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[PMID]:29220191
[Au] Autor:Zoi I; Antoniou D; Schwartz SD
[Ad] Endereço:Department of Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
[Ti] Título:Electric Fields and Fast Protein Dynamics in Enzymes.
[So] Source:J Phys Chem Lett;8(24):6165-6170, 2017 Dec 21.
[Is] ISSN:1948-7185
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In recent years, there has been much discussion regarding the origin of enzymatic catalysis and whether including protein dynamics is necessary for understanding catalytic enhancement. An important contribution in this debate was made with the application of the vibrational Stark effect spectroscopy to measure electric fields in the active site. This provided a window on electric fields at the transition state in enzymatic reactions. We performed computational studies on two enzymes where we have shown that fast dynamics is part of the reaction mechanism and calculated the electric field near the bond-breaking event. We found that the fast motions that we had identified lead to an increase of the electric field, thus preparing an enzymatic configuration that is electrostatically favorable for the catalytic chemical step. We also studied the enzyme that has been the subject of Stark spectroscopy, ketosteroid isomerase, and found electric fields of a similar magnitude to the two previous examples.
[Mh] Termos MeSH primário: Enzimas/química
Conformação Proteica
Eletricidade Estática
[Mh] Termos MeSH secundário: Catálise
Domínio Catalítico
Eletricidade
Modelos Moleculares
Esteroide Isomerases
Vibração
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzymes); EC 5.3.3.- (Steroid Isomerases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171209
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jpclett.7b02989


  2 / 692 MEDLINE  
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[PMID]:28916923
[Au] Autor:Fang H; Yuan B; Han L; Xin X; Wang H; Yu F; Zheng C; Shen C
[Ad] Endereço:State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, China.
[Ti] Título:Single-cell analysis reveals the relevance of foot-and-mouth disease virus persistence to emopamil-binding protein gene expression in host cells.
[So] Source:Arch Virol;162(12):3791-3802, 2017 Dec.
[Is] ISSN:1432-8798
[Cp] País de publicação:Austria
[La] Idioma:eng
[Ab] Resumo:Foot-and-mouth disease virus (FMDV) infects host cells in either an acute or persistent manner. In this study, we examined the relevance of the establishment of FMDV persistence to the expression of the emopamil-binding protein (EBP) gene in 231 individual persistently infected baby hamster kidney (BHK-21) cells after passages 28, 38, and 68 (PI28, PI38, and PI68). At PI28, the stage at which persistent infection of FDMV becomes unstable, the percentage of cells carrying FMDV was 66.7%, while 80.2% of cells were EBP positive. Additionally, in 55.6% of the EBP-positive cells at PI28, EBP expression was upregulated approximately 149.9% compared to uninfected BHK-21 cells. This was the highest expression level among all cell passages measured. Interestingly, in a parallel experiment, the average EBP expression level in the whole cell population at PI28 was only slightly higher (108.2%) than that in uninfected BHK-21 cells. At PI38, 98.7% of the cells were positive for FMDV 3D (an RNA-dependent RNA polymerase enzyme gene), and its maximum expression level observed at this passage. The expression level of EBP in 78.2% of the total cells, however, was reduced significantly. At PI68, 95.8% of the cells were 3D positive, and the expression of both the EBP and 3D genes were at the lowest levels of all the passages. Our studies using single cells yielded data that are otherwise inaccessible a using whole cell population. These results suggest that the establishment of persistent infection by FMDV is a dynamic process that results from the continuous adaptation and coevolution of viruses and cells to reach an equilibrium.
[Mh] Termos MeSH primário: Vírus da Febre Aftosa/fisiologia
Expressão Gênica
Análise de Célula Única
Esteroide Isomerases/metabolismo
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Cricetinae
Perfilação da Expressão Gênica
Inoculações Seriadas
Esteroide Isomerases/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 5.3.3.- (Steroid Isomerases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170917
[St] Status:MEDLINE
[do] DOI:10.1007/s00705-017-3546-3


  3 / 692 MEDLINE  
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[PMID]:28375745
[Au] Autor:Fried SD; Boxer SG
[Ad] Endereço:Proteins and Nucleic Acid Chemistry Division, Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom; email: sf537@cam.ac.uk.
[Ti] Título:Electric Fields and Enzyme Catalysis.
[So] Source:Annu Rev Biochem;86:387-415, 2017 Jun 20.
