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[PMID]:28813599
[Au] Autor:Thapa HR; Tang S; Sacchettini JC; Devarenne TP
[Ad] Endereço:Department of Biochemistry & Biophysics, Texas A&M University , College Station, Texas 77843, United States.
[Ti] Título:Tetraterpene Synthase Substrate and Product Specificity in the Green Microalga Botryococcus braunii Race L.
[So] Source:ACS Chem Biol;12(9):2408-2416, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Recently, the biosynthetic pathway for lycopadiene, a C tetraterpenoid hydrocarbon, was deciphered from the L race of Botryococcus braunii, an alga that produces hydrocarbon oils capable of being converted into combustible fuels. The lycopadiene pathway is initiated by the squalene synthase (SS)-like enzyme lycopaoctaene synthase (LOS), which catalyzes the head-to-head condensation of two C geranylgeranyl diphosphate (GGPP) molecules to produce C lycopaoctaene. LOS shows unusual substrate promiscuity for SS or SS-like enzymes by utilizing C farnesyl diphosphate (FPP) and C phytyl diphosphate in addition to GGPP as substrates. These three substrates can be combined by LOS individually or in combinations to produce six different hydrocarbons of C , C , and C chain lengths. To understand LOS substrate and product specificity, rational mutagenesis experiments were conducted based on sequence alignment with several SS proteins as well as a structural comparison with the human SS (HSS) crystal structure. Characterization of the LOS mutants in vitro identified Ser276 and Ala288 in the LOS active site as key amino acids responsible for controlling substrate binding, and thus the promiscuity of this enzyme. Mutating these residues to those found in HSS largely converted LOS from lycopaoctaene production to C squalene production. Furthermore, these studies were confirmed in vivo by expressing LOS in E. coli cells metabolically engineered to produce high FPP and GGPP levels. These studies also offer insights into tetraterpene hydrocarbon metabolism in B. braunii and provide a foundation for engineering LOS for robust production of specific hydrocarbons of a desired chain length.
[Mh] Termos MeSH primário: Clorófitas/enzimologia
Farnesil-Difosfato Farnesiltransferase/metabolismo
Microalgas/enzimologia
Fosfatos de Poli-Isoprenil/metabolismo
Esqualeno/metabolismo
Terpenos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Vias Biossintéticas
Clorófitas/química
Clorófitas/metabolismo
Farnesil-Difosfato Farnesiltransferase/química
Seres Humanos
Microalgas/química
Microalgas/metabolismo
Modelos Moleculares
Alinhamento de Sequência
Sesquiterpenos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polyisoprenyl Phosphates); 0 (Sesquiterpenes); 0 (Terpenes); 79W6B01D07 (farnesyl pyrophosphate); 7QWM220FJH (Squalene); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase); N21T0D88LX (geranylgeranyl pyrophosphate)
[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:170817
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00457


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[PMID]:28728107
[Au] Autor:Katselou MG; Matralis AN; Kourounakis AP
[Ad] Endereço:Division of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, National and Kapodistrian University of Athens, 15771 Athens, Greece.
[Ti] Título:Developing potential agents against atherosclerosis: Design, synthesis and pharmacological evaluation of novel dual inhibitors of oxidative stress and Squalene Synthase activity.
[So] Source:Eur J Med Chem;138:748-760, 2017 Sep 29.
[Is] ISSN:1768-3254
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:For the treatment of multifactorial and complex diseases, it has become increasingly apparent that compounds acting at multiple targets often deliver superior efficacy compared to compounds with high specificity for only a single target. Based on previous studies demonstrating the important antioxidant and anti-hyperlipidemic effect of morpholine and 1,4-benzo(x/thi)azine derivatives (A-E), we hereby present the design, synthesis and pharmacological evaluation of novel dual-acting molecules as a therapeutic approach for atherosclerosis. Analogues 1-10 were rationally designed through structural modifications of their parent compounds (A-E) in order for structure-activity relationship studies to be carried out. Most compounds showed a significant inhibition against Squalene Synthase activity exhibiting at the same time a very potent multimodal antioxidant (against lipid peroxidation and as free-radical scavengers) effect, thus bringing to light the 2-aryl-1,4-benzo(x/thia)zin-2-ol scaffold as an outstanding pharmacophore for the design of potent antioxidants. Finally, the replacement of the octahydro-1,4-benzoxazine moiety of lead compound D with its respective 1,4-benzothiazine (compound 4), although conserved (anti-hypercholesterolemic) or even improved (anti-hyperlipidemic) activity, did not preserve the anti-diabetic effect of D.
