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  1 / 1397 MEDLINE  
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[PMID]:28919416
[Au] Autor:Martín Del Campo JS; Eckshtain-Levi M; Sobrado P
[Ad] Endereço:Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA.
[Ti] Título:Identification of eukaryotic UDP-galactopyranose mutase inhibitors using the ThermoFAD assay.
[So] Source:Biochem Biophys Res Commun;493(1):58-63, 2017 Nov 04.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aspergillus fumigatus is a human pathogen responsible for deadly infections in immune-compromised patients. A potential strategy for treating A. fumigatus infections is by targeting the biosynthesis of cell wall components, such as galactofuranase, which is absent in humans. Galactofuranose biosynthesis is initiated by the flavoenzyme UDP-galactopyranose mutase (UGM), which converts UDP-galactopyranose (UDP-Galp) to UDP-galactofuranose (UDP-Galf). UGM requires the reduced form of the flavin for activity, which is obtained by reacting with NADPH. We aimed to identify inhibitors of UGM by screening a kinase inhibitor library using ThermoFAD, a flavin fluorescence thermal shift assay. The screening assay identified flavopiridol as a compound that increased the melting temperature of A. fumigatus UGM. Further characterization showed that flavopiridol is a non-competitive inhibitor of UGM and docking studies suggest that it binds in the active site. This compound does not inhibit the prokaryotic UGM from Mycobacteria tuberculosis.
[Mh] Termos MeSH primário: Aspergillus fumigatus/enzimologia
Avaliação Pré-Clínica de Medicamentos/métodos
Inibidores Enzimáticos/química
Flavonoides/química
Transferases Intramoleculares/antagonistas & inibidores
Piperidinas/química
Espectrometria de Fluorescência/métodos
[Mh] Termos MeSH secundário: Ativação Enzimática
Flavinas/química
Transferases Intramoleculares/análise
Mapeamento de Interação de Proteínas
Temperatura Ambiente
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Flavins); 0 (Flavonoids); 0 (Piperidines); 45AD6X575G (alvocidib); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.9 (UDP-galactopyranose mutase)
[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:170919
[St] Status:MEDLINE


  2 / 1397 MEDLINE  
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[PMID]:28881085
[Au] Autor:Tenkovskaia L; Murakami M; Okuno K; Ueda D; Sato T
[Ad] Endereço:Department of Applied Biological Chemistry, Faculty of Agriculture, and, Graduate School of Science and Technology, Niigata University, Ikarashi 2-8050, Nishi-ku, Niigata, 950-2181, Japan.
[Ti] Título:Analysis of the Catalytic Mechanism of Bifunctional Triterpene/Sesquarterpene Cyclase: Tyr167 Functions To Terminate Cyclization of Squalene at the Bicyclic Step.
[So] Source:Chembiochem;18(19):1910-1913, 2017 Oct 05.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Onoceroids are a group of triterpenes biosynthesized from squalene or dioxidosqualene by cyclization from both termini. We previously identified a bifunctional triterpene/sesquarterpene cyclase (TC) that constructs a tetracyclic scaffold from tetraprenyl-ß-curcumene (C ) but a bicyclic scaffold from squalene (C ) in the first reaction. TC also accepts the bicyclic intermediate as a substrate and generates tetracyclic and pentacyclic onoceroids in the second reaction. In this study, we analyzed the catalytic mechanism of an onoceroid synthase by using mutated enzymes. TC produced an unnatural tricyclic triterpenol, but TC , TC , and TC formed small quantities of tricyclic compounds, which suggested that the bulk size at Y167 contributed to termination of the cyclization of squalene at the bicyclic step. Our findings provide insight into the unique catalytic mechanism of TC, which triggers different cyclization modes depending on the substrate. These findings may facilitate the large-scale production of an onoceroid for which natural sources are limited.
[Mh] Termos MeSH primário: Biocatálise
Transferases Intramoleculares/metabolismo
Esqualeno/metabolismo
Tirosina/metabolismo
[Mh] Termos MeSH secundário: Bacillus/enzimologia
Ciclização
Estrutura Molecular
Esqualeno/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
42HK56048U (Tyrosine); 7QWM220FJH (Squalene); EC 5.4.- (Intramolecular Transferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700329


  3 / 1397 MEDLINE  
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[PMID]:28732158
[Au] Autor:Winton VJ; Justen AM; Deng H; Kiessling LL
[Ad] Endereço:Department of Chemistry, University of Wisconsin-Madison , 1101 University Avenue, Madison, Wisconsin 53706-1322, United States.