[Is] ISSN:1545-4509
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:What happens inside an enzyme's active site to allow slow and difficult chemical reactions to occur so rapidly? This question has occupied biochemists' attention for a long time. Computer models of increasing sophistication have predicted an important role for electrostatic interactions in enzymatic reactions, yet this hypothesis has proved vexingly difficult to test experimentally. Recent experiments utilizing the vibrational Stark effect make it possible to measure the electric field a substrate molecule experiences when bound inside its enzyme's active site. These experiments have provided compelling evidence supporting a major electrostatic contribution to enzymatic catalysis. Here, we review these results and develop a simple model for electrostatic catalysis that enables us to incorporate disparate concepts introduced by many investigators to describe how enzymes work into a more unified framework stressing the importance of electric fields at the active site.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Hidrolases/química
Cetosteroides/química
Pseudomonas/enzimologia
Esteroide Isomerases/química
[Mh] Termos MeSH secundário: Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biocatálise
Domínio Catalítico
Expressão Gênica
Hidrolases/genética
Hidrolases/metabolismo
Cetosteroides/metabolismo
Cinética
Modelos Químicos
Simulação de Dinâmica Molecular
Mutação
Pseudomonas/química
Pseudomonas/genética
Espectrofotometria Infravermelho/métodos
Eletricidade Estática
Esteroide Isomerases/genética
Esteroide Isomerases/metabolismo
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Ketosteroids); EC 3.- (Hydrolases); EC 3.8.1.- (4-chlorobenzoyl coenzyme A dehalogenase); EC 5.3.3.- (Steroid Isomerases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170919
[Lr] Data última revisão:
170919
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE
[do] DOI:10.1146/annurev-biochem-061516-044432


  4 / 692 MEDLINE  
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[PMID]:28045505
[Au] Autor:Lamba V; Sanchez E; Fanning LR; Howe K; Alvarez MA; Herschlag D; Forconi M
[Ad] Endereço:Department of Biochemistry, Stanford University , Stanford, California 94305, United States.
[Ti] Título:Kemp Eliminase Activity of Ketosteroid Isomerase.
[So] Source:Biochemistry;56(4):582-591, 2017 Jan 31.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Kemp eliminases represent the most successful class of computationally designed enzymes, with rate accelerations of up to 10 -fold relative to the rate of the same reaction in aqueous solution. Nevertheless, several other systems such as micelles, catalytic antibodies, and cavitands are known to accelerate the Kemp elimination by several orders of magnitude. We found that the naturally occurring enzyme ketosteroid isomerase (KSI) also catalyzes the Kemp elimination. Surprisingly, mutations of D38, the residue that acts as a general base for its natural substrate, produced variants that catalyze the Kemp elimination up to 7000-fold better than wild-type KSI does, and some of these variants accelerate the Kemp elimination more than the computationally designed Kemp eliminases. Analysis of the D38N general base KSI variant suggests that a different active site carboxylate residue, D99, performs the proton abstraction. Docking simulations and analysis of inhibition by active site binders suggest that the Kemp elimination takes place in the active site of KSI and that KSI uses the same catalytic strategies of the computationally designed enzymes. In agreement with prior observations, our results strengthen the conclusion that significant rate accelerations of the Kemp elimination can be achieved with very few, nonspecific interactions with the substrate if a suitable catalytic base is present in a hydrophobic environment. Computational design can fulfill these requirements, and the design of more complex and precise environments represents the next level of challenges for protein design.