[Mh] Termos MeSH primário: Aterosclerose/tratamento farmacológico
Diabetes Mellitus Tipo 2/tratamento farmacológico
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores
Hipolipemiantes/farmacologia
[Mh] Termos MeSH secundário: Animais
Ciclo-Oxigenase 1/metabolismo
Ciclo-Oxigenase 2/metabolismo
Diabetes Mellitus Tipo 2/induzido quimicamente
Modelos Animais de Doenças
Relação Dose-Resposta a Droga
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Farnesil-Difosfato Farnesiltransferase/metabolismo
Seres Humanos
Hipolipemiantes/síntese química
Hipolipemiantes/química
Masculino
Camundongos
Camundongos Pelados
Estrutura Molecular
Morfolinas/síntese química
Morfolinas/química
Morfolinas/farmacologia
Estresse Oxidativo/efeitos dos fármacos
Ratos
Relação Estrutura-Atividade
Tiazinas/síntese química
Tiazinas/química
Tiazinas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1,4-benzothiazine); 0 (Enzyme Inhibitors); 0 (Hypolipidemic Agents); 0 (Morpholines); 0 (Thiazines); 8B2ZCK305O (morpholine); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Cyclooxygenase 2); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
[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:170721
[St] Status:MEDLINE


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[PMID]:28360334
[Au] Autor:Kerr AG; Tam LCS; Hale AB; Cioroch M; Douglas G; Agkatsev S; Hibbitt O; Mason J; Holt-Martyn J; Bataille CJR; Wynne GM; Channon KM; Russell AJ; Wade-Martins R
[Ad] Endereço:Departments of Physiology, Anatomy, and Genetics (A.G.K., L.C.S.T., M.C., S.A., O.H., J.H.-M., R.W.-M.) and Pharmacology (A.J.R.), University of Oxford, Oxford, United Kingdom; Division of Cardiovascular Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, John Rad
[Ti] Título:A Genomic DNA Reporter Screen Identifies Squalene Synthase Inhibitors That Act Cooperatively with Statins to Upregulate the Low-Density Lipoprotein Receptor.
[So] Source:J Pharmacol Exp Ther;361(3):417-428, 2017 Jun.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Hypercholesterolemia remains one of the leading risk factors for the development of cardiovascular disease. Many large double-blind studies have demonstrated that lowering low-density lipoprotein (LDL) cholesterol using a statin can reduce the risk of having a cardiovascular event by approximately 30%. However, despite the success of statins, some patient populations are unable to lower their LDL cholesterol to meet the targeted lipid levels, due to compliance or potency issues. This is especially true for patients with heterozygous familial hypercholesterolemia who may require additional upregulation of the low-density lipoprotein receptor (LDLR) to reduce LDL cholesterol levels below those achievable with maximal dosing of statins. Here we identify a series of small molecules from a genomic DNA reporter screen that upregulate the LDLR in mouse and human liver cell lines at nanomolar potencies (EC = 39 nM). Structure-activity relationship studies carried out on the lead compound, OX03771 [( )- , -dimethyl-3-(4-styrylphenoxy)propan-1-amine], led to the identification of compound OX03050 [( )-3-(4-styrylphenoxy)propan-1-ol], which had similar potency (EC = 26 nM) but a much-improved pharmacokinetic profile and showed in vivo efficacy. Compounds OX03050 and OX03771 were found to inhibit squalene synthase, the first committed step in cholesterol biosynthesis. These squalene synthase inhibitors were shown to act cooperatively with statins to increase LDLR expression in vitro. Overall, we demonstrated here a novel series of small molecules with the potential to be further developed to treat patients either alone or in combination with statins.