[Ti] Título:Deleterious Consequences of UDP-Galactopyranose Mutase Inhibition for Nematodes.
[So] Source:ACS Chem Biol;12(9):2354-2361, 2017 Sep 15.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Parasitic nematodes pose a serious threat to agriculture, livestock, and human health. Increasing resistance to antiparasitic agents underscores the need to replenish our anthelmintic arsenal. The nonpathogenic Caenorhabditis elegans, which serves as an effective model of parasitic helminths, has been used to search for new anthelmintic leads. We previously reported small-molecule inhibitors of the essential C. elegans protein UDP-galactopyranose mutase (UGM or Glf). This enzyme is required for the generation of galactofuranose (Galf)-containing glycans and is needed in nematodes for proper cuticle formation. Though our first-generation inhibitors were effective in vitro, they elicited no phenotypic effects. These findings are consistent with the known difficulty of targeting nematodes. C. elegans is recalcitrant to pharmacological modulation; typically, less than 0.02% of small molecules elicit a phenotypic effect, even at 40 µM. We postulated that the lack of activity of the UGM inhibitors was due to their carboxylic acid group, which can be exploited by nematodes for detoxification. We therefore tested whether replacement of the carboxylate with an N-acylsulfonamide surrogate would result in active compounds. UGM inhibitors with the carboxylate mimetic can phenocopy the deleterious consequences of UGM depletion in C. elegans. These findings support the use of UGM inhibitors as anthelmintic agents. They also outline a strategy to render small-molecule carboxylates more effective against nematodes.
[Mh] Termos MeSH primário: Anti-Helmínticos/química
Anti-Helmínticos/farmacologia
Caenorhabditis elegans/efeitos dos fármacos
Caenorhabditis elegans/enzimologia
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Transferases Intramoleculares/antagonistas & inibidores
[Mh] Termos MeSH secundário: Acilação
Animais
Caenorhabditis elegans/fisiologia
Transferases Intramoleculares/metabolismo
Sulfonamidas/química
Sulfonamidas/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anthelmintics); 0 (Enzyme Inhibitors); 0 (Sulfonamides); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.9 (UDP-galactopyranose mutase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170722
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00487


  4 / 1397 MEDLINE  
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[PMID]:28652025
[Au] Autor:Sobrado P; Tanner JJ
[Ad] Endereço:Department of Biochemistry, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address: psobrado@vt.edu.
[Ti] Título:Multiple functionalities of reduced flavin in the non-redox reaction catalyzed by UDP-galactopyranose mutase.
[So] Source:Arch Biochem Biophys;632:59-65, 2017 Oct 15.
[Is] ISSN:1096-0384
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Flavin cofactors are widely used by enzymes to catalyze a broad range of chemical reactions. Traditionally, flavins in enzymes are regarded as redox centers, which enable enzymes to catalyze the oxidation or reduction of substrates. However, a new class of flavoenzyme has emerged over the past quarter century in which the flavin functions as a catalytic center in a non-redox reaction. Here we introduce the unifying concept of flavin hot spots to understand and categorize the mechanisms and reactivities of both traditional and noncanonical flavoenzymes. The major hot spots of reactivity include the N5, C4a, and C4O atoms of the isoalloxazine, and the 2' hydroxyl of the ribityl chain. The role of hot spots in traditional flavoenzymes, such as monooxygenases, is briefly reviewed. A more detailed description of flavin hot spots in noncanonical flavoenzymes is provided, with a focus on UDP-galactopyranose mutase, where the N5 functions as a nucleophile that attacks the anomeric carbon atom of the substrate. Recent results from mechanistic enzymology, kinetic crystallography, and computational chemistry provide a complete picture of the chemical mechanism of UDP-galactopyranose mutase.
[Mh] Termos MeSH primário: Dinitrocresóis/química
Flavoproteínas/química
Transferases Intramoleculares/química
[Mh] Termos MeSH secundário: Catálise
Dinitrocresóis/metabolismo
Flavoproteínas/metabolismo
Transferases Intramoleculares/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Dinitrocresols); 0 (Flavoproteins); 1604ZJR09T (4,6-dinitro-o-cresol); EC 5.4.- (Intramolecular Transferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170628
[St] Status:MEDLINE


  5 / 1397 MEDLINE  
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[PMID]:28608671
[Au] Autor:Wangkanont K; Winton VJ; Forest KT; Kiessling LL
[Ad] Endereço:Department of Chemistry, ‡Department of Biochemistry, and §Department of Bacteriology, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
[Ti] Título:Conformational Control of UDP-Galactopyranose Mutase Inhibition.