[Mh] Termos MeSH primário: Proteínas de Bactérias/química
Comamonas testosteroni/química
Liases Intramoleculares/química
Cetosteroides/química
Oxazóis/química
Prótons
Esteroide Isomerases/química
[Mh] Termos MeSH secundário: Arginina/química
Arginina/metabolismo
Ácido Aspártico/química
Ácido Aspártico/metabolismo
Proteínas de Bactérias/antagonistas & inibidores
Proteínas de Bactérias/genética
Proteínas de Bactérias/metabolismo
Biocatálise
Clonagem Molecular
Comamonas testosteroni/enzimologia
Inibidores Enzimáticos/síntese química
Inibidores Enzimáticos/química
Escherichia coli/genética
Escherichia coli/metabolismo
Expressão Gênica
Interações Hidrofóbicas e Hidrofílicas
Liases Intramoleculares/antagonistas & inibidores
Liases Intramoleculares/genética
Liases Intramoleculares/metabolismo
Cetosteroides/metabolismo
Cinética
Simulação de Acoplamento Molecular
Mutação
Oxazóis/metabolismo
Engenharia de Proteínas
Proteínas Recombinantes/química
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Esteroide Isomerases/antagonistas & inibidores
Esteroide Isomerases/genética
Esteroide Isomerases/metabolismo
Relação Estrutura-Atividade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Bacterial Proteins); 0 (Enzyme Inhibitors); 0 (Ketosteroids); 0 (Oxazoles); 0 (Protons); 0 (Recombinant Proteins); 30KYC7MIAI (Aspartic Acid); 94ZLA3W45F (Arginine); EC 5.3.3.- (Steroid Isomerases); EC 5.5.- (Intramolecular Lyases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170528
[Lr] Data última revisão:
170528
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170104
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.6b00762


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[PMID]:27128796
[Au] Autor:Myat TS; Tetsuka M
[Ad] Endereço:Division of Animal Production, The United Graduate School of Agricultural Sciences, Iwate University, Morioka, Iwate, Japan.
[Ti] Título:Gossypol inhibits LH-induced steroidogenesis in bovine theca cells.
[So] Source:Anim Sci J;88(1):63-71, 2017 Jan.
[Is] ISSN:1740-0929
[Cp] País de publicação:Australia
[La] Idioma:eng
[Ab] Resumo:Gossypol, a polyphenolic aldehyde found in cottonseed, has been shown to perturb steroidogenesis in granulosa and luteal cells of rats, pigs and cattle. However, little is known about the direct effect of gossypol on theca cell functions in any species. The present study was conducted to investigate the effect of gossypol on the steroidogenesis and the expression of genes involved in it in cultured bovine theca cells. Theca cells were isolated from healthy preovulatory follicles and were cultured in the presence of luteinizing hormone (LH) for up to 7 days. During the culture period, main steroid products of the theca cells shifted from androstenedione (A4) at day 1 to progesterone (P4) from day 2 onward. At days 1 and 7, theca cells were treated with gossypol (0-25 µg/mL) for 24 h. Gossypol inhibited LH-stimulated theca cell A4 and P4 production in a dose-dependent manner at both occasions. The viability of theca cells was not affected by gossypol at any doses used. Gossypol down-regulated expressions of steroidogenic enzymes CYP11A1, HSD3B1 and CYP17A1, but not that of LHR. These results indicate that gossypol inhibits thecal steroidogenesis through down-regulating gene expressions of steroidogenic enzymes but without affecting cell viability in cattle.
[Mh] Termos MeSH primário: Androstenodiona/biossíntese
Gossipol/farmacologia
Hormônio Luteinizante/farmacologia
Progesterona/biossíntese
Células Tecais/metabolismo
[Mh] Termos MeSH secundário: Animais
Bovinos
Células Cultivadas
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética
Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo
Óleo de Sementes de Algodão
Relação Dose-Resposta a Droga
Regulação para Baixo/efeitos dos fármacos
Feminino
Expressão Gênica/efeitos dos fármacos
Complexos Multienzimáticos/genética
Complexos Multienzimáticos/metabolismo
Progesterona Redutase/genética
Progesterona Redutase/metabolismo
Esteroide 17-alfa-Hidroxilase/genética
Esteroide 17-alfa-Hidroxilase/metabolismo
Esteroide Isomerases/genética
Esteroide Isomerases/metabolismo
Células Tecais/enzimologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase); 0 (Cottonseed Oil); 0 (Multienzyme Complexes); 409J2J96VR (Androstenedione); 4G7DS2Q64Y (Progesterone); 9002-67-9 (Luteinizing Hormone); EC 1.1.1.145 (Progesterone Reductase); EC 1.14.14.19 (CYP17A1 protein, human); EC 1.14.14.19 (Steroid 17-alpha-Hydroxylase); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme); EC 5.3.3.- (Steroid Isomerases); KAV15B369O (Gossypol)
[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:160430
[St] Status:MEDLINE
[do] DOI:10.1111/asj.12596


  6 / 692 MEDLINE  
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[PMID]:27683264
[Au] Autor:Roche J; Ramé C; Reverchon M; Mellouk N; Cornuau M; Guerif F; Froment P; Dupont J
[Ad] Endereço:Unité de Physiologie de la Reproduction et des Comportements, Institut National de la Recherche Agronomique, Nouzilly, France.
