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[PMID]: 28816437 [Au] Autor: Mascarenhas R; Le HV; Clevenger KD; Lehrer HJ; Ringe D; Kelleher NL; Silverman RB; Liu D [Ad] Endereço: Department of Chemistry and Biochemistry, Loyola University Chicago , Chicago, Illinois 60660, United States. [Ti] Título: Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover. [So] Source: Biochemistry;56(37):4951-4961, 2017 Sep 19. [Is] ISSN: 1520-4995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or γ-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms. [Mh] Termos MeSH primário: 4-Aminobutirato Transaminase/antagonistas & inibidores Aspartato Aminotransferases/antagonistas & inibidores Cicloleucina/análogos & derivados Inibidores Enzimáticos/farmacologia Modelos Moleculares Ornitina-Oxo-Ácido Transaminase/antagonistas & inibidores Fosfato de Piridoxal/metabolismo [Mh] Termos MeSH secundário: 4-Aminobutirato Transaminase/química 4-Aminobutirato Transaminase/metabolismo Aspartato Aminotransferases/química Aspartato Aminotransferases/genética Aspartato Aminotransferases/metabolismo Sítios de Ligação Domínio Catalítico Cristalografia por Raios X Cicloleucina/química Cicloleucina/metabolismo Cicloleucina/farmacologia Bases de Dados de Compostos Químicos Bases de Dados de Proteínas Inibidores Enzimáticos/química Inibidores Enzimáticos/metabolismo Proteínas de Escherichia coli/antagonistas & inibidores Proteínas de Escherichia coli/química Proteínas de Escherichia coli/genética Proteínas de Escherichia coli/metabolismo Seres Humanos Ligantes Conformação Molecular Ornitina-Oxo-Ácido Transaminase/química Ornitina-Oxo-Ácido Transaminase/genética Ornitina-Oxo-Ácido Transaminase/metabolismo Conformação Proteica Fosfato de Piridoxal/química Piridoxamina/química Piridoxamina/metabolismo Proteínas Recombinantes/química Proteínas Recombinantes/metabolismo Homologia Estrutural de Proteína Especificidade por Substrato [Pt] Tipo de publicação: COMPARATIVE STUDY; JOURNAL ARTICLE [Nm] Nome de substância: 0 (3-amino-4-fluorocyclopentane-1-carboxylic acid); 0 (Enzyme Inhibitors); 0 (Escherichia coli Proteins); 0 (Ligands); 0 (Recombinant Proteins); 0TQU7668EI (Cycloleucine); 5V5IOJ8338 (Pyridoxal Phosphate); 6466NM3W93 (Pyridoxamine); EC 2.6.1.1 (Aspartate Aminotransferases); EC 2.6.1.13 (Ornithine-Oxo-Acid Transaminase); EC 2.6.1.19 (4-Aminobutyrate Transaminase) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171003 [Lr] Data última revisão: 171003 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170818 [St] Status: MEDLINE [do] DOI: 10.1021/acs.biochem.7b00499