[So] Source:Biochemistry;56(30):3983-3992, 2017 Aug 01.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:UDP-galactopyranose mutase (Glf or UGM) catalyzes the formation of uridine 5'-diphosphate-α-d-galactofuranose (UDP-Galf) from UDP-galactopyranose (UDP-Galp). The enzyme is required for the production of Galf-containing glycans. UGM is absent in mammals, but members of the Corynebacterineae suborder require UGM for cell envelope biosynthesis. The need for UGM in some pathogens has prompted the search for inhibitors that could serve as antibiotic leads. Optimizing inhibitor potency, however, has been challenging. The UGM from Klebsiella pneumoniae (KpUGM), which is not required for viability, is more effectively impeded by small-molecule inhibitors than are essential UGMs from species such as Mycobacterium tuberculosis or Corynebacterium diphtheriae. Why KpUGM is more susceptible to inhibition than other orthologs is not clear. One potential source of difference is UGM ortholog conformation. We previously determined a structure of CdUGM bound to a triazolothiadiazine inhibitor in the open form, but it was unclear whether the small-molecule inhibitor bound this form or to the closed form. By varying the terminal tag (CdUGM-His and GSG-CdUGM), we crystallized CdUGM to capture the enzyme in different conformations. These structures reveal a pocket in the active site that can be exploited to augment inhibitor affinity. Moreover, they suggest the inhibitor binds the open form of most prokaryotic UGMs but can bind the closed form of KpUGM. This model and the structures suggest strategies for optimizing inhibitor potency by exploiting UGM conformational flexibility.
[Mh] Termos MeSH primário: Antibacterianos/farmacologia
Proteínas de Bactérias/antagonistas & inibidores
Inibidores Enzimáticos/farmacologia
Transferases Intramoleculares/antagonistas & inibidores
Klebsiella pneumoniae/enzimologia
Modelos Moleculares
[Mh] Termos MeSH secundário: Antibacterianos/química
Antibacterianos/metabolismo
Proteínas de Bactérias/química
Proteínas de Bactérias/metabolismo
Sítios de Ligação
Domínio Catalítico
Corynebacterium diphtheriae/enzimologia
Cristalografia por Raios X
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Transferases Intramoleculares/química
Transferases Intramoleculares/metabolismo
Cinética
Ligantes
Conformação Molecular
Mutagênese Sítio-Dirigida
Mutação
Mycobacterium tuberculosis/enzimologia
Conformação Proteica
Dobramento de Proteína
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/metabolismo
Especificidade da Espécie
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Ligands); 0 (Recombinant Fusion Proteins); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.9 (UDP-galactopyranose mutase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170811
[Lr] Data última revisão:
170811
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00189


  6 / 1397 MEDLINE  
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[PMID]:28528213
[Au] Autor:Makins C; Whitelaw DA; McGregor M; Petit A; Mothersole RG; Prosser KE; Wolthers KR
[Ad] Endereço:Department of Chemistry, University of British Columbia, 3247 University Way, Kelowna, BC V1V 1V7, Canada.
[Ti] Título:Optimal electrostatic interactions between substrate and protein are essential for radical chemistry in ornithine 4,5-aminomutase.