[Mh] Termos MeSH primário: Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores
Testes Genéticos/métodos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem
Receptores de LDL/biossíntese
Bibliotecas de Moléculas Pequenas/administração & dosagem
Regulação para Cima/fisiologia
[Mh] Termos MeSH secundário: Animais
Células CHO
Linhagem Celular Tumoral
Cricetinae
Cricetulus
Relação Dose-Resposta a Droga
Sinergismo Farmacológico
Inibidores Enzimáticos
Farnesil-Difosfato Farnesiltransferase/metabolismo
Seres Humanos
Masculino
Camundongos
Bibliotecas de Moléculas Pequenas/farmacologia
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (LDLR protein, human); 0 (Receptors, LDL); 0 (Small Molecule Libraries); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170614
[Lr] Data última revisão:
170614
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170401
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.239574


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[PMID]:27884675
[Au] Autor:Jiang D; Rong Q; Chen Y; Yuan Q; Shen Y; Guo J; Yang Y; Zha L; Wu H; Huang L; Liu C
[Ad] Endereço:School of Chinese Pharmacy, Beijing University of Chinese Medicine, Beijing 100102, China; State Key Laboratory Breeding Base of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
[Ti] Título:Molecular cloning and functional analysis of squalene synthase (SS) in Panax notoginseng.
[So] Source:Int J Biol Macromol;95:658-666, 2017 Feb.
[Is] ISSN:1879-0003
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Panax notoginseng (Burk.) F. H. Chen, which is a used traditional Chinese medicine known as Sanqi or Tianqi in China, is widely studied for its ability to accumulate the triterpene saponins. Squalene synthase (SS: EC 2.5.1.21) catalyzes the first enzymatic step from the central isoprenoid pathway toward sterol and triterpenoid biosynthesis. In this study, SS from P. notoginseng was cloned and investigated followed by its recombinant expression and preliminary enzyme activity. The nucleotide sequence of the ORF contains 1 248 nucleotides and encodes 415 amino acid residues with molecular weight of 47.16kDa and pI of 6.50. Bioinformatics analysis revealed that the deduced PnSS protein had a high similarity with other plant squalene synthases. To obtain soluble recombinant enzymes, 29 hydrophobic amino acids were deleted from the carboxy terminus and expressed as GST-Tag fusion protein in Escherichia coli BL21 (DE3). Approximately 66.46kDa recombinant protein was checked on SDS-PAGE and Western Blot analysis. Preliminary activity of the resultant bacterial crude extract was analyzed by gas chromatograph-mass spectrometer (GC-MS). The identification and function of PnSS is important for further studies of the triterpene saponins biosynthesis in P. notoginseng.
[Mh] Termos MeSH primário: Farnesil-Difosfato Farnesiltransferase/química
Farnesil-Difosfato Farnesiltransferase/metabolismo
Panax notoginseng/enzimologia
Panax notoginseng/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sequência de Bases
Clonagem Molecular
Farnesil-Difosfato Farnesiltransferase/genética
Farnesil-Difosfato Farnesiltransferase/isolamento & purificação
Seres Humanos
Modelos Moleculares
Filogenia
Conformação Proteica
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/isolamento & purificação
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Recombinant Proteins); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170411
[Lr] Data última revisão:
170411
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161126
[St] Status:MEDLINE


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[PMID]:27725246
[Au] Autor:Liu M; Li LN; Pan YT; Kong JQ
[Ad] Endereço:Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College (State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Ministry of Health Key Laboratory of Biosynthesis of Natural Products), Beijing, 100050, China.
[Ti] Título:cDNA isolation and functional characterization of squalene synthase gene from Ornithogalum caudatum.
[So] Source:Protein Expr Purif;130:63-72, 2017 Feb.