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[PMID]: 28704609 [Au] Autor: Pansuwan H; Ditmangklo B; Vilaivan C; Jiangchareon B; Pan-In P; Wanichwecharungruang S; Palaga T; Nuanyai T; Suparpprom C; Vilaivan T [Ad] Endereço: Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Naresuan University , Ta-Po District, Muang, Phitsanulok 65000, Thailand. [Ti] Título: Hydrophilic and Cell-Penetrable Pyrrolidinyl Peptide Nucleic Acid via Post-synthetic Modification with Hydrophilic Side Chains. [So] Source: Bioconjug Chem;28(9):2284-2292, 2017 Sep 20. [Is] ISSN: 1520-4812 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Peptide nucleic acid (PNA) is a nucleic acid mimic in which the deoxyribose-phosphate was replaced by a peptide-like backbone. The absence of negative charge in the PNA backbone leads to several unique behaviors including a stronger binding and salt independency of the PNA-DNA duplex stability. However, PNA possesses poor aqueous solubility and cannot directly penetrate cell membranes. These are major obstacles that limit in vivo applications of PNA. In previous strategies, the PNA can be conjugated to macromolecular carriers or modified with positively charged side chains such as guanidinium groups to improve the aqueous solubility and cell permeability. In general, a preformed modified PNA monomer was required. In this study, a new approach for post-synthetic modification of PNA backbone with one or more hydrophilic groups was proposed. The PNA used in this study was the conformationally constrained pyrrolidinyl PNA with prolyl-2-aminocyclopentanecarboxylic acid dipeptide backbone (acpcPNA) that shows several advantages over the conventional PNA. The aldehyde modifiers carrying different linkers (alkylene and oligo(ethylene glycol)) and end groups (-OH, -NH , and guanidinium) were synthesized and attached to the backbone of modified acpcPNA by reductive alkylation. The hybrids between the modified acpcPNAs and DNA exhibited comparable or superior thermal stability with base-pairing specificity similar to those of unmodified acpcPNA. Moreover, the modified apcPNAs also showed the improvement of aqueous solubility (10-20 folds compared to unmodified PNA) and readily penetrate cell membranes without requiring any special delivery agents. This study not only demonstrates the practicality of the proposed post-synthetic modification approach for PNA modification, which could be readily applied to other systems, but also opens up opportunities for using pyrrolidinyl PNA in various applications such as intracellular RNA sensing, specific gene detection, and antisense and antigene therapy. [Mh] Termos MeSH primário: Cicloleucina/análogos & derivados Dipeptídeos/química Ácidos Nucleicos Peptídicos/química Pirrolidinas/química [Mh] Termos MeSH secundário: Permeabilidade da Membrana Celular Cicloleucina/síntese química Cicloleucina/metabolismo Dipeptídeos/síntese química Dipeptídeos/metabolismo Células HEK293 Seres Humanos Interações Hidrofóbicas e Hidrofílicas Ácidos Nucleicos Peptídicos/síntese química Ácidos Nucleicos Peptídicos/metabolismo Permeabilidade Pirrolidinas/síntese química Pirrolidinas/metabolismo Solubilidade Temperatura Ambiente [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Dipeptides); 0 (Peptide Nucleic Acids); 0 (Pyrrolidines); 0TQU7668EI (Cycloleucine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171009 [Lr] Data última revisão: 171009 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170714 [St] Status: MEDLINE [do] DOI: 10.1021/acs.bioconjchem.7b00308

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[PMID]: 28137973 [Au] Autor: Howarth C; Sutherland B; Choi HB; Martin C; Lind BL; Khennouf L; LeDue JM; Pakan JM; Ko RW; Ellis-Davies G; Lauritzen M; Sibson NR; Buchan AM; MacVicar BA [Ad] Endereço: Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. [Ti] Título: A Critical Role for Astrocytes in Hypercapnic Vasodilation in Brain. [So] Source: J Neurosci;37(9):2403-2414, 2017 Mar 01. [Is] ISSN: 1529-2401 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO , arterial O , and brain activity and is largely constant in the awake state. Although small changes in arterial CO are particularly potent to change CBF (1 mmHg variation in arterial CO changes CBF by 3%-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E (PgE ) plays a key role for cerebrovascular CO reactivity, and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with work in rats and C57BL/6J mice to examine the hemodynamic responses to CO and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE synthesis. We demonstrate that hypercapnia (increased CO ) evokes an increase in astrocyte [Ca ] and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that, when glutathione levels are reduced, astrocyte calcium-evoked release of PgE is decreased and vasodilation triggered by increased astrocyte [Ca ] and by hypercapnia is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO Reductions in glutathione levels in aging, stroke, or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage. Neuronal activity leads to the generation of CO , which has previously been shown to evoke cerebral blood flow (CBF) increases via the release of the vasodilator PgE We demonstrate that hypercapnia (increased CO ) evokes increases in astrocyte calcium signaling, which in turn stimulates COX-1 activity and generates downstream PgE production. We demonstrate that astrocyte calcium-evoked production of the vasodilator PgE is critically dependent on brain levels of the antioxidant glutathione. These data suggest a novel role for astrocytes in the regulation of CO -evoked CBF responses. Furthermore, these results suggest that depleted glutathione levels, which occur in aging and stroke, will give rise to dysfunctional CBF regulation and may result in subsequent neuronal damage. [Mh] Termos MeSH primário: Astrócitos/metabolismo Hipocampo/patologia Hipercapnia/patologia [Mh] Termos MeSH secundário: Agonistas de Receptores Adrenérgicos alfa 2/farmacologia Agonistas alfa-Adrenérgicos/farmacologia Animais Animais Recém-Nascidos Dióxido de Carbono/metabolismo Dióxido de Carbono/farmacologia Circulação Cerebrovascular/efeitos dos fármacos Clonidina/farmacologia Cicloleucina/análogos & derivados Cicloleucina/farmacologia Ciclo-Oxigenase 1/metabolismo Dinoprostona/metabolismo Feminino Proteína Glial Fibrilar Ácida/metabolismo Glutationa/metabolismo Técnicas In Vitro Masculino Proteínas de Membrana/metabolismo Camundongos Camundongos Endogâmicos C57BL Fármacos Neuroprotetores/farmacologia Norepinefrina/farmacologia Ratos Ratos Wistar Vibrissas/inervação [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Adrenergic alpha-2 Receptor Agonists); 0 (Adrenergic alpha-Agonists); 0 (Glial Fibrillary Acidic Protein); 0 (Membrane Proteins); 0 (Neuroprotective Agents); 0TQU7668EI (Cycloleucine); 111900-32-4 (1-amino-1,3-dicarboxycyclopentane); 142M471B3J (Carbon Dioxide); EC 1.14.99.1 (Cyclooxygenase 1); EC 1.14.99.1 (Ptgs1 protein, mouse); GAN16C9B8O (Glutathione); K7Q1JQR04M (Dinoprostone); MN3L5RMN02 (Clonidine); X4W3ENH1CV (Norepinephrine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 170818 [Lr] Data última revisão: 170818 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170201 [St] Status: MEDLINE [do] DOI: 10.1523/JNEUROSCI.0005-16.2016