[So] Source:Biochim Biophys Acta;1865(8):1077-1084, 2017 08.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Ornithine 4,5-aminomutase (OAM) from Clostridium sticklandii is an adenosylcobalamin (AdoCbl) and pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes a 1,2-amino shift, interconverting d-ornithine and 2S, 4R-diaminopentanoate. The reaction occurs via a radical-based mechanism whereby a PLP-bound substrate radical undergoes intramolecular isomerization via an azacyclopropylcarbinyl radical intermediate. Herein, we investigated the catalytic role of active site residues that form non-covalent interactions with PLP and/or substrate, d-ornithine. Kinetic analyses revealed that residues that form salt bridges to the α-carboxylate (R297) or the α-amine (E81) of d-ornithine are most critical for OAM activity as conservative substitutions of these residues results in a 300-600-fold reduction in catalytic turnover and a more pronounced 1000- to 14,000-fold decrease in catalytic efficiency. In contrast, mutating residues that solely interact with the PLP cofactor led to more modest decreases (10-60-fold) in k and k /K . All but one variant (S162A) elicited an increase in the kinetic isotope effect on k and k /K with d,l-ornithine-3,3,4,4,5,5-d as the substrate, which indicates that hydrogen atom abstraction is more rate determining. Electron paramagnetic resonance spectra of the variants reveal that while the substitutions decrease the extent of CoC bond homolysis, they do not affect the structural integrity of the active site. Our experimental results, discussed in context with published computational work, suggests that the protonation state of the PLP cofactor has less of a role in radical-mediated chemistry compared to electrostatic interactions between the substrate and protein.
[Mh] Termos MeSH primário: Transferases Intramoleculares/metabolismo
Ornitina/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Domínio Catalítico/fisiologia
Clostridium sticklandii/metabolismo
Espectroscopia de Ressonância de Spin Eletrônica/métodos
Cinética
Conformação Proteica
Eletricidade Estática
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
E524N2IXA3 (Ornithine); EC 5.4.- (Intramolecular Transferases); EC 5.4.3.5 (ornithine 5,4-aminomutase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170926
[Lr] Data última revisão:
170926
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170522
[St] Status:MEDLINE


  7 / 1397 MEDLINE  
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[PMID]:28479228
[Au] Autor:Rabelo VW; Romeiro NC; Abreu PA
[Ad] Endereço:Laboratório de Modelagem Molecular e Pesquisa em Ciências Farmacêuticas, LaMCiFar, Universidade Federal do Rio de Janeiro - Campus Macaé, Av. São José do Barreto, Macaé 27965-045, RJ, Brazil; Programa de Pós-Graduação em Produtos Bioativos e Biociências, Universidade Federal do Rio de Janeiro, Campus Macaé Professor Aloísio Teixeira, Macaé, RJ, Brazil.
[Ti] Título:Design strategies of oxidosqualene cyclase inhibitors: Targeting the sterol biosynthetic pathway.
[So] Source:J Steroid Biochem Mol Biol;171:305-317, 2017 Jul.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Targeting the sterol biosynthesis pathway has been explored for the development of new bioactive compounds. Among the enzymes of this pathway, oxidosqualene cyclase (OSC) which catalyzes lanosterol cyclization from 2,3-oxidosqualene has emerged as an attractive target. In this work, we reviewed the most promising OSC inhibitors from different organisms and their potential for the development of new antiparasitic, antifungal, hypocholesterolemic and anticancer drugs. Different strategies have been adopted for the discovery of new OSC inhibitors, such as structural modifications of the natural substrate or the reaction intermediates, the use of the enzyme's structural information to discover compounds with novel chemotypes, modifications of known inhibitors and the use of molecular modeling techniques such as docking and virtual screening to search for new inhibitors. This review brings new perspectives on structural insights of OSC from different organisms and reveals the broad structural diversity of OSC inhibitors which may help evidence lead compounds for further investigations with various therapeutic applications.
[Mh] Termos MeSH primário: Anti-Infecciosos/farmacologia
Anticolesterolemiantes/farmacologia
Antineoplásicos/farmacologia
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
Transferases Intramoleculares/antagonistas & inibidores
Modelos Moleculares
[Mh] Termos MeSH secundário: Animais
Anti-Infecciosos/química
Anti-Infecciosos/metabolismo
Anticolesterolemiantes/química
Anticolesterolemiantes/metabolismo
Antifúngicos/química
Antifúngicos/metabolismo
Antifúngicos/farmacologia
Antineoplásicos/química
Antineoplásicos/metabolismo
Antiparasitários/química
Antiparasitários/metabolismo
Antiparasitários/farmacologia
Domínio Catalítico
Avaliação Pré-Clínica de Medicamentos/tendências
Inibidores Enzimáticos/química
Inibidores Enzimáticos/metabolismo
Seres Humanos
Transferases Intramoleculares/química
Transferases Intramoleculares/metabolismo
Conformação Molecular
Simulação de Acoplamento Molecular/tendências
Conformação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Anti-Infective Agents); 0 (Anticholesteremic Agents); 0 (Antifungal Agents); 0 (Antineoplastic Agents); 0 (Antiparasitic Agents); 0 (Enzyme Inhibitors); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.7 (lanosterol synthase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170509
[St] Status:MEDLINE


  8 / 1397 MEDLINE  
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[PMID]:28432181
[Au] Autor:Deryusheva S; Gall JG
[Ad] Endereço:Department of Embryology, Carnegie Institution for Science, Baltimore, Maryland 21218, USA.