[Is] ISSN:1096-0279
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:As the first step of ongoing efforts to investigate the genes responsible for the biosynthesis of steroidal saponins in the medicinal plant Ornithogalum caudatum, this investigation reported the cDNA isolation, prokaryotic expression and functional characterization of squalene synthase (SQS) gene from O. caudatum for the first time. Specifically, two unigenes showing high sequence identity to SQS were retrieved from RNA-Taq data, and then a full-length OcSQS1 corresponding to the two unigenes was isolated from O. caudatum genome by a nested PCR assay. The open reading frame of OcSQS1 was 1230 bp and encoded a polypeptide of 409 aa. OcSQS1 was predicted to be a membrane-bound protein with at least four conserved motifs associated with binding, regulatory and catalytic activities of OcSQS1 and two transmembrane domains. Next, many attempts to generate soluble OcSQS1 in heterologous Escherichia coli were made, including optimization of expression conditions, application of varied expression plasmids with different tags, secretory peptides and molecular chaperones, and truncated mutation of OcSQS1. Finally, the successful availability of a soluble, truncated OcSQS1 mutant was achieved by combinational use of the utensils from the vast genetic toolbook. Moreover, this truncated OcSQS1 mutant retained the folding capability as well as its catalytic activity, converting FPP to form squalene. Importantly, the present research tentatively verified the involvement of the second transmembrane domain in the proper folding of the recombinant OcSQS1 protein.
[Mh] Termos MeSH primário: Clonagem Molecular
DNA Complementar
Escherichia coli/metabolismo
Farnesil-Difosfato Farnesiltransferase
Ornithogalum/genética
Proteínas de Plantas
[Mh] Termos MeSH secundário: DNA Complementar/genética
DNA Complementar/isolamento & purificação
Escherichia coli/genética
Farnesil-Difosfato Farnesiltransferase/biossíntese
Farnesil-Difosfato Farnesiltransferase/química
Farnesil-Difosfato Farnesiltransferase/genética
Farnesil-Difosfato Farnesiltransferase/isolamento & purificação
Ornithogalum/enzimologia
Proteínas de Plantas/biossíntese
Proteínas de Plantas/química
Proteínas de Plantas/genética
Proteínas de Plantas/isolamento & purificação
Proteínas Recombinantes/biossíntese
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/isolamento & purificação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Complementary); 0 (Plant Proteins); 0 (Recombinant Proteins); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170713
[Lr] Data última revisão:
170713
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161012
[St] Status:MEDLINE


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[PMID]:27649606
[Au] Autor:Zhang P; Cao X; Li C; Zheng Z; Yong S; Jiang JH
[Ad] Endereço:Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, Jiangsu Normal University, Xuzhou, China.
[Ti] Título:Cloning and Characterization of a Squalene Synthase Gene from the Chaga Medicinal Mushroom, Inonotus obliquus (Agaricomycetes).
[So] Source:Int J Med Mushrooms;18(5):445-55, 2016.
[Is] ISSN:1940-4344
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Squalene synthase catalyzes the condensation of 2 molecules of farnesyl diphosphate to produce squalene, the first committed precursor for sterol, brassinosteroid, and triterpene biosynthesis. A squalene synthase gene, designated IoSQS, was isolated from Inonotus obliquus, a medicinal mushroom that produces a plethora of bioactive triterpenes. IoSQS complementary DNA was found to contain an open reading frame of 1476 bp, encoding a protein of 491 amino acids with a calculated molecular mass of 55.85 kDa. The IoSQS genomic DNA sequence consisted of 1813 bp and contained 4 exons and 3 introns. The restriction fragment polymorphisms revealed by Southern blot analysis suggested that IoSQS was a single-copy gene. Promoter analysis indicated that the 5' upstream region of IoSQS possessed various potential elements associated with physiological and environmental factors. The expression pattern of IoSQS in different stages and under methyl jasmonate treatment correlated with the accumulation of total triterpenoids and was consistent with the predicted results of the IoSQS promoter region. The N-terminal 466 residues of the hydrophilic sequence were expressed as a His-tagged protein in Escherichia coli, and the resultant bacterial crude extract was incubated with farnesyl diphosphate and NADPH. Squalene was detected in vitro in reaction mixture by high-performance liquid chromatography analysis. These results suggest that the IoSQS enzyme is involved in squalene production in I. obliquus.