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[PMID]: 27413752 [Au] Autor: Blandford SN; Baldridge WH [Ad] Endereço: Retina and Optic Nerve Research Laboratory, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2; Department of Medical Neuroscience, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4R2. [Ti] Título: The Effect of Glutamate Receptor Agonists on Mouse Retinal Astrocyte [Ca(2+)]i. [So] Source: Biomed Res Int;2016:8178162, 2016. [Is] ISSN: 2314-6141 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Calcium-imaging techniques were used to determine if mouse retinal astrocytes in situ respond to agonists of ionotropic (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, AMPA; N-methyl-D-aspartate, NMDA) and metabotropic (S-3,5-dihydroxyphenylglycine, DHPG; trans-1-amino-1,3-cyclopentanedicarboxylic acid, ACPD) glutamate receptors. In most cases we found no evidence that retinal astrocyte intracellular calcium ion concentration ([Ca(2+)]i) increased in response to these glutamate agonists. The one exception was AMPA that increased [Ca(2+)]i in some, but not all, mouse retinal astrocytes in situ. However, AMPA did not increase [Ca(2+)]i in mouse retinal astrocytes in vitro, suggesting that the effect of AMPA in situ may be indirect. [Mh] Termos MeSH primário: Astrócitos/metabolismo Cálcio/metabolismo Agonistas de Aminoácidos Excitatórios/farmacologia Receptores de Glutamato/metabolismo Retina/citologia [Mh] Termos MeSH secundário: Animais Astrócitos/efeitos dos fármacos Cicloleucina/análogos & derivados Cicloleucina/farmacologia Fura-2/metabolismo Metoxi-Hidroxifenilglicol/análogos & derivados Metoxi-Hidroxifenilglicol/farmacologia Camundongos Endogâmicos C57BL N-Metilaspartato/farmacologia Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Excitatory Amino Acid Agonists); 0 (Receptors, Glutamate); 0TQU7668EI (Cycloleucine); 111900-32-4 (1-amino-1,3-dicarboxycyclopentane); 534-82-7 (Methoxyhydroxyphenylglycol); 6384-92-5 (N-Methylaspartate); 77521-29-0 (alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid); CF5G2G268A (dihydroxyphenylethylene glycol); SY7Q814VUP (Calcium); TSN3DL106G (Fura-2) [Em] Mês de entrada: 1702 [Cu] Atualização por classe: 170222 [Lr] Data última revisão: 170222 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160715 [St] Status: MEDLINE [do] DOI: 10.1155/2016/8178162