[Ti] Título:Apelin (APLN) and Apelin Receptor (APLNR) in Human Ovary: Expression, Signaling, and Regulation of Steroidogenesis in Primary Human Luteinized Granulosa Cells.
[So] Source:Biol Reprod;95(5):104, 2016 Nov.
[Is] ISSN:1529-7268
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Apelin (APLN) is a recently discovered adipokine involved in the regulation of various metabolic functions. Its receptor, APLNR, is expressed in reproductive tissues, however, its role in human ovarian cells is unknown. In this study, we identified APLN and APLNR in human ovarian follicles and analyzed their expression in granulosa cells and follicular fluid obtained from obese and nonobese patients, with or without polycystic ovary syndrome (PCOS). We also investigated the effect of APLN on steroidogenesis in cultured human luteinized granulosa cells (hGCs) from nonobese patients without PCOS. Using RT-PCR and immunoblotting, we found that APLN and APLNR were expressed in hGCs and cumulus and theca cells. We confirmed these data immunohistochemically and observed that APLNR and APLN are present in human oocytes at different stages of follicular development. In patients with PCOS, we observed that follicular fluid APLN concentration and granulosa cell APLN and APLNR mRNA expression was higher than that observed in control patients. In cultured hGCs from nonobese patients without PCOS, insulin-like growth factor 1 (IGF1) increased APLNR expression, and recombinant human APLN (APLN-13 and APLN-17) increased both basal and IGF1-induced steroid secretion. These effects on steroid production were reversed when cultured in the presence of ML221, an APLNR antagonist, which was associated with an increased 3beta-hydrosteroid dehydrogenase (HSD3B) protein concentration. We showed that these effects were dependent on the activation of the AKT and MAPK3/1 pathways using pharmacological inhibitors. Our results show that APLN and APLNR are present in human ovarian cells and APLN increases IGF1-induced steroidogenesis in granulosa cells through an increase in HSD3B protein expression and activation of the MAPK3/1 and Akt pathways. Therefore, APLN and APLNR may play a role in human follicular development and the pathogenesis of PCOS.
[Mh] Termos MeSH primário: Células da Granulosa/metabolismo
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Células Lúteas/metabolismo
Luteinização/metabolismo
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Apelina
Receptores de Apelina
Estradiol/metabolismo
Feminino
Células da Granulosa/efeitos dos fármacos
Seres Humanos
Fator de Crescimento Insulin-Like I/farmacologia
Células Lúteas/efeitos dos fármacos
Complexos Multienzimáticos/metabolismo
Síndrome do Ovário Policístico/metabolismo
Progesterona/metabolismo
Progesterona Redutase/metabolismo
Transdução de Sinais/efeitos dos fármacos
Esteroide Isomerases/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase); 0 (APLN protein, human); 0 (APLNR protein, human); 0 (Apelin); 0 (Apelin Receptors); 0 (Intercellular Signaling Peptides and Proteins); 0 (Multienzyme Complexes); 0 (Receptors, G-Protein-Coupled); 4G7DS2Q64Y (Progesterone); 4TI98Z838E (Estradiol); 67763-96-6 (Insulin-Like Growth Factor I); EC 1.1.1.145 (Progesterone Reductase); EC 5.3.3.- (Steroid Isomerases)
[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:160930
[St] Status:MEDLINE


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[PMID]:27575027
[Au] Autor:Hearn JWD; AbuAli G; Reichard CA; Reddy CA; Magi-Galluzzi C; Chang KH; Carlson R; Rangel L; Reagan K; Davis BJ; Karnes RJ; Kohli M; Tindall D; Klein EA; Sharifi N
[Ad] Endereço:Department of Radiation Oncology, Taussig Cancer Institute, Cleveland, OH, USA; Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
[Ti] Título:HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study.
[So] Source:Lancet Oncol;17(10):1435-1444, 2016 Oct.
