor. Together, our findings indicate that DGBP is a more potent and selective compound than zoledronate in inducing apoptosis mediated through pathways that include caspases and MEK/ERK. These findings support the further development of GGDPS inhibitors as anticancer therapeutics.
[Mh] Termos MeSH primário: Apoptose/efeitos dos fármacos
Caspases/metabolismo
Inibidores Enzimáticos/farmacologia
Farnesiltranstransferase/antagonistas & inibidores
Sistema de Sinalização das MAP Quinases/efeitos dos fármacos
Fosforilação/efeitos dos fármacos
Fosfatos de Poli-Isoprenil/farmacologia
[Mh] Termos MeSH secundário: Linhagem Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Difosfonatos/farmacologia
Seres Humanos
Imidazóis/farmacologia
Células Jurkat
Leucócitos Mononucleares/efeitos dos fármacos
Leucócitos Mononucleares/metabolismo
Ácido Mevalônico/metabolismo
Fosfatos de Poli-Isoprenil/metabolismo
Sesquiterpenos/metabolismo
Terpenos/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diphosphonates); 0 (Enzyme Inhibitors); 0 (Imidazoles); 0 (Polyisoprenyl Phosphates); 0 (Sesquiterpenes); 0 (Terpenes); 0 (digeranyl bisphosphonate); 6XC1PAD3KF (zoledronic acid); 79W6B01D07 (farnesyl pyrophosphate); EC 2.5.1.29 (Farnesyltranstransferase); EC 3.4.22.- (Caspases); N21T0D88LX (geranylgeranyl pyrophosphate); S5UOB36OCZ (Mevalonic Acid)
[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:170317
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2017.101


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[PMID]:28232115
[Au] Autor:Moutinho M; Nunes MJ; Rodrigues E
[Ad] Endereço:Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Portugal, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
[Ti] Título:The mevalonate pathway in neurons: It's not just about cholesterol.
[So] Source:Exp Cell Res;360(1):55-60, 2017 Nov 01.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cholesterol homeostasis greatly impacts neuronal function due to the essential role of this sterol in the brain. The mevalonate (MVA) pathway leads to the synthesis of cholesterol, but also supplies cells with many other intermediary molecules crucial for neuronal function. Compelling evidence point to a model in which neurons shutdown cholesterol synthesis, and rely on a shuttle derived from astrocytes to meet their cholesterol needs. Nevertheless, several reports suggest that neurons maintain the MVA pathway active, even with sustained cholesterol supply by astrocytes. Hence, in this review we focus not on cholesterol production, but rather on the role of the MVA pathway in the synthesis of particular intermediaries, namely isoprenoids, and on their role on neuronal function. Isoprenoids act as anchors for membrane association, after being covalently bound to proteins, such as most of the small guanosine triphosphate-binding proteins, which are critical to neuronal cell function. Based on literature, on our own results, and on the analysis of public transcriptomics databases, we raise the idea that in neurons there is a shift of the MVA pathway towards the non-sterol branch, responsible for isoprenoid synthesis, in detriment to post-squalene branch, and that this is ultimately essential for synaptic activity. Nevertheless new tools that facilitate imaging and the biochemical characterization and quantification of the prenylome in neurons and astrocytes are needed to understand the regulation of isoprenoid production and protein prenylation in the brain, and to analyze its differences on diverse physiological or pathological conditions, such as aging and neurodegenerative states.
[Mh] Termos MeSH primário: Colesterol/metabolismo
Ácido Mevalônico/metabolismo
Neurônios/metabolismo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Seres Humanos
Neurônios/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
97C5T2UQ7J (Cholesterol); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE



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