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[PMID]: 26957228 [Au] Autor: Aira Z; Barrenetxea T; Buesa I; Martínez E; Azkue JJ [Ad] Endereço: Department of Neurosciences, School of Medicine and Dentistry, University of the Basque Country UPV/EHU, Barrio Sarriena s/n, 48940 Leioa, Spain. [Ti] Título: Spinal D1-like dopamine receptors modulate NMDA receptor-induced hyperexcitability and NR1 subunit phosphorylation at serine 889. [So] Source: Neurosci Lett;618:152-158, 2016 Apr 08. [Is] ISSN: 1872-7972 [Cp] País de publicação: Ireland [La] Idioma: eng [Ab] Resumo: Activation of the N-methyl-d-aspartate receptor (NMDAR) in dorsal horn neurons is recognized as a fundamental mechanism of central sensitization and pathologic pain. This study assessed the influence of dopaminergic, D1-like receptor-mediated input to the spinal dorsal horn on NMDAR function. Spinal superfusion with selective NMDAR agonist cis-ACPD significantly increased C-fiber-evoked field potentials in rats subjected to spinal nerve ligation (SNL), but not in sham-operated rats. Simultaneous application of D1LR antagonist SCH 23390 dramatically reduced hyperexcitability induced by cis-ACPD. Furthermore, cis-ACPD-induced hyperexcitability seen in nerve-ligated rats could be mimicked in unin-jured rats during stimulation of D1LRs by agonist SKF 38393 at subthreshold concentration. Phosphorylation of NMDAR subunit NR1 at serine 889 at postsynaptic sites was found to be increased in dorsal horn neurons 90 min after SNL, as assessed by increased co-localization with postsynaptic marker PSD-95. Increased NR1 phosphorylation was attenuated in the presence of SCH 23390 in the spinal superfusate. The present results support that D1LRs regulate most basic determinants of NMDAR function in dorsal horn neurons, suggesting a potential mechanism whereby dopaminergic input to the dorsal horn can modulate central sensitization and pathologic pain. [Mh] Termos MeSH primário: Receptores de Dopamina D1/metabolismo Receptores de N-Metil-D-Aspartato/metabolismo Serina/metabolismo Medula Espinal/fisiopatologia [Mh] Termos MeSH secundário: Animais Cicloleucina/análogos & derivados Cicloleucina/farmacologia Potenciais Evocados Masculino Fibras Nervosas Amielínicas/fisiologia Neuralgia/metabolismo Neuralgia/fisiopatologia Neurônios/fisiologia Fosforilação Subunidades Proteicas/agonistas Subunidades Proteicas/metabolismo Ratos Sprague-Dawley Receptores de Dopamina D1/antagonistas & inibidores Receptores de N-Metil-D-Aspartato/agonistas Nervo Isquiático/lesões Medula Espinal/efeitos dos fármacos Corno Dorsal da Medula Espinal/efeitos dos fármacos Corno Dorsal da Medula Espinal/fisiopatologia [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (NR1 NMDA receptor); 0 (Protein Subunits); 0 (Receptors, Dopamine D1); 0 (Receptors, N-Methyl-D-Aspartate); 0TQU7668EI (Cycloleucine); 111900-32-4 (1-amino-1,3-dicarboxycyclopentane); 452VLY9402 (Serine) [Em] Mês de entrada: 1608 [Cu] Atualização por classe: 170728 [Lr] Data última revisão: 170728 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 160310 [St] Status: MEDLINE

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[PMID]: 26633314 [Au] Autor: Kiss L; Forró E; Orsy G; Ábrahámi R; Fülöp F [Ad] Endereço: Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Hungary. kiss.lorand@pharm.u-szeged.hu. [Ti] Título: Stereo- and Regiocontrolled Syntheses of Exomethylenic Cyclohexane ß-Amino Acid Derivatives. [So] Source: Molecules;20(12):21094-102, 2015 Nov 27. [Is] ISSN: 1420-3049 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: Cyclohexane analogues of the antifungal icofungipen [(1R,2S)-2-amino-4-methylenecyclopentanecarboxylic acid] were selectively synthesized from unsaturated bicyclic ß-lactams by transformation of the ring olefinic bond through three different regio- and stereocontrolled hydroxylation techniques, followed by hydroxy group oxidation and oxo-methylene interconversion with a phosphorane. Starting from an enantiomerically pure bicyclic ß-lactam obtained by enzymatic resolution of the racemic compound, an enantiodivergent procedure led to the preparation of both dextro- and levorotatory cyclohexane analogues of icofungipen. [Mh] Termos MeSH primário: Aminoácidos/química Antifúngicos/síntese química Cicloexanos/química Fungos/efeitos dos fármacos beta-Lactamas/química [Mh] Termos MeSH secundário: Antifúngicos/farmacologia Cicloleucina/análogos & derivados Hidroxilação Estrutura Molecular Oxirredução [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Amino Acids); 0 (Antifungal Agents); 0 (Cyclohexanes); 0 (beta-Lactams); 0TQU7668EI (Cycloleucine); 48K5MKG32S (Cyclohexane); I20202Q8M8 (2-amino-4-methylenecyclopentane-1-carboxylic acid) [Em] Mês de entrada: 1609 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 151204 [St] Status: MEDLINE [do] DOI: 10.3390/molecules201219749