[Is] ISSN:1474-5488
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: HSD3B1 (1245A>C) has been mechanistically linked to castration-resistant prostate cancer because it encodes an altered enzyme that augments dihydrotestosterone synthesis from non-gonadal precursors. We postulated that men inheriting the HSD3B1 (1245C) allele would exhibit resistance to androgen-deprivation therapy (ADT). METHODS: In this multicohort study, we determined HSD3B1 genotype retrospectively in men treated with ADT for post-prostatectomy biochemical failure and correlated genotype with long-term clinical outcomes. We used data and samples from prospectively maintained prostate cancer registries at the Cleveland Clinic (Cleveland, OH, USA; primary study cohort) and the Mayo Clinic (Rochester, MN, USA; post-prostatectomy and metastatic validation cohorts). In the post-prostatectomy cohorts, patients of any age were eligible if they underwent prostatectomy between Jan 1, 1996, and Dec 31, 2009 (at the Cleveland Clinic; primary cohort), or between Jan 1, 1987, and Dec 31, 2011 (at the Mayo Clinic; post-prostatectomy cohort) and were treated with ADT for biochemical failure or for non-metastatic clinical failure. In the metastatic validation cohort, patients of any age were eligible if they were enrolled at Mayo Clinic between Sept 1, 2009, and July 31, 2013, with metastatic castration-resistant prostate cancer. The primary endpoint was progression-free survival according to HSD3B1 genotype. We did prespecified multivariable analyses to assess the independent predictive value of HSD3B1 genotype on outcomes. FINDINGS: We included and genotyped 443 patients: 118 in the primary cohort (who underwent prostatectomy), 137 in the post-prostatectomy validation cohort, and 188 in the metastatic validation cohort. In the primary study cohort, median progression-free survival diminished as a function of the number of variant alleles inherited: 6·6 years (95% CI 3·8-not reached) in men with homozygous wild-type genotype, 4·1 years (3·0-5·5) in men with heterozygous variant genotype, and 2·5 years (0·7 to not reached) in men with homozygous variant genotype (p=0·011). Relative to the homozygous wild-type genotype, inheritance of two copies of the variant allele was predictive of decreased progression-free survival (hazard ratio [HR] 2·4 [95% CI 1·1-5·3], p=0·029), as was inheritance of one copy of the variant allele (HR 1·7 [1·0-2·9], p=0·041). Findings were similar for distant metastasis-free survival and overall survival. The effect of the HSD3B1 genotype was independently confirmed in the validation cohorts. INTERPRETATION: Inheritance of the HSD3B1 (1245C) allele that enhances dihydrotestosterone synthesis is associated with prostate cancer resistance to ADT. HSD3B1 could therefore potentially be a powerful genetic biomarker capable of distinguishing men who are a priori likely to fare favourably with ADT from those who harbour disease liable to behave more aggressively, and who therefore might warrant early escalated therapy. FUNDING: Prostate Cancer Foundation, National Institutes of Health, US Department of Defense, Howard Hughes Medical Institute, American Cancer Society, Conquer Cancer Foundation of the American Society of Clinical Oncology, Cleveland Clinic Research Programs Committee and Department of Radiation Oncology, Gail and Joseph Gassner Development Funds.
[Mh] Termos MeSH primário: Antagonistas de Androgênios/uso terapêutico
Complexos Multienzimáticos/genética
Progesterona Redutase/genética
Neoplasias da Próstata/tratamento farmacológico
Esteroide Isomerases/genética
[Mh] Termos MeSH secundário: Idoso
Estudos de Coortes
Genótipo
Seres Humanos
Masculino
Meia-Idade
Polimorfismo de Nucleotídeo Único
Prostatectomia
Neoplasias da Próstata/genética
Neoplasias da Próstata/mortalidade
Estudos Retrospectivos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase); 0 (Androgen Antagonists); 0 (Multienzyme Complexes); EC 1.1.1.145 (Progesterone Reductase); EC 5.3.3.- (Steroid Isomerases)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171001
[Lr] Data última revisão:
171001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160831
[St] Status:MEDLINE


  8 / 692 MEDLINE  
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[PMID]:27497162
[Au] Autor:Wang X; He X; Zhang JZ
[Ad] Endereço:Center for Optics & Optoelectronics Research, College of Science, Zhejiang University of Technology, Hangzhou, Zhejiang, China; School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.
[Ti] Título:Accurate Calculation of Electric Fields Inside Enzymes.
