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[PMID]:28463490
[Au] Autor:Tomita T; Kim SY; Teramoto K; Meguro A; Ozaki T; Yoshida A; Motoyoshi Y; Mori N; Ishigami K; Watanabe H; Nishiyama M; Kuzuyama T
[Ti] Título:Structural Insights into the CotB2-Catalyzed Cyclization of Geranylgeranyl Diphosphate to the Diterpene Cyclooctat-9-en-7-ol.
[So] Source:ACS Chem Biol;12(6):1621-1628, 2017 06 16.
[Is] ISSN:1554-8937
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The diterpene cyclase CotB2 catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to the tricyclic cyclooctat-9-en-7-ol, which is characterized by a 5-8-5-fused ring skeleton. We have previously proposed a cyclization cascade involving a unique carbon-carbon bond rearrangement combined with multiple hydride shifts, all occurring at a single active site. Here, we report the first high-resolution X-ray crystal structure of CotB2 with bound substrate analog geranylgeranyl thiodiphosphate (GGSPP). In the GGSPP-bound form, GGSPP folds into a unique S-shaped conformation that probably reflects the substrate-bound state prior to ionization of the substrate GGPP. The folded framework of GGSPP is surrounded by hydrophobic residues and several aromatic and asparagine residues that are well-positioned to stabilize a series of reactive carbocation intermediates through a combination of cation-π and dipole charge interactions. The combined crystal structures and mutagenesis-based biochemical assays provide a structural basis for exquisite control of ring formation and stereochemistry during CotB2 catalysis.
[Mh] Termos MeSH primário: Proteínas de Bactérias/metabolismo
Biocatálise
Diterpenos/química
Oxirredutases Intramoleculares/metabolismo
Fosfatos de Poli-Isoprenil/química
[Mh] Termos MeSH secundário: Proteínas de Bactérias/química
Cristalografia por Raios X
Ciclização
Ciclo-Octanos/química
Ciclo-Octanos/metabolismo
Enzimas/química
Enzimas/metabolismo
Mutagênese Sítio-Dirigida
Streptomyces/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Cyclooctanes); 0 (Diterpenes); 0 (Enzymes); 0 (Polyisoprenyl Phosphates); EC 5.3.- (Intramolecular Oxidoreductases); N21T0D88LX (geranylgeranyl pyrophosphate)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180201
[Lr] Data última revisão:
180201
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1021/acschembio.7b00154


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[PMID]:28872301
[Au] Autor:Huang LY; Wang SC; Cheng TR; Wong CH
[Ad] Endereço:Genomics Research Center, Academia Sinica , Taipei 115, Taiwan.
[Ti] Título:Undecaprenyl Phosphate Phosphatase Activity of Undecaprenol Kinase Regulates the Lipid Pool in Gram-Positive Bacteria.
[So] Source:Biochemistry;56(40):5417-5427, 2017 Oct 10.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Bacteria cell walls contain many repeating glycan structures, such as peptidoglycans, lipopolysaccharides, teichoic acids, and capsular polysaccharides. Their synthesis starts in the cytosol, and they are constructed from a glycan lipid carrier, undecaprenyl phosphate (C P), which is essential for cell growth and survival. The lipid derivative undecaprenol (C OH) is predominant in many Gram-positive bacteria but has not been detected in Gram-negative bacteria; its origin and role have thus remained unknown. Recently, a homologue of diacylglycerol kinase (DgkA) in Escherichia coli (E. coli) was demonstrated to be an undecaprenol kinase (UK) in the Gram-positive bacterium Streptococcus mutans (S. mutans). In this study, we found that S. mutans UK was not only an undecaprenol kinase but also a Mg-ADP-dependent undecaprenyl phosphate phosphatase (UpP), catalyzing the hydrolysis of C P to C OH and a free inorganic phosphate. Furthermore, the naturally undetectable C OH was observed in E. coli cells expressing S. mutans dgkA, supporting the phosphatase activity of UK/UpP in vivo. These two activities were indispensable to each other and utilized identical essential residues binding to their substrates, suggesting that both activities share the same active site and might involve a direct phosphoryl transfer mechanism. This study revealed a unique membrane enzyme displaying bifunctional activities determined by substrate binding and C OH production. The reciprocal conversion of C P and the undecaprenol pool efficiently regulate cell wall synthesis, especially in Gram-positive bacteria.
[Mh] Termos MeSH primário: Metabolismo dos Lipídeos
Monoéster Fosfórico Hidrolases/metabolismo
Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo
Fosfatos de Poli-Isoprenil/metabolismo
Streptococcus mutans/enzimologia
[Mh] Termos MeSH secundário: Difosfato de Adenosina/metabolismo
Modelos Moleculares
Monoéster Fosfórico Hidrolases/química
Fosforilação
Estrutura Secundária de Proteína
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polyisoprenyl Phosphates); 25126-51-6 (undecaprenyl phosphate); 61D2G4IYVH (Adenosine Diphosphate); EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)); EC 2.7.1.66 (undecaprenol kinase); EC 3.1.3.2 (Phosphoric Monoester Hydrolases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171019
[Lr] Data última revisão:
171019
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170906
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00603