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[PMID]: 26280490 [Au] Autor: Borisek J; Vizovisek M; Sosnowski P; Turk B; Turk D; Mohar B; Novic M [Ad] Endereço: National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia. [Ti] Título: Development of N-(Functionalized benzoyl)-homocycloleucyl-glycinonitriles as Potent Cathepsin K Inhibitors. [So] Source: J Med Chem;58(17):6928-37, 2015 Sep 10. [Is] ISSN: 1520-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site. [Mh] Termos MeSH primário: Benzoatos/química Catepsina K/antagonistas & inibidores Cicloleucina/química Dipeptídeos/química Glicina/química Nitrilos/química [Mh] Termos MeSH secundário: Benzoatos/síntese química Benzoatos/farmacologia Cristalografia por Raios X Dipeptídeos/síntese química Dipeptídeos/farmacologia Seres Humanos Cinética Modelos Moleculares Simulação de Acoplamento Molecular Nitrilos/síntese química Nitrilos/farmacologia Ligação Proteica Relação Quantitativa Estrutura-Atividade [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Benzoates); 0 (Dipeptides); 0 (Nitriles); 0TQU7668EI (Cycloleucine); EC 3.4.22.38 (Cathepsin K); TE7660XO1C (Glycine) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 150910 [Lr] Data última revisão: 150910 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150818 [St] Status: MEDLINE [do] DOI: 10.1021/acs.jmedchem.5b00746

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[PMID]: 25725156 [Au] Autor: Wang X; Zhu L; Chen J; Wang Y [Ad] Endereço: College of Animal Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, China; Zhejiang Provincial Laboratory of Feed and Animal Nu [Ti] Título: mRNA m6A methylation downregulates adipogenesis in porcine adipocytes. [So] Source: Biochem Biophys Res Commun;459(2):201-7, 2015 Apr 03. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Fat Mass and Obesity-associated protein (FTO), associated with obesity, is proved to demethylate N6-methyladenosine (m(6)A), which raises questions regarding whether m(6)A plays vital roles in adipogenesis. To prove this, overexpression and knockdown of FTO and METTL3, as well as the chemical treatment in procine adipocytes were conducted. The results showed FTO negatively regulated m(6)A levels and positively regulated adipogenesis, while METTL3 positively correlated with m(6)A levels and negatively with adipogenesis. To remove the potential effect of FTO and METTL3 gene, chemical reagents of methylation inhibitor cycloleucine and methyl donor betaine were used to test the regulation effect of m(6)A on adipogenesis. The results showed the inverse effect of m(6)A on lipid accumulation in porcine adipocytes. These findings provide compelling evidence that m(6)A plays a critical role in the regulation of adipogenesis. [Mh] Termos MeSH primário: Adenosina/análogos & derivados Adipócitos/metabolismo Adipogenia/genética Adipogenia/fisiologia RNA Mensageiro/genética RNA Mensageiro/metabolismo [Mh] Termos MeSH secundário: Adenosina/química Adenosina/metabolismo Adipócitos/efeitos dos fármacos Adipogenia/efeitos dos fármacos Animais Betaína/farmacologia Células Cultivadas Cicloleucina/farmacologia Regulação para Baixo Técnicas de Silenciamento de Genes Metabolismo dos Lipídeos Metilação Metiltransferases/antagonistas & inibidores Metiltransferases/genética Metiltransferases/metabolismo RNA Mensageiro/química Suínos [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (RNA, Messenger); 0TQU7668EI (Cycloleucine); 1867-73-8 (N(6)-methyladenosine); 3SCV180C9W (Betaine); EC 2.1.1.- (Methyltransferases); EC 2.1.1.62 (mRNA (2'-O-methyladenosine-N6-)-methyltransferase); K72T3FS567 (Adenosine) [Em] Mês de entrada: 1506 [Cu] Atualização por classe: 150324 [Lr] Data última revisão: 150324 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150301 [St] Status: MEDLINE