[Ti] Título:Dual nature of pseudouridylation in U2 snRNA: Pus1p-dependent and Pus1p-independent activities in yeasts and higher eukaryotes.
[So] Source:RNA;23(7):1060-1067, 2017 Jul.
[Is] ISSN:1469-9001
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The pseudouridine at position 43 in vertebrate U2 snRNA is one of the most conserved post-transcriptional modifications of spliceosomal snRNAs; the equivalent position is pseudouridylated in U2 snRNAs in different phyla including fungi, insects, and worms. Pseudouridine synthase Pus1p acts alone on U2 snRNA to form this pseudouridine in yeast and mouse. Furthermore, in , Pus1p is the only pseudouridine synthase for this position. Using an in vivo yeast cell system, we tested enzymatic activity of Pus1p from the fission yeast , the worm , the fruit fly , and the frog We demonstrated that Pus1p from has no enzymatic activity on U2 snRNA when expressed in yeast cells, whereas in similar experiments, position 44 in yeast U2 snRNA (equivalent to position 43 in vertebrates) is a genuine substrate for Pus1p from , , , , and mouse. However, when we analyzed U2 snRNAs from knockout mice and the strain, we could not detect any changes in their modification patterns when compared to wild-type U2 snRNAs. In , we found a novel box H/ACA RNA encoded downstream from the gene and experimentally verified its guide RNA activity for positioning Ψ43 and Ψ44 in U2 snRNA. In vertebrates, we showed that SCARNA8 (also known as U92 scaRNA) is a guide for U2-Ψ43 in addition to its previously established targets U2-Ψ34/Ψ44.
[Mh] Termos MeSH primário: Transferases Intramoleculares/metabolismo
RNA Guia/metabolismo
RNA Nuclear Pequeno/metabolismo
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/genética
Caenorhabditis elegans/metabolismo
Drosophila melanogaster/genética
Drosophila melanogaster/metabolismo
Técnicas de Inativação de Genes
Transferases Intramoleculares/genética
Camundongos
Pseudouridina/metabolismo
RNA Fúngico/metabolismo
RNA Nuclear Pequeno/química
Schizosaccharomyces/genética
Schizosaccharomyces/metabolismo
Xenopus/genética
Xenopus/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (RNA, Fungal); 0 (RNA, Guide); 0 (RNA, Small Nuclear); 0 (U2 small nuclear RNA); 1445-07-4 (Pseudouridine); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.- (pseudouridine synthases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170423
[St] Status:MEDLINE
[do] DOI:10.1261/rna.061226.117


  9 / 1397 MEDLINE  
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[PMID]:28407739
[Au] Autor:Li J; Zhu X; Chen J; Zhao D; Zhang X; Bi C
[Ad] Endereço:Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, People's Republic of China.
[Ti] Título:Construction of a novel anaerobic pathway in Escherichia coli for propionate production.
[So] Source:BMC Biotechnol;17(1):38, 2017 Apr 14.
[Is] ISSN:1472-6750
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Propionate is widely used as an important preservative and important chemical intermediate for synthesis of cellulose fibers, herbicides, perfumes and pharmaceuticals. Biosynthetic propionate has mainly been produced by Propionibacterium, which has various limitations for industrial application. RESULTS: In this study, we engineered E. coli by combining reduced TCA cycle with the native sleeping beauty mutase (Sbm) cycle to construct a redox balanced and energy viable fermentation pathway for anaerobic propionate production. As the cryptic Sbm operon was over-expressed in E. coli MG1655, propionate titer reached 0.24 g/L. To increase precursor supply for the Sbm cycle, genetic modification was made to convert mixed fermentation products to succinate, which slightly increased propionate production. For optimal expression of Sbm operon, different types of promoters were examined. A strong constitutive promoter Pbba led to the highest titer of 2.34 g/L. Methylmalonyl CoA mutase from Methylobacterium extorquens AM1 was added to strain T110(pbba-Sbm) to enhance this rate limiting step. With optimized expression of this additional Methylmalonyl CoA mutase, the highest production strain was obtained with a titer of 4.95 g/L and a yield of 0.49 mol/mol glucose. CONCLUSIONS: With various metabolic engineering strategies, the propionate titer from fermentation achieved 4.95 g/L. This is the reported highest anaerobic production of propionate by heterologous host. Due to host advantages, such as non-strict anaerobic condition, mature engineering and fermentation techniques, and low cost minimal media, our work has built the basis for industrial propionate production with E. coli chassis.
