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[PMID]: 29354835 [Au] Autor: Avilés-Moreno JR; Berden G; Oomens J; Martínez-Haya B [Ad] Endereço: Department of Physical, Chemical and Natural Systems, Universidad Pablo de Olavide, E-41013 Seville, Spain. bmarhay@upo.es. [Ti] Título: Guanidinium/ammonium competition and proton transfer in the interaction of the amino acid arginine with the tetracarboxylic 18-crown-6 ionophore. [So] Source: Phys Chem Chem Phys;20(6):4067-4073, 2018 Feb 07. [Is] ISSN: 1463-9084 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: The recognition of arginine plays a central role in modern proteomics and genomics. Arginine is unique among natural amino acids due to the high basicity of its guanidinium side chain, which sustains specific interactions and proton exchange biochemical processes. The search for suitable macrocyclic ionophores constitutes a promising route towards the development of arginine receptors. This study evaluates the conformational features involved in the binding of free arginine by the polyether macrocycle (18-crown-6)-tetracarboxylic acid. Infrared action vibrational spectroscopy and quantum-chemical computations are combined to characterize the complexes with net charges +1 and +2. The spectrum of the +1 complex can be explained in terms of a configuration predominantly stabilized by a robust bidentate coordination of guanidinium with a carboxylate group formed from the deprotonation of one side group of the crown ether. The released proton is transferred to the amino terminus of arginine, which then coordinates with the crown ether ring. In an alternative type of conformation, partly consistent with experiment, the amino terminus is neutral and the guanidinium group inserts into the crown ether cavity. In the +2 complexes, arginine is always doubly protonated and the most stable conformations are characterized by a tripodal coordination of the ammonium -NH group of arginine with the oxygen atoms of the macrocycle ring, while the interactions of the amino acid with the side carboxylic acid groups of the crown ether acquire a remarkable lesser role. [Mh] Termos MeSH primário: Compostos de Amônio/química Arginina/química Éteres de Coroa/química Guanidina/química [Mh] Termos MeSH secundário: Prótons Teoria Quântica Espectrofotometria Infravermelho [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ammonium Compounds); 0 (Crown Ethers); 0 (Protons); 63J177NC5B (18-crown-6); 94ZLA3W45F (Arginine); JU58VJ6Y3B (Guanidine) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180226 [Lr] Data última revisão: 180226 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180123 [St] Status: MEDLINE [do] DOI: 10.1039/c7cp07975c

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[PMID]: 29309999 [Au] Autor: Millan S; Satish L; Bera K; Konar M; Sahoo H [Ad] Endereço: Department of Chemistry, National Institute of Technology (NIT), Rourkela, Odisha, India. [Ti] Título: Exploring the effect of 5-Fluorouracil on conformation, stability and activity of lysozyme by combined approach of spectroscopic and theoretical studies. [So] Source: J Photochem Photobiol B;179:23-31, 2018 Feb. [Is] ISSN: 1873-2682 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: In this present work, a detailed investigation of the effect of an anticancer drug, 5-Fluorouracil (5-FU), on conformation, stability and activity of lysozyme (Lyz) was reported. The interaction between Lyz and 5-FU was reflected in terms of intrinsic fluorescence quenching and change in secondary structure of Lyz. The mode of quenching mechanism involved was evaluated by the steady-state and time-resolved fluorescence measurements. Synchronous and Circular Dichroism (CD) results revealed the conformational changes induced in Lyz upon complexation with 5-FU. Additionally, the effect of temperature and chemical denaturant on the stability of Lyz-5FU complex was carried out. As well as the activity of Lyz in the absence and presence of 5-FU were measured using Micrococcus luteus strain. To support our experimental findings, in vitro interaction between Lyz and 5-FU was done by theoretical studies. The current study will provide a better understanding on the nature of the interactions possible between proteins and drug molecules, which might create a bench mark in medical science in terms of the toxic effect or biological benefits of drug molecules on protein structure and conformation. [Mh] Termos MeSH primário: Fluoruracila/metabolismo Modelos Moleculares Muramidase/metabolismo [Mh] Termos MeSH secundário: Sítios de Ligação Dicroísmo Circular Fluoruracila/química Guanidina/química Muramidase/química Ligação Proteica Desnaturação Proteica Estabilidade Proteica Estrutura Secundária de Proteína Espectrometria de Fluorescência Temperatura Ambiente Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: EC 3.2.1.17 (Muramidase); JU58VJ6Y3B (Guanidine); U3P01618RT (Fluorouracil) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180223 [Lr] Data última revisão: 180223 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180109 [St] Status: MEDLINE