[Mh] Termos MeSH primário: Agaricales/enzimologia
Agaricales/genética
Clonagem Molecular
Farnesil-Difosfato Farnesiltransferase/metabolismo
[Mh] Termos MeSH secundário: Agaricales/metabolismo
Sequência de Bases
Southern Blotting
DNA Complementar/genética
DNA Fúngico/genética
Escherichia coli/metabolismo
Farnesil-Difosfato Farnesiltransferase/genética
Regulação Enzimológica da Expressão Gênica
Regulação Fúngica da Expressão Gênica
Filogenia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Complementary); 0 (DNA, Fungal); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170310
[Lr] Data última revisão:
170310
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160922
[St] Status:MEDLINE


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[PMID]:27320012
[Au] Autor:Linscott KB; Niehaus TD; Zhuang X; Bell SA; Chappell J
[Ad] Endereço:Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506-9983, United States.
[Ti] Título:Mapping a kingdom-specific functional domain of squalene synthase.
[So] Source:Biochim Biophys Acta;1861(9 Pt A):1049-1057, 2016 09.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Squalene synthase catalyzes the first committed step in sterol biosynthesis and consists of both an amino-terminal catalytic domain and a carboxy-terminal domain tethering the enzyme to the ER membrane. While the overall architecture of this enzyme is identical in eukaryotes, it was previously shown that plant and animal genes cannot complement a squalene synthase knockout mutation in yeast unless the carboxy-terminal domain is swapped for one of fungal origin. This implied a unique component of the fungal carboxy-terminal domain was responsible for the complementation phenotype. To identify this motif, we used Saccharomyces cerevisiae with a squalene synthase knockout mutation, and expressed intact and chimeric squalene synthases originating from fungi, plants, and animals. In contrast to previous observations, all enzymes tested could partially complement the knockout mutation when the genes were weakly expressed. However, when highly expressed, non-fungal squalene synthases could not complement the yeast mutation and instead led to the accumulation of a toxic intermediate(s) as defined by mutations of genes downstream in the ergosterol pathway. Restoration of the complete complementation phenotype was mapped to a 26-amino acid hinge region linking the catalytic and membrane-spanning domains specific to fungal squalene synthases. Over-expression of the C-terminal domain containing a hinge domain from fungi, not from animals or plants, led to growth inhibition of wild-type yeast. Because this hinge region is unique to and highly conserved within each kingdom of life, the data suggests that the hinge domain plays an essential functional role, such as assembly of ergosterol multi-enzyme complexes in fungi.
[Mh] Termos MeSH primário: Farnesil-Difosfato Farnesiltransferase/genética
Saccharomyces cerevisiae/genética
Esqualeno/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos/genética
Ergosterol/metabolismo
Farnesil-Difosfato Farnesiltransferase/metabolismo
Técnicas de Inativação de Genes
Mutação
Saccharomyces cerevisiae/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
7QWM220FJH (Squalene); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase); Z30RAY509F (Ergosterol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170830
[Lr] Data última revisão:
170830
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160621
[St] Status:MEDLINE


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[PMID]:27120199
[Au] Autor:Hong YF; Kim H; Kim HS; Park WJ; Kim JY; Chung DK
[Ad] Endereço:Graduate School of Biotechnology and Institute of Life Science and Resources, Kyung Hee University, Yongin, 446-701, Republic of Korea.
[Ti] Título:Lactobacillus acidophilus K301 Inhibits Atherogenesis via Induction of 24 (S), 25-Epoxycholesterol-Mediated ABCA1 and ABCG1 Production and Cholesterol Efflux in Macrophages.
[So] Source:PLoS One;11(4):e0154302, 2016.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lactobacillus acidophilus species are well-known probiotics with the beneficial activity of regulating cholesterol levels. In this study, we showed that L. acidophilus K301 reduced the level of cholesterol through reverse transport in macrophages. L. acidophilus K301 upregulated the mRNA and protein levels of genes such as ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) under the control of liver X receptor (LXR), resulting in increased apoA-I-dependent cholesterol efflux in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells. L. acidophilus K301 induced both ABCA1 and ABCG1 through the endogenous LXR agonist 24(S), 25-epoxcycholesterol, which is synthesized by intracellular cholesterol synthetic pathways. In vivo studies using L. acidophilus K301-treated ApoE-/- mice showed reduced accumulation of lipoproteins in the arterial lumen. The inhibitory effects of L. acidophilus K301 on accumulation of lipoprotein in atherosclerotic plaques were mediated by the induction of squalene reductase (SQLE) and oxidosqualene cyclase (OSC) and resulted in ABCA1-mediated cholesterol efflux. Taken together, our findings revealed that Lactobacillus acidophilus K301 regulates the expression of genes related to cholesterol reverse transport via the induction of endogenous LXR agonist, suggesting the therapeutic potential of Lactobacillus acidophilus K301 as an anti-atherosclerotic agent.