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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]:28478108
[Au] Autor:Kajiura H; Suzuki N; Tokumoto Y; Yoshizawa T; Takeno S; Fujiyama K; Kaneko Y; Matsumura H; Nakazawa Y
[Ad] Endereço:Technical Research Institute, Hitachi Zosen Corporation, 2-2-11 Funamachi, Taisyo, Osaka, 551-0022, Japan.
[Ti] Título:Two Eucommia farnesyl diphosphate synthases exhibit distinct enzymatic properties leading to end product preferences.
[So] Source:Biochimie;139:95-106, 2017 Aug.
[Is] ISSN:1638-6183
[Cp] País de publicação:France
[La] Idioma:eng
[Ab] Resumo:Farnesyl diphosphate synthase (FPS) is an essential enzyme in the biosynthesis of prenyl precursors for the production of primary and secondary metabolites, including sterols, dolichols, carotenoids and ubiquinones, and for the modification of proteins. Here we identified and characterized two FPSs (EuFPS1 and EuFPS2) from the plant Eucommia ulmoides. The EuFPSs had seven highly conserved prenyltransferase-specific domains that are critical for activity. Complementation and biochemical analyses using bacterially produced recombinant EuFPS isoforms showed that the EuFPSs had FPP synthesis activities both in vivo and in vitro. In addition to the typical reaction mechanisms of FPS, EuFPSs utilized farnesyl diphosphate (FPP) as an allylic substrate and participated in further elongation of the isoprenyl chain, resulting in the synthesis of geranylgeranyl diphosphate. However, despite the high amino acid similarities between the two EuFPS isozymes, their specific activities, substrate preferences, and final reaction products were different. The use of dimethylallyl diphosphate (DMAPP) as an allylic substrate highlighted the differences between the two enzymes: depending on the pH, the metal ion cofactor, and the cofactor concentration, EuFPS2 accumulated geranyl diphosphate as an intermediate product at a constant rate, whereas EuFPS1 synthesized little geranyl diphosphate. The reaction kinetics of the EuFPSs demonstrated that isopentenyl diphosphate and DMAPP were used both as substrates and as inhibitors of EuFPS activity. Taken together, the results indicate that the biosynthesis of FPP is highly regulated by various factors indispensable for EuFPS reactions in plants.
[Mh] Termos MeSH primário: Eucommiaceae/enzimologia
Geraniltranstransferase/metabolismo
Hemiterpenos/metabolismo
Compostos Organofosforados/metabolismo
Fosfatos de Poli-Isoprenil/metabolismo
Sesquiterpenos/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Geraniltranstransferase/química
Cinética
Modelos Moleculares
Homologia de Sequência de Aminoácidos
Especificidade por Substrato
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hemiterpenes); 0 (Organophosphorus Compounds); 0 (Polyisoprenyl Phosphates); 0 (Sesquiterpenes); 358-71-4 (isopentenyl pyrophosphate); 358-72-5 (3,3-dimethylallyl pyrophosphate); 79W6B01D07 (farnesyl pyrophosphate); EC 2.5.1.10 (Geranyltranstransferase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170912
[Lr] Data última revisão:
170912
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170508
[St] Status:MEDLINE