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[PMID]: 27770745 [Au] Autor: Kocak A; Erol I; Yildiz M; Can H [Ad] Endereço: Department of Chemistry, Gebze Technical University, 41400, Gebze, Kocaeli, Turkey. Electronic address: kocak@gtu.edu.tr. [Ti] Título: Computational insights into the protonation states of catalytic dyad in BACE1-acyl guanidine based inhibitor complex. [So] Source: J Mol Graph Model;70:226-235, 2016 11. [Is] ISSN: 1873-4243 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Developing small compound based drugs targeting the ß-secretase (BACE) enzyme is one of the most promising strategies in treatment of the Alzheimer's disease. As the enzyme shows the activity based on the acid-base reaction at a very narrow pH range, the protonation state of aspartic acids with the residue number 32 and 228 (Asp32 and Asp228), which forms the active site dyad, along with the protonation state of the ligand (substrate or inhibitor) play very critical role in interactions between the ligand and enzyme. Thus, understanding the nature of the protonation state of both enzyme's active site dyad and ligand is crucial for drug design in Alzheimer's disease field. Here we have investigated the protonation state of the Asp32 and Asp228 residues in the presence of a highly potent beta secretase inhibitor, containing acyl guanidine warhead that have recently been devised but not extensively studied. Our Quantum Mechanical, Molecular Dynamics and Docking studies on all the possible protonation states have suggested that the dyad residues are in di-deprotonated states in the presence of protonated inhibitor. [Mh] Termos MeSH primário: Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores Secretases da Proteína Precursora do Amiloide/química Biocatálise Guanidina/farmacologia Modelos Moleculares Inibidores de Proteases/química Inibidores de Proteases/farmacologia Prótons [Mh] Termos MeSH secundário: Acilação Guanidina/química Ligações de Hidrogênio Ligantes Simulação de Acoplamento Molecular Simulação de Dinâmica Molecular Teoria Quântica Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Ligands); 0 (Protease Inhibitors); 0 (Protons); EC 3.4.- (Amyloid Precursor Protein Secretases); JU58VJ6Y3B (Guanidine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180216 [Lr] Data última revisão: 180216 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 161023 [St] Status: MEDLINE

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[PMID]: 28454733 [Au] Autor: Liu C; Deng Q; Fang G; Dang M; Wang S [Ad] Endereço: Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin Food Safety & Low Carbon Manufacturing Collaborative Innovation Center, Tianjin University of Science and Technology, Tianjin 300457, China; Department of Food Science and Biology Engineering, Tianjin Agricultural Univer [Ti] Título: Capillary electrochromatography immunoassay for alpha-fetoprotein based on poly(guanidinium ionic liquid) monolithic material. [So] Source: Anal Biochem;530:50-56, 2017 08 01. [Is] ISSN: 1096-0309 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Alpha-fetoprotein (AFP) is widely used as a tumor marker for the serum diagnosis of primary hepatoma. Sensitive detection of AFP level plays an important role in the early diagnosis of disease and highly reliable prediction. In this study, a novel non-competitive immunoassay (IA) based on poly(guanidinium ionic liquid) monolithic material was developed for detecting ultra trace levels of AFP in capillary electrochromatography (CEC) mode. The AFP was mixed with an excess amount of fluorescently labeled antibody. After incubation, the immunocomplex was separated from the free labeled antibody and detected by CEC coupled with laser-induced fluorescence detector. Under the optimized conditions, the developed CEC-IA performed a low detection limit of 0.05 µg L (S/N = 3) and a wide linearity ranging from 0.1 to 1000 µg L for AFP, which can be largely attributed to the high separation and enrichment efficiency of poly(guanidinium ionic liquid) monolithic material for the targets. The application of this method was demonstrated by determining AFP in human serum. [Mh] Termos MeSH primário: Eletrocromatografia Capilar/métodos Guanidina/química Imunoensaio/métodos Líquidos Iônicos/química alfa-Fetoproteínas/análise [Mh] Termos MeSH secundário: Anticorpos/imunologia Seres Humanos Limite de Detecção [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Antibodies); 0 (Ionic Liquids); 0 (alpha-Fetoproteins); JU58VJ6Y3B (Guanidine) [Em] Mês de entrada: 1708 [Cu] Atualização por classe: 180207 [Lr] Data última revisão: 180207 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170430 [St] Status: MEDLINE