[Mh] Termos MeSH primário: Transportador 1 de Cassete de Ligação de ATP/metabolismo
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo
Aterosclerose/prevenção & controle
Colesterol/análogos & derivados
Lactobacillus acidophilus/fisiologia
Placa Aterosclerótica/prevenção & controle
Probióticos/farmacologia
[Mh] Termos MeSH secundário: Transportador 1 de Cassete de Ligação de ATP/genética
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética
Animais
Apolipoproteína A-I/genética
Apolipoproteína A-I/metabolismo
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Aterosclerose/genética
Aterosclerose/metabolismo
Aterosclerose/patologia
Transporte Biológico
Linhagem Celular
Colesterol/metabolismo
Farnesil-Difosfato Farnesiltransferase/genética
Farnesil-Difosfato Farnesiltransferase/metabolismo
Regulação da Expressão Gênica
Células HEK293
Seres Humanos
Transferases Intramoleculares/genética
Transferases Intramoleculares/metabolismo
Receptores X do Fígado/genética
Receptores X do Fígado/metabolismo
Macrófagos/citologia
Macrófagos/efeitos dos fármacos
Macrófagos/metabolismo
Camundongos
Camundongos Knockout
Placa Aterosclerótica/genética
Placa Aterosclerótica/metabolismo
Placa Aterosclerótica/patologia
Transdução de Sinais
Acetato de Tetradecanoilforbol/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (ABCA1 protein, mouse); 0 (ABCG1 protein, mouse); 0 (ATP Binding Cassette Transporter 1); 0 (ATP Binding Cassette Transporter, Sub-Family G, Member 1); 0 (Apolipoprotein A-I); 0 (Apolipoproteins E); 0 (Liver X Receptors); 68138-65-8 (24,25-epoxycholesterol); 97C5T2UQ7J (Cholesterol); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.7 (lanosterol synthase); NI40JAQ945 (Tetradecanoylphorbol Acetate)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170316
[Lr] Data última revisão:
170316
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160428
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0154302


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[PMID]:27050299
[Au] Autor:Thapa HR; Naik MT; Okada S; Takada K; Molnár I; Xu Y; Devarenne TP
[Ad] Endereço:Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, USA.
[Ti] Título:A squalene synthase-like enzyme initiates production of tetraterpenoid hydrocarbons in Botryococcus braunii Race L.
[So] Source:Nat Commun;7:11198, 2016 Apr 06.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The green microalga Botryococcus braunii is considered a promising biofuel feedstock producer due to its prodigious accumulation of hydrocarbon oils that can be converted into fuels. B. braunii Race L produces the C40 tetraterpenoid hydrocarbon lycopadiene via an uncharacterized biosynthetic pathway. Structural similarities suggest this pathway follows a biosynthetic mechanism analogous to that of C30 squalene. Confirming this hypothesis, the current study identifies C20 geranylgeranyl diphosphate (GGPP) as a precursor for lycopaoctaene biosynthesis, the first committed intermediate in the production of lycopadiene. Two squalene synthase (SS)-like complementary DNAs are identified in race L with one encoding a true SS and the other encoding an enzyme with lycopaoctaene synthase (LOS) activity. Interestingly, LOS uses alternative C15 and C20 prenyl diphosphate substrates to produce combinatorial hybrid hydrocarbons, but almost exclusively uses GGPP in vivo. This discovery highlights how SS enzyme diversification results in the production of specialized tetraterpenoid oils in race L of B. braunii.