[So] Source:Methods Enzymol;578:45-72, 2016.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The specific electric field generated by a protease at its active site is considered as an important source of the catalytic power. Accurate calculation of electric field at the active site of an enzyme has both fundamental and practical importance. Measuring site-specific changes of electric field at internal sites of proteins due to, eg, mutation, has been realized by using molecular probes with CO or CN groups in the context of vibrational Stark effect. However, theoretical prediction of change in electric field inside a protein based on a conventional force field, such as AMBER or OPLS, is often inadequate. For such calculation, quantum chemical approach or quantum-based polarizable or polarized force field is highly preferable. Compared with the result from conventional force field, significant improvement is found in predicting experimentally measured mutation-induced electric field change using quantum-based methods, indicating that quantum effect such as polarization plays an important role in accurate description of electric field inside proteins. In comparison, the best theoretical prediction comes from fully quantum mechanical calculation in which both polarization and inter-residue charge transfer effects are included for accurate prediction of electrostatics in proteins.
[Mh] Termos MeSH primário: Aldeído Redutase/química
Elétrons
Transcriptase Reversa do HIV/química
Eletricidade Estática
Esteroide Isomerases/química
[Mh] Termos MeSH secundário: Substituição de Aminoácidos
Benzoxazinas/química
Biocatálise
Domínio Catalítico
Seres Humanos
Cinética
Simulação de Dinâmica Molecular
Sondas Moleculares/química
Nitrilos/química
Teoria Quântica
Análise Espectral/métodos
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Benzoxazines); 0 (IDD743); 0 (Molecular Probes); 0 (Nitriles); EC 1.1.1.21 (AKR1B1 protein, human); EC 1.1.1.21 (Aldehyde Reductase); EC 2.7.7.- (reverse transcriptase, Human immunodeficiency virus 1); EC 2.7.7.49 (HIV Reverse Transcriptase); EC 5.3.3.- (Steroid Isomerases); JE6H2O27P8 (efavirenz)
[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:160807
[St] Status:MEDLINE


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[PMID]:27387444
[Au] Autor:Nakamura I; Kusakabe M; Swanson P; Young G
[Ad] Endereço:School of Aquatic and Fishery Sciences, University of Washington, Seattle, WA 98105, USA; Atmosphere and Ocean Research Institute, University of Tokyo, Chiba 277-8564, Japan.
[Ti] Título:Regulation of sex steroid production and mRNAs encoding gonadotropin receptors and steroidogenic proteins by gonadotropins, cyclic AMP and insulin-like growth factor-I in ovarian follicles of rainbow trout (Oncorhynchus mykiss) at two stages of vitellogenesis.
[So] Source:Comp Biochem Physiol A Mol Integr Physiol;201:132-140, 2016 Nov.
[Is] ISSN:1531-4332
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:At the completion of vitellogenesis, the steroid biosynthetic pathway in teleost ovarian follicles switches from estradiol-17ß (E2) to maturational progestin production, associated with decreased follicle stimulating hormone (Fsh) and increased luteinizing hormone (Lh) signaling. This study compared effects of gonadotropins, human insulin-like growth factor-I (IGF1), and cAMP/protein kinase A signaling (forskolin) on E2 production and levels of mRNAs encoding steroidogenic proteins and gonadotropin receptors using midvitellogenic (MV) and late/postvitellogenic (L/PV) ovarian follicles of rainbow trout. Fsh, Lh and forskolin, but not IGF1, increased testosterone and E2 production in MV and L/PV follicles. Fsh increased steroidogenic acute regulatory protein (star; MV), 3ß-hydroxysteroid dehydrogenase/Δ(5-4) isomerase (hsd3b; MV) and P450 aromatase (cyp19a1a; MV) transcript levels. Lh increased star mRNA levels (MV, L/PV) but reduced cyp19a1a transcripts in L/PV follicles. At both follicle stages, IGF1 reduced levels of hsd3b transcripts. In MV follicles, IGF1 decreased P450 side-chain cleavage enzyme (cyp11a1) transcripts but increased cyp19a1a transcripts. In MV follicles only, forskolin increased star and hsd3b transcripts. Forskolin reduced MV follicle cyp11a1 transcripts and reduced cyp19a1a transcripts in follicles at both stages. Fsh and Lh reduced fshr transcripts in L/PV follicles. Lh also reduced lhcgr transcripts (L/PV). IGF1 had no effect on gonadotropin receptor transcripts. Forskolin reduced MV follicle fshr transcript levels and reduced lhcgr transcripts in L/PV follicles. These results reveal hormone- and stage-specific transcriptional regulation of steroidogenic protein and gonadotropin receptor genes and suggest that the steroidogenic shift at the completion of vitellogenesis involves loss of stimulatory effects of Fsh and Igfs on cyp19a1a expression and inhibition of cyp19a1a transcription by Lh.