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[PMID]: 29351301 [Au] Autor: Chang HC; Kung CC; Chang TT; Jao SC; Hsu YT; Li WS [Ad] Endereço: Institute of Chemistry, Academia Sinica, Taipei, Taiwan. [Ti] Título: Investigation of the proton relay system operative in human cystosolic aminopeptidase P. [So] Source: PLoS One;13(1):e0190816, 2018. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Aminopeptidase P, a metalloprotease, targets Xaa-Proline peptides for cleavage [1-4]. There are two forms of human AMPP, a membrane-bound form (hmAMPP) and a soluble cytosolic form (hcAMPP)[5]. Similar to the angiotensin-I-converting enzyme, AMPP plays an important role in the catabolism of inflammatory and vasoactive peptides, known as kinins. The plasma kinin, bradykinin, was used as the substrate to conduct enzymatic activity analyses and to determine the Michaelis constant (Km) of 174 µM and the catalytic rate constant (kcat) of 10.8 s-1 for hcAMPP. Significant differences were observed in the activities of Y527F and R535A hcAMPP mutants, which displayed a 6-fold and 13.5-fold for decrease in turnover rate, respectively. Guanidine hydrochloride restored the activity of R535A hcAMPP, increasing the kcat/Km 20-fold, yet it had no impact on the activities of the wild-type or Y527F mutant hcAMPPs. Activity restoration by guanidine derivatives followed the order guanidine hydrochloride >> methyl-guanidine > amino-guanidine > N-ethyl-guanidine. Overall, the results indicate the participation of R535 in the hydrogen bond network that forms a proton relay system. The quaternary structure of hcAMPP was determined by using analytical ultracentrifugation (AUC). The results show that alanine replacement of Arg535 destabilizes the hcAMPP dimer and that guanidine hydrochloride restores the native monomer-dimer equilibrium. It is proposed that Arg535 plays an important role in hcAMMP catalysis and in stabilization of the catalytically active dimeric state. [Mh] Termos MeSH primário: Aminopeptidases/metabolismo [Mh] Termos MeSH secundário: Sequência de Aminoácidos Substituição de Aminoácidos Aminopeptidases/química Aminopeptidases/genética Catálise Citosol/enzimologia Estabilidade Enzimática Guanidina/farmacologia Seres Humanos Ligações de Hidrogênio Cinética Modelos Moleculares Mutagênese Sítio-Dirigida Desnaturação Proteica Multimerização Proteica Estrutura Quaternária de Proteína Prótons Proteínas Recombinantes/química Proteínas Recombinantes/genética Proteínas Recombinantes/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T [Nm] Nome de substância: 0 (Protons); 0 (Recombinant Proteins); EC 3.4.11.- (Aminopeptidases); EC 3.4.11.9 (X-Pro aminopeptidase); JU58VJ6Y3B (Guanidine) [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: 180120 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0190816

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[PMID]: 29193962 [Au] Autor: Tan Z; Dhande YK; Reineke TM [Ad] Endereço: Department of Chemistry, University of Minnesota , 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States. [Ti] Título: Cell Penetrating Polymers Containing Guanidinium Trigger Apoptosis in Human Hepatocellular Carcinoma Cells unless Conjugated to a Targeting N-Acetyl-Galactosamine Block. [So] Source: Bioconjug Chem;28(12):2985-2997, 2017 Dec 20. [Is] ISSN: 1520-4812 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: A series of 3-guanidinopropyl methacrylamide (GPMA)-based polymeric gene delivery vehicles were developed via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The polymers have been evaluated for their cellular internalization ability, transfection efficiency, and cytotoxicity. Two homopolymers: P(GPMA ), P(GPMA ), were synthesized to study the effect of guanidium polymer length on delivery efficiency and toxicity. In addition, an N-acetyl-d-galactosamine (GalNAc)-based hydrophilic block was incorporated to produce diblock polymers, which provides a neutral hydrophilic block that sterically protects plasmid-polymer complexes (polyplexes) from colloidal aggregation and aids polyplex targeting to hepatocytes via binding to asialoglycoprotein receptors (ASGPRs). Polyplexes formed with P(GPMA ) (x = 20, 34) homopolymers were shown to be internalized via both energy-dependent and independent pathways, whereas polyplexes formed with block polymers were internalized through endocytosis. Notably, P(GPMA ) polyplexes enter cells very efficiently but are also very toxic to human hepatocellular carcinoma (HepG2) cells and triggered cell apoptosis. In comparison, the presence of a carbohydrate block in the polymer structures reduced the cytotoxicity of the polyplex formulations and increased gene delivery efficiency with HepG2 cells. Transfection efficiency and toxicity studies were also carried out with HEK 293T (human embryonic kidney) cells for comparison. Results showed that polyplexes formed with the P(GPMA ) homopolymers exhibit much higher transfection efficiency and lower toxicity with HEK 293T cells. The presence of the carbohydrate block did not further increase transfection efficiency in comparison to the homopolymers with HEK 293T cells, likely due to the lack of ASGPRs on the HEK 293T cell line. This study revealed that although guanidinium-based polymers have high membrane permeability, their application as plasmid delivery vehicles may be limited by their high cytotoxicity to certain cell types. Thus, the use of cell penetrating structures in polyplex formulations should be used with caution and carefully tailored toward individual cell/tissue types. [Mh] Termos MeSH primário: Acetilgalactosamina/química Apoptose/efeitos dos fármacos Carcinoma Hepatocelular/patologia Portadores de Fármacos/química Guanidina/química Neoplasias Hepáticas/patologia Polímeros/química [Mh] Termos MeSH secundário: Transporte Biológico Sobrevivência Celular/efeitos dos fármacos Portadores de Fármacos/metabolismo Portadores de Fármacos/toxicidade Células Hep G2 Seres Humanos Interações Hidrofóbicas e Hidrofílicas Polimerização Transfecção [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Drug Carriers); 0 (Polymers); JU58VJ6Y3B (Guanidine); KM15WK8O5T (Acetylgalactosamine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180105 [Lr] Data última revisão: 180105 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 171202 [St] Status: MEDLINE [do] DOI: 10.1021/acs.bioconjchem.7b00598

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[PMID]: 28807826 [Au] Autor: Mahalakshmi R; Maurya SR; Burdak B; Surti P; Patel MS; Jain V [Ad] Endereço: Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India. Electronic address: maha@iiserb.ac.in. [Ti] Título: Structural plasticity of T4 transcription co-activator gp33 revealed by a protease-resistant unfolded state. [So] Source: Biochem Biophys Res Commun;492(1):61-66, 2017 Oct 07. [Is] ISSN: 1090-2104 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Gene 33 protein (gp33) is a transcriptional coactivator for late genes of the T4 bacteriophage. gp33 possesses a 5-helix bundle core, with unstructured N- and C-terminal regions that account for >50% of the protein sequence. It plays a unique role of interacting with host RNA polymerase, couples transcription with DNA replication, and plays the dual function as repressor and co-activator in phage transcription. Here, we identify protein structural plasticity as the molecular basis of the dual nature in gp33. We find that gp33 has the peculiar property of remaining protease insensitive in its urea-unfolded state. Using NMR studies with spectroscopic measurements, we propose that intra-protein interactions are replaced by protein-urea interactions in gp33. This process not only unfolds gp33 but also renders it protease-resistant. Our studies shed new light on the unique structural malleability of gp33 that might be important in its transition from a repressor to a late transcription co-activator. [Mh] Termos MeSH primário: Peptídeo Hidrolases/metabolismo Desdobramento de Proteína Proteínas Virais/química [Mh] Termos MeSH secundário: Guanidina/farmacologia Modelos Moleculares Conformação Proteica Desdobramento de Proteína/efeitos dos fármacos Ureia/farmacologia Proteínas Virais/isolamento & purificação Proteínas Virais/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Viral Proteins); 0 (gene 33 protein, Enterobacteria phage T4); 8W8T17847W (Urea); EC 3.4.- (Peptide Hydrolases); JU58VJ6Y3B (Guanidine) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170925 [Lr] Data última revisão: 170925 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170816 [St] Status: MEDLINE