[Mh] Termos MeSH primário: Escherichia coli/genética
Escherichia coli/metabolismo
Metilmalonil-CoA Mutase/metabolismo
Propionatos/metabolismo
[Mh] Termos MeSH secundário: Reatores Biológicos
Cromatografia Líquida de Alta Pressão
Clonagem Molecular
DNA Bacteriano/genética
DNA Bacteriano/metabolismo
Escherichia coli/enzimologia
Proteínas de Escherichia coli/biossíntese
Proteínas de Escherichia coli/genética
Proteínas de Escherichia coli/metabolismo
Fermentação
Glucose/metabolismo
Microbiologia Industrial
Transferases Intramoleculares/genética
Transferases Intramoleculares/metabolismo
Engenharia Metabólica/métodos
Metilmalonil-CoA Mutase/biossíntese
Metilmalonil-CoA Mutase/genética
Methylobacterium/enzimologia
Methylobacterium/genética
Óperon
Reação em Cadeia da Polimerase
Ácido Succínico/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (DNA, Bacterial); 0 (Escherichia coli Proteins); 0 (Propionates); AB6MNQ6J6L (Succinic Acid); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.2 (Methylmalonyl-CoA Mutase); IY9XDZ35W2 (Glucose)
[Em] Mês de entrada:1704
[Cu] Atualização por classe:170425
[Lr] Data última revisão:
170425
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170415
[St] Status:MEDLINE
[do] DOI:10.1186/s12896-017-0354-5


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[PMID]:28379198
[Au] Autor:Yang Y; Ge F; Sun Y; Liu D; Chen C
[Ad] Endereço:Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming 650500, China. yangyan3650199@163.com.
[Ti] Título:Strengthening Triterpene Saponins Biosynthesis by Over-Expression of Farnesyl Pyrophosphate Synthase Gene and RNA Interference of Cycloartenol Synthase Gene in Panax notoginseng Cells.
[So] Source:Molecules;22(4), 2017 Apr 05.
[Is] ISSN:1420-3049
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:To conform to the multiple regulations of triterpene biosynthesis, the gene encoding farnesyl pyrophosphate synthase (FPS) was transformed into ( ) cells in which RNA interference (RNAi) of the cycloartenol synthase (CAS) gene had been accomplished. Transgenic cell lines showed both higher expression levels of and lower expression levels of compared to the wild-type (WT) cells. In the triterpene and phytosterol analysis, transgenic cell lines provided a higher accumulation of total triterpene saponins, and a lower amount of phytosterols in comparison with the WT cells. Compared with the cells in which RNAi of the gene was achieved, the cells with simultaneously over-expressed and silenced showed higher triterpene contents. These results demonstrate that over-expression of can break the rate-limiting reaction catalyzed by FPS in the triterpene saponins biosynthetic pathway; and inhibition of expression can decrease the synthesis metabolic flux of the phytosterol branch. Thus, more precursors flow in the direction of triterpene synthesis, and ultimately promote the accumulation of saponins. Meanwhile, silencing and over-expressing key enzyme genes simultaneously is more effective than just manipulating one gene in the regulation of saponin biosynthesis.
[Mh] Termos MeSH primário: Expressão Gênica
Geraniltranstransferase/genética
Transferases Intramoleculares/genética
Panax notoginseng/genética
Panax notoginseng/metabolismo
Interferência de RNA
Saponinas/biossíntese
Triterpenos/metabolismo
[Mh] Termos MeSH secundário: Vias Biossintéticas
Ordem dos Genes
Vetores Genéticos/genética
Células Vegetais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Saponins); 0 (Triterpenes); EC 2.5.1.10 (Geranyltranstransferase); EC 5.4.- (Intramolecular Transferases); EC 5.4.99.8 (cycloartenol synthase)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170531
[Lr] Data última revisão:
170531
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170406
[St] Status:MEDLINE



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