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[PMID]:28823151
[Au] Autor:Komor AJ; Rivard BS; Fan R; Guo Y; Que L; Lipscomb JD
[Ti] Título:CmlI N-Oxygenase Catalyzes the Final Three Steps in Chloramphenicol Biosynthesis without Dissociation of Intermediates