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[PMID]:28371548
[Au] Autor:Styles MQ; Nesbitt EA; Marr S; Hutchby M; Leak DJ
[Ad] Endereço:Department of Biology and Biochemistry, University of Bath, UK.
[Ti] Título:Characterization of the first naturally thermostable terpene synthases and development of strategies to improve thermostability in this family of enzymes.
[So] Source:FEBS J;284(11):1700-1711, 2017 Jun.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The terpenoid family of natural products is being targeted for heterologous microbial production as a cheaper and more reliable alternative to extraction from plants. The key enzyme responsible for diversification of terpene structure is the class-I terpene synthase (TS), and these often require engineering to improve properties such as thermostability, robustness and catalytic activity before they are suitable for industrial use. Improving thermostability typically relies on screening a large number of mutants, as there are no naturally thermostable TSs described upon which to base rational design decisions. We have characterized the first examples of natural TSs exhibiting thermostability, which catalyse the formation of the sesquiterpene τ-muurolol at temperatures up to 78 °C. We also report an enzyme with a k value of 0.95 s at 65 °C, the highest k recorded for a bacterial sesquiterpene synthase. In turn, these thermostable enzymes were used as a model to inform the rational engineering of another TS, with the same specificity but low sequence identity to the model. The newly engineered variant displayed increased thermostability and turnover. Given the high structural homology of the class-I TS domain, this approach could be generally applicable to improving the properties of other enzymes in this class. DATABASE: Model data are available in the PMDB database under the accession number PM0080780.
[Mh] Termos MeSH primário: Alquil e Aril Transferases/química
Chloroflexi/enzimologia
[Mh] Termos MeSH secundário: Escherichia coli
Temperatura Alta
Cinética
Modelos Químicos
Modelos Moleculares
Fosfatos de Poli-Isoprenil/metabolismo
Conformação Proteica
Estabilidade Proteica
Proteínas Recombinantes/metabolismo
Sesquiterpenos/metabolismo
Relação Estrutura-Atividade
Terpenos/metabolismo
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polyisoprenyl Phosphates); 0 (Recombinant Proteins); 0 (Sesquiterpenes); 0 (Terpenes); 79W6B01D07 (farnesyl pyrophosphate); EC 2.5.- (Alkyl and Aryl Transferases); EC 2.5.1.- (terpene synthase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14072


  6 / 1451 MEDLINE  
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[PMID]:28369701
[Au] Autor:Mendez-Perez D; Alonso-Gutierrez J; Hu Q; Molinas M; Baidoo EEK; Wang G; Chan LJG; Adams PD; Petzold CJ; Keasling JD; Lee TS
[Ad] Endereço:Joint BioEnergy Institute (JBEI), 5885 Hollis Street, 4th floor, Emeryville, California, 94608, USA.
[Ti] Título:Production of jet fuel precursor monoterpenoids from engineered Escherichia coli.
[So] Source:Biotechnol Bioeng;114(8):1703-1712, 2017 Aug.
[Is] ISSN:1097-0290
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Monoterpenes (C isoprenoids) are the main components of essential oils and are possible precursors for many commodity chemicals and high energy density fuels. Monoterpenes are synthesized from geranyl diphosphate (GPP), which is also the precursor for the biosynthesis of farnesyl diphosphate (FPP). FPP biosynthesis diverts the carbon flux from monoterpene production to C products and quinone biosynthesis. In this study, we tested a chromosomal mutation of Escherichia coli's native FPP synthase (IspA) to improve GPP availability for the production of monoterpenes using a heterologous mevalonate pathway. Monoterpene production at high levels required not only optimization of GPP production but also a basal level of FPP to maintain growth. The optimized strains produced two jet fuel precursor monoterpenoids 1,8-cineole and linalool at the titer of 653 mg/L and 505 mg/L, respectively, in batch cultures with 1% glucose. The engineered strains developed in this work provide useful resources for the production of high-value monoterpenes. Biotechnol. Bioeng. 2017;114: 1703-1712. © 2017 Wiley Periodicals, Inc.
[Mh] Termos MeSH primário: Difosfatos/metabolismo
Diterpenos/metabolismo
Proteínas de Escherichia coli/genética
Escherichia coli/fisiologia
Melhoramento Genético/métodos
Geraniltranstransferase/genética
Hidrocarbonetos/síntese química
Monoterpenos/metabolismo
Fosfatos de Poli-Isoprenil/metabolismo
Sesquiterpenos/metabolismo
[Mh] Termos MeSH secundário: Monoterpenos/química
Mutação/genética
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Diphosphates); 0 (Diterpenes); 0 (Escherichia coli Proteins); 0 (Hydrocarbons); 0 (Monoterpenes); 0 (Polyisoprenyl Phosphates); 0 (Recombinant Proteins); 0 (Sesquiterpenes); 0 (geranyl diphosphate); 79W6B01D07 (farnesyl pyrophosphate); 8008-20-6 (JP5 jet fuel); EC 2.5.1.10 (Geranyltranstransferase); EC 2.5.1.10 (IspA protein, E coli)
[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:170404
[St] Status:MEDLINE
[do] DOI:10.1002/bit.26296