[Mh] Termos MeSH primário: Proteínas de Peixes/genética
Hormônios Esteroides Gonadais/biossíntese
Oncorhynchus mykiss/genética
Oncorhynchus mykiss/fisiologia
Receptores da Gonadotropina/genética
[Mh] Termos MeSH secundário: Animais
Aromatase/genética
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética
Colforsina/farmacologia
AMP Cíclico/metabolismo
Estradiol/biossíntese
Feminino
Fator de Crescimento Insulin-Like I/metabolismo
Complexos Multienzimáticos/genética
Folículo Ovariano/efeitos dos fármacos
Folículo Ovariano/fisiologia
Fosfoproteínas/genética
Progesterona Redutase/genética
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Esteroide Isomerases/genética
Testosterona/biossíntese
Vitelogênese/genética
Vitelogênese/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase); 0 (Fish Proteins); 0 (Gonadal Steroid Hormones); 0 (Multienzyme Complexes); 0 (Phosphoproteins); 0 (RNA, Messenger); 0 (Receptors, Gonadotropin); 0 (steroidogenic acute regulatory protein); 1F7A44V6OU (Colforsin); 3XMK78S47O (Testosterone); 4TI98Z838E (Estradiol); 67763-96-6 (Insulin-Like Growth Factor I); E0399OZS9N (Cyclic AMP); EC 1.1.1.145 (Progesterone Reductase); EC 1.14.14.1 (Aromatase); EC 1.14.15.6 (Cholesterol Side-Chain Cleavage Enzyme); EC 5.3.3.- (Steroid Isomerases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171008
[Lr] Data última revisão:
171008
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160709
[St] Status:MEDLINE


  10 / 692 MEDLINE  
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[PMID]:27375051
[Au] Autor:Cha HJ; Jang do S; Jeong JH; Hong BH; Yun YS; Shin EJ; Choi KY
[Ad] Endereço:Pohang Accelerator Laboratory, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
[Ti] Título:Role of conserved Met112 residue in the catalytic activity and stability of ketosteroid isomerase.
[So] Source:Biochim Biophys Acta;1864(10):1322-7, 2016 10.
[Is] ISSN:0006-3002
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Ketosteroid isomerase (3-oxosteroid Δ(5)-Δ(4)-isomerase, KSI) from Pseudomonas putida catalyzes allylic rearrangement of the 5,6-double bond of Δ(5)-3-ketosteroid to 4,5-position by stereospecific intramolecular transfer of a proton. The active site of KSI is formed by several hydrophobic residues and three catalytic residues (Tyr14, Asp38, and Asp99). In this study, we investigated the role of a hydrophobic Met112 residue near the active site in the catalysis, steroid binding, and stability of KSI. Replacing Met112 with alanine (yields M112A) or leucine (M112L) decreased the kcat by 20- and 4-fold, respectively. Compared with the wild type (WT), M112A and M112L KSIs showed increased KD values for equilenin, an intermediate analogue; these changes suggest that loss of packing at position 112 might lead to unfavorable steroid binding, thereby resulting in decreased catalytic activity. Furthermore, M112A and M112L mutations reduced melting temperature (Tm) by 6.4°C and 2.5°C, respectively. These changes suggest that favorable packing in the core is important for the maintenance of stability in KSI. The M112K mutation decreased kcat by 2000-fold, compared with the WT. In M112K KSI structure, a new salt bridge was formed between Asp38 and Lys112. This bridge could change the electrostatic potential of Asp38, and thereby contribute to the decreased catalytic activity. The M112K mutation also decreased the stability by reducing Tm by 4.1°C. Our data suggest that the Met112 residue may contribute to the catalytic activity and stability of KSI by providing favorable hydrophobic environments and compact packing in the catalytic core.
[Mh] Termos MeSH primário: Cetosteroides/metabolismo
Metionina/genética
Esteroide Isomerases/genética
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Substituição de Aminoácidos/genética
Catálise
Domínio Catalítico/genética
Ligações de Hidrogênio
Interações Hidrofóbicas e Hidrofílicas
Mutação/genética
Pseudomonas putida/genética
Pseudomonas putida/metabolismo
Alinhamento de Sequência
Temperatura de Transição
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Ketosteroids); AE28F7PNPL (Methionine); EC 5.3.3.- (Steroid Isomerases)
[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:160705
[St] Status:MEDLINE



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