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[PMID]: 25677195 [Au] Autor: Olajos G; Hetényi A; Wéber E; Németh LJ; Szakonyi Z; Fülöp F; Martinek TA [Ad] Endereço: Institute of Pharmaceutical Analysis, SZTE-MTA Lendület Foldamer Research Group, University of Szeged, 6720 Szeged (Hungary). [Ti] Título: Induced folding of protein-sized foldameric ß-sandwich models with core ß-amino acid residues. [So] Source: Chemistry;21(16):6173-80, 2015 Apr 13. [Is] ISSN: 1521-3765 [Cp] País de publicação: Germany [La] Idioma: eng [Ab] Resumo: The mimicry of protein-sized ß-sheet structures with unnatural peptidic sequences (foldamers) is a considerable challenge. In this work, the de novo designed betabellin-14 ß-sheet has been used as a template, and αâ†’ß residue mutations were carried out in the hydrophobic core (positions 12 and 19). ß-Residues with diverse structural properties were utilized: Homologous ß(3) -amino acids, (1R,2S)-2-aminocyclopentanecarboxylic acid (ACPC), (1R,2S)-2-aminocyclohexanecarboxylic acid (ACHC), (1R,2S)-2-aminocyclohex-3-enecarboxylic acid (ACEC), and (1S,2S,3R,5S)-2-amino-6,6-dimethylbicyclo[3.1.1]heptane-3-carboxylic acid (ABHC). Six α/ß-peptidic chains were constructed in both monomeric and disulfide-linked dimeric forms. Structural studies based on circular dichroism spectroscopy, the analysis of NMR chemical shifts, and molecular dynamics simulations revealed that dimerization induced ß-sheet formation in the 64-residue foldameric systems. Core replacement with (1R,2S)-ACHC was found to be unique among the ß-amino acid building blocks studied because it was simultaneously able to maintain the interstrand hydrogen-bonding network and to fit sterically into the hydrophobic interior of the ß-sandwich. The novel ß-sandwich model containing 25 % unnatural building blocks afforded protein-like thermal denaturation behavior. [Mh] Termos MeSH primário: Dobramento de Proteína Proteínas/química [Mh] Termos MeSH secundário: Sequência de Aminoácidos Ácidos Cicloexanocarboxílicos/química Cicloexilaminas/química Cicloleucina/química Simulação de Dinâmica Molecular Dados de Sequência Molecular Desnaturação Proteica Multimerização Proteica Estrutura Secundária de Proteína [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Cyclohexanecarboxylic Acids); 0 (Cyclohexylamines); 0 (Proteins); 0TQU7668EI (Cycloleucine); 160275-36-5 (betabellin 14); 5691-19-0 (2-aminocyclohexanecarboxylic acid) [Em] Mês de entrada: 1512 [Cu] Atualização por classe: 150401 [Lr] Data última revisão: 150401 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150214 [St] Status: MEDLINE [do] DOI: 10.1002/chem.201405581

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MEDLINE

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[PMID]: 25660526 [Au] Autor: Ilisz I; Gecse Z; Lajkó G; Nonn M; Fülöp F; Lindner W; Péter A [Ad] Endereço: Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. [Ti] Título: Investigation of the structure-selectivity relationships and van't Hoff analysis of chromatographic stereoisomer separations of unusual isoxazoline-fused 2-aminocyclopentanecarboxylic acids on Cinchona alkaloid-based chiral stationary phases. [So] Source: J Chromatogr A;1384:67-75, 2015 Mar 06. [Is] ISSN: 1873-3778 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: The enantiomers of four unusual, rather rigid isoxazoline-fused 2-aminocyclopentanecarboxylic acids were directly separated on a quinine- or a quinidine-based zwitterionic ion-exchanger as chiral selector. The effects of the mobile phase composition, the structures of the analytes and temperature on the separations were investigated. Experiments were performed at constant mobile phase composition in the temperature range 10-50°C to study the effects of temperature, and thermodynamic parameters were calculated from plots of ln α versus 1/T. Some mechanistic aspects of the chiral recognition process are discussed with respect to the structures of the analytes. It was found that the enantiomer separations were in most cases predominantly enthalpy-driven, but entropically-driven separations were also observed. The sequence of elution of the enantiomers was determined in all cases. [Mh] Termos MeSH primário: Ácidos Carboxílicos/isolamento & purificação Cromatografia Alcaloides de Cinchona/química Extração Líquido-Líquido/métodos Temperatura Ambiente [Mh] Termos MeSH secundário: Cicloleucina/química Quinina/química Estereoisomerismo Relação Estrutura-Atividade Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Carboxylic Acids); 0 (Cinchona Alkaloids); 0TQU7668EI (Cycloleucine); A7V27PHC7A (Quinine) [Em] Mês de entrada: 1506 [Cu] Atualização por classe: 150216 [Lr] Data última revisão: 150216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 150210 [St] Status: MEDLINE

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