  7 / 1451 MEDLINE  
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[PMID]:28340291
[Au] Autor:Schwalen CJ; Feng X; Liu W; O-Dowd B; Ko TP; Shin CJ; Guo RT; Mitchell DA; Oldfield E
[Ad] Endereço:Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, IL, 61801, USA.
[Ti] Título:Head-to-Head Prenyl Synthases in Pathogenic Bacteria.
[So] Source:Chembiochem;18(11):985-991, 2017 Jun 01.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Many organisms contain head-to-head isoprenoid synthases; we investigated three such types of enzymes from the pathogens Neisseria meningitidis, Neisseria gonorrhoeae, and Enterococcus hirae. The E. hirae enzyme was found to produce dehydrosqualene, and we solved an inhibitor-bound structure that revealed a fold similar to that of CrtM from Staphylococcus aureus. In contrast, the homologous proteins from Neisseria spp. carried out only the first half of the reaction, yielding presqualene diphosphate (PSPP). Based on product analyses, bioinformatics, and mutagenesis, we concluded that the Neisseria proteins were HpnDs (PSPP synthases). The differences in chemical reactivity to CrtM were due, at least in part, to the presence of a PSPP-stabilizing arginine in the HpnDs, decreasing the rate of dehydrosqualene biosynthesis. These results show that not only S. aureus but also other bacterial pathogens contain head-to-head prenyl synthases, although their biological functions remain to be elucidated.
[Mh] Termos MeSH primário: Bactérias/enzimologia
Neopreno/metabolismo
Terpenos/metabolismo
[Mh] Termos MeSH secundário: Enterococcus hirae/enzimologia
Neisseria gonorrhoeae/enzimologia
Neisseria meningitidis/enzimologia
Fosfatos de Poli-Isoprenil/metabolismo
Prenilação
Esqualeno/análogos & derivados
Esqualeno/metabolismo
Staphylococcus aureus/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Polyisoprenyl Phosphates); 0 (Terpenes); 0 (prenyl); 11051-27-7 (dehydrosqualene); 29849-75-0 (presqualene pyrophosphate); 7QWM220FJH (Squalene); 9010-98-4 (Neoprene)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170826
[Lr] Data última revisão:
170826
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170325
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700099


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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