[Mh] Termos MeSH primário: Proteínas de Algas/metabolismo
Clorófitas/metabolismo
Farnesil-Difosfato Farnesiltransferase/metabolismo
Esqualeno/análogos & derivados
Terpenos/metabolismo
[Mh] Termos MeSH secundário: Proteínas de Algas/genética
Biocatálise
Clorófitas/genética
Clonagem Molecular
DNA Complementar/genética
DNA Complementar/metabolismo
Ensaios Enzimáticos
Escherichia coli/genética
Escherichia coli/metabolismo
Farnesil-Difosfato Farnesiltransferase/genética
Expressão Gênica
Isoenzimas/genética
Isoenzimas/metabolismo
Cinética
Fosfatos de Poli-Isoprenil/metabolismo
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Esqualeno/metabolismo
Especificidade por Substrato
Trítio/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Algal Proteins); 0 (DNA, Complementary); 0 (Isoenzymes); 0 (Polyisoprenyl Phosphates); 0 (Recombinant Proteins); 0 (Terpenes); 10028-17-8 (Tritium); 7QWM220FJH (Squalene); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase); N21T0D88LX (geranylgeranyl pyrophosphate)
[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:160407
[St] Status:MEDLINE
[do] DOI:10.1038/ncomms11198


  10 / 537 MEDLINE  
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[PMID]:27011383
[Au] Autor:Ebihara T; Takeuchi T; Moriya Y; Tagawa Y; Kondo T; Moriwaki T; Asahi S
[Ad] Endereço:Pharmaceutical Research Division, Drug Metabolism and Pharmacokinetics Research Laboratories, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
[Ti] Título:Characterization of Transporters in the Hepatic Uptake of TAK-475 M-I, a Squalene Synthase Inhibitor, in Rats and Humans.
[So] Source:Drug Res (Stuttg);66(6):316-23, 2016 Jun.
[Is] ISSN:2194-9387
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:TAK-475 (lapaquistat acetate) is a squalene synthase inhibitor and M-I is a pharmacologically active metabolite of TAK-475. Preclinical pharmacokinetic studies have demonstrated that most of the dosed TAK-475 was hydrolyzed to M-I during the absorption process and the concentrations of M-I in the liver, the main organ of cholesterol biosynthesis, were much higher than those in the plasma after oral administration to rats. In the present study, the mechanism of the hepatic uptake of M-I was investigated.The uptake studies of (14)C-labeled M-I into rat and human hepatocytes indicated that the uptakes of M-I were concentrative, temperature-dependent and saturable in both species with Km values of 4.7 and 2.8 µmol/L, respectively. M-I uptake was also inhibited by cyclosporin A, an inhibitor for hepatic uptake transporters including organic anion transporting polypeptide (OATP). In the human hepatocytes, M-I uptake was hardly inhibited by estrone 3-sulfate as an inhibitor for OATP1B1, and most of the M-I uptake was Na(+)-independent. Uptake studies using human transporter-expressing cells revealed the saturable uptake of M-I for OATP1B3 with a Km of 2.13 µmol/L. No obvious uptake of M-I was observed in the OATP1B1-expressing cells.These results indicated that M-I was taken up into hepatocytes via transporters in both rats and humans. OATP1B3 would be mainly involved in the hepatic uptake of M-I in humans. These findings suggested that hepatic uptake transporters might contribute to the liver-selective inhibition of cholesterol synthesis by TAK-475. This is the first to clarify a carrier-mediated hepatic uptake mechanism for squalene synthase inhibitors.
[Mh] Termos MeSH primário: Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores
Fígado/metabolismo
Oxazepinas/metabolismo
Piperidinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Radioisótopos de Carbono
Células Cultivadas
Ciclosporina/farmacologia
Estrona/análogos & derivados
Estrona/farmacologia
Hepatócitos/metabolismo
Seres Humanos
Fígado/citologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid); 0 (Carbon Radioisotopes); 0 (Oxazepines); 0 (Piperidines); 2DI9HA706A (Estrone); 83HN0GTJ6D (Cyclosporine); EC 2.5.1.21 (Farnesyl-Diphosphate Farnesyltransferase); QTL48N278K (estrone sulfate)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170504
[Lr] Data última revisão:
170504
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160325
[St] Status:MEDLINE
[do] DOI:10.1055/s-0035-1569441



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