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[PMID]: 28802174 [Au] Autor: Gupta VK; Fakhri A; Agarwal S; Ahmadi E; Nejad PA [Ad] Endereço: Department of Applied Chemistry, University of Johannesburg, Johannesburg, South Africa. Electronic address: vinodfcy@gmail.com. [Ti] Título: Synthesis and characterization of MnO /NiO nanocomposites for photocatalysis of tetracycline antibiotic and modification with guanidine for carriers of Caffeic acid phenethyl ester-an anticancer drug. [So] Source: J Photochem Photobiol B;174:235-242, 2017 Sep. [Is] ISSN: 1873-2682 [Cp] País de publicação: Switzerland [La] Idioma: eng [Ab] Resumo: In the present studies, modified NiO nanoparticles and MnO /NiO nanocomposites with guanidine were synthesized by anchoring method for carriers of anticancer drug "Caffeic acid phenethyl ester". The prepared nanocomposites were characterized by using Scanning Electron Microscopy, Raman and Fourier transform infrared spectroscopy, X-ray diffraction, Vibrating sample magnetometer. The results from XRD indicated that the crystalline size of NiO nanoparticles and MnO /NiO nanocomposites are 12 and 15nm, respectively. Saturation magnetization (Ms) for NiO NPs and MnO /NiO nanocomposites was to be 0.60, and 0.68emu/g indicating that these are superparamagnetic and ferromagnetic properties in nature. The prepared nanocomposites were evaluated as catalyst for degradation of antibiotics in photocatalysis process. Particularly, the MnO /NiO composite demonstrated the higher degradation rate (89.55%) of tetracycline antibiotic under UV light irradiation than the NiO (67.80%). Drug load on and release from nanopowders was investigated by using UV-Vis spectroscopy method. Time of drug loading was 100min and the drug release in 1-10h with 20-80% drug release were found, and then, it's applicable to in-vivo drug delivery. Therefore, the NiO nanoparticles and MnO /NiO nanocomposites are promising for targeted Caffeic acid phenethyl ester anticancer drug delivery applications. The anticancer drug loaded on guanidine-NiO and guanidine-MnO /NiO in high concentration has an antioxidant property. [Mh] Termos MeSH primário: Ácidos Cafeicos/química Guanidina/química Compostos de Manganês/química Nanocompostos/química Níquel/química Óxidos/química Álcool Feniletílico/análogos & derivados Fotólise Tetraciclinas/química [Mh] Termos MeSH secundário: Antibacterianos/química Antineoplásicos/química Catálise Técnicas de Química Sintética Portadores de Fármacos/síntese química Portadores de Fármacos/química Liberação Controlada de Fármacos Depuradores de Radicais Livres/síntese química Depuradores de Radicais Livres/química Nanopartículas/química Álcool Feniletílico/química Água/química [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Anti-Bacterial Agents); 0 (Antineoplastic Agents); 0 (Caffeic Acids); 0 (Drug Carriers); 0 (Free Radical Scavengers); 0 (Manganese Compounds); 0 (Oxides); 0 (Tetracyclines); 059QF0KO0R (Water); 64J2OA7MH3 (manganese oxide); 7OV03QG267 (Nickel); C3574QBZ3Y (nickel monoxide); G960R9S5SK (caffeic acid phenethyl ester); JU58VJ6Y3B (Guanidine); ML9LGA7468 (Phenylethyl Alcohol) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171012 [Lr] Data última revisão: 171012 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170813 [St] Status: MEDLINE

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[PMID]: 28774748 [Au] Autor: Ricci C; Carrotta R; Rappa GC; Mangione MR; Librizzi F; San Biagio PL; Amenitsch H; Ortore MG; Vilasi S [Ad] Endereço: Dept. Life and Environmental Sciences, Marche Polytechnic University, Ancona 60131, Italy. Electronic address: c.ricci@univpm.it. [Ti] Título: Investigation on different chemical stability of mitochondrial Hsp60 and its precursor. [So] Source: Biophys Chem;229:31-38, 2017 Oct. [Is] ISSN: 1873-4200 [Cp] País de publicação: Netherlands [La] Idioma: eng [Ab] Resumo: In the large class of molecules that maintain protein homeostasis, called molecular chaperones, chaperonins constitute a subclass that specifically assist the correct folding of newly synthesized proteins. Among them, Hsp60 is composed of a double heptameric ring structure with a large central cavity where the unfolded protein binds via hydrophobic interactions and is supported, in this function, by the co-chaperonin Hsp10. Hsp60 is typically located in the mitochondria, but in some pathological situations, such as cancers and chronic inflammatory diseases, Hsp60 accumulates in the cytoplasm. In these cases, cytoplasmatic Hsp60 is a mixture of mitochondrial Hsp60 secreted from mitochondria upon stress, and its precursor, called naïve Hsp60, never entered into the organella. The difference between the naïve and mitochondrial Hsp60s resides in the absence of the mitochondrial import signal (MIS) in the mitochondrial form, but information on their different structure and stability is still lacking. We present here a study on the stability against a chemical denaturant, of the different cytoplasmic Hsp60 species. By combining Circular Dichroism and Small Angle X-ray Scattering as experimental biophysical techniques to investigate Hsp60, we find that naïve and mitochondrial Hsp60 (mtHsp60) forms differ in their stability. Furthermore, specific responses from the two forms are discussed in terms of the biological environment they are working in, thus opening new questions on their biological function. [Mh] Termos MeSH primário: Chaperonina 60/química Mitocôndrias/metabolismo [Mh] Termos MeSH secundário: Chaperonina 60/genética Chaperonina 60/metabolismo Dicroísmo Circular Escherichia coli/metabolismo Guanidina/química Desnaturação Proteica Precursores de Proteínas/química Precursores de Proteínas/metabolismo Estabilidade Proteica Proteínas Recombinantes/biossíntese Proteínas Recombinantes/química Proteínas Recombinantes/isolamento & purificação Espalhamento a Baixo Ângulo Difração de Raios X [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Chaperonin 60); 0 (Protein Precursors); 0 (Recombinant Proteins); JU58VJ6Y3B (Guanidine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171010 [Lr] Data última revisão: 171010 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170805 [St] Status: MEDLINE

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[PMID]: 28714672 [Au] Autor: Malhotra P; Jethva PN; Udgaonkar JB [Ad] Endereço: National Centre for Biological Sciences , Tata Institute of Fundamental Research, Bengaluru 560065, India. [Ti] Título: Chemical Denaturants Smoothen Ruggedness on the Free Energy Landscape of Protein Folding. [So] Source: Biochemistry;56(31):4053-4063, 2017 Aug 08. [Is] ISSN: 1520-4995 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: To characterize experimentally the ruggedness of the free energy landscape of protein folding is challenging, because the distributed small free energy barriers are usually dominated by one, or a few, large activation free energy barriers. This study delineates changes in the roughness of the free energy landscape by making use of the observation that a decrease in ruggedness is accompanied invariably by an increase in folding cooperativity. Hydrogen exchange (HX) coupled to mass spectrometry was used to detect transient sampling of local energy minima and the global unfolded state on the free energy landscape of the small protein single-chain monellin. Under native conditions, local noncooperative openings result in interconversions between Boltzmann-distributed intermediate states, populated on an extremely rugged "uphill" energy landscape. The cooperativity of these interconversions was increased by selectively destabilizing the native state via mutations, and further by the addition of a chemical denaturant. The perturbation of stability alone resulted in seven backbone amide sites exchanging cooperatively. The size of the cooperatively exchanging and/or unfolding unit did not depend on the extent of protein destabilization. Only upon the addition of a denaturant to a destabilized mutant variant did seven additional backbone amide sites exchange cooperatively. Segmentwise analysis of the HX kinetics of the mutant variants further confirmed that the observed increase in cooperativity was due to the smoothing of the ruggedness of the free energy landscape of folding of the protein by the chemical denaturant. [Mh] Termos MeSH primário: Guanidina/química Indicadores e Reagentes/química Menispermaceae/metabolismo Modelos Moleculares Proteínas de Plantas/química [Mh] Termos MeSH secundário: Substituição de Aminoácidos Medição da Troca de Deutério Transferência de Energia/efeitos dos fármacos Cinética Mutagênese Sítio-Dirigida Mutação Proteínas de Plantas/genética Proteínas de Plantas/metabolismo Conformação Proteica/efeitos dos fármacos Desnaturação Proteica/efeitos dos fármacos Dobramento de Proteína/efeitos dos fármacos Estabilidade Proteica/efeitos dos fármacos Termodinâmica [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Indicators and Reagents); 0 (Plant Proteins); 0 (monellin protein, Dioscoreophyllum cumminsii); JU58VJ6Y3B (Guanidine) [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: 170718 [St] Status: MEDLINE [do] DOI: 10.1021/acs.biochem.7b00367

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