  9 / 1451 MEDLINE  
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[PMID]:28272876
[Au] Autor:Kumar RP; Morehouse BR; Matos JO; Malik K; Lin H; Krauss IJ; Oprian DD
[Ad] Endereço:Department of Biochemistry, Brandeis University , Waltham, Massachusetts 02454, United States.
[Ti] Título:Structural Characterization of Early Michaelis Complexes in the Reaction Catalyzed by (+)-Limonene Synthase from Citrus sinensis Using Fluorinated Substrate Analogues.
[So] Source:Biochemistry;56(12):1716-1725, 2017 Mar 28.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The stereochemical course of monoterpene synthase reactions is thought to be determined early in the reaction sequence by selective binding of distinct conformations of the geranyl diphosphate (GPP) substrate. We explore here formation of early Michaelis complexes of the (+)-limonene synthase [(+)-LS] from Citrus sinensis using monofluorinated substrate analogues 2-fluoro-GPP (FGPP) and 2-fluoroneryl diphosphate (FNPP). Both are competitive inhibitors for (+)-LS with K values of 2.4 ± 0.5 and 39.5 ± 5.2 µM, respectively. The K values are similar to the K for the respective nonfluorinated substrates, indicating that fluorine does not significantly perturb binding of the ligand to the enzyme. FGPP and FNPP are also substrates, but with dramatically reduced rates (k values of 0.00054 ± 0.00005 and 0.00024 ± 0.00002 s , respectively). These data are consistent with a stepwise mechanism for (+)-LS involving ionization of the allylic GPP substrate to generate a resonance-stabilized carbenium ion in the rate-limiting step. Crystals of apo-(+)-LS were soaked with FGPP and FNPP to obtain X-ray structures at 2.4 and 2.2 Å resolution, respectively. The fluorinated analogues are found anchored in the active site through extensive interactions involving the diphosphate, three metal ions, and three active-site Asp residues. Electron density for the carbon chains extends deep into a hydrophobic pocket, while the enzyme remains mostly in the open conformation observed for the apoprotein. While FNPP was found in multiple conformations, FGPP, importantly, was in a single, relatively well-defined, left-handed screw conformation, consistent with predictions for the mechanism of stereoselectivity in the monoterpene synthases.
[Mh] Termos MeSH primário: Apoproteínas/química
Citrus sinensis/química
Cicloexenos/química
Diterpenos/química
Inibidores Enzimáticos/química
Liases Intramoleculares/química
Organofosfatos/química
Proteínas de Plantas/química
Terpenos/química
[Mh] Termos MeSH secundário: Apoproteínas/antagonistas & inibidores
Apoproteínas/genética
Apoproteínas/metabolismo
Domínio Catalítico
Citrus sinensis/enzimologia
Clonagem Molecular
Cristalografia por Raios X
Cicloexenos/metabolismo
Diterpenos/metabolismo
Ensaios Enzimáticos
Inibidores Enzimáticos/metabolismo
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Liases Intramoleculares/antagonistas & inibidores
Liases Intramoleculares/genética
Liases Intramoleculares/metabolismo
Cinética
Ligantes
Modelos Moleculares
Organofosfatos/metabolismo
Proteínas de Plantas/antagonistas & inibidores
Proteínas de Plantas/genética
Proteínas de Plantas/metabolismo
Fosfatos de Poli-Isoprenil/química
Fosfatos de Poli-Isoprenil/metabolismo
Domínios Proteicos
Estrutura Secundária de Proteína
Proteínas Recombinantes de Fusão/química
Proteínas Recombinantes de Fusão/genética
Proteínas Recombinantes de Fusão/metabolismo
Estereoisomerismo
Terpenos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-fluorogeranylgeranyl diphosphate); 0 (Apoproteins); 0 (Cyclohexenes); 0 (Diterpenes); 0 (Enzyme Inhibitors); 0 (Ligands); 0 (Organophosphates); 0 (Plant Proteins); 0 (Polyisoprenyl Phosphates); 0 (Recombinant Fusion Proteins); 0 (Terpenes); 9MC3I34447 (limonene); EC 5.5.- (Intramolecular Lyases); EC 5.5.- (pinene cyclase I); N21T0D88LX (geranylgeranyl pyrophosphate)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00144


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[PMID]:28270685
[Au] Autor:Shinde SS; Minami A; Chen Z; Tokiwano T; Toyomasu T; Kato N; Sassa T; Oikawa H
[Ad] Endereço:Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Japan.
[Ti] Título:Cyclization mechanism of phomopsene synthase: mass spectrometry based analysis of various site-specifically labeled terpenes.
[So] Source:J Antibiot (Tokyo);70(5):632-638, 2017 May.
[Is] ISSN:0021-8820
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:Elucidation of the cyclization mechanism catalyzed by terpene synthases is important for the rational engineering of terpene cyclases. We developed a chemoenzymatic method for the synthesis of systematically deuterium-labeled geranylgeranyl diphosphate (GGPP), starting from site-specifically deuterium-labeled isopentenyl diphosphates (IPPs) using IPP isomerase and three prenyltransferases. We examined the cyclization mechanism of tetracyclic diterpene phomopsene with phomopsene synthase. A detailed EI-MS analysis of phomopsene labeled at various positions allowed us to propose the structures corresponding to the most intense peaks, and thus elucidate a cyclization mechanism involving double 1,2-alkyl shifts and a 1,2-hydride shift via a dolabelladien-15-yl cation. Our study demonstrated that this newly developed method is highly sensitive and provides sufficient information for a reliable assignment of the structures of fragmented ions.
[Mh] Termos MeSH primário: Alquil e Aril Transferases/metabolismo
Espectrometria de Massas/métodos
Fosfatos de Poli-Isoprenil/síntese química
Terpenos/química
[Mh] Termos MeSH secundário: Ciclização
Deutério/química
Hemiterpenos/química
Compostos Organofosforados/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Hemiterpenes); 0 (Organophosphorus Compounds); 0 (Polyisoprenyl Phosphates); 0 (Terpenes); 358-71-4 (isopentenyl pyrophosphate); AR09D82C7G (Deuterium); EC 2.5.- (Alkyl and Aryl Transferases); EC 2.5.1.- (terpene synthase); N21T0D88LX (geranylgeranyl pyrophosphate)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170309
[St] Status:MEDLINE
[do] DOI:10.1038/ja.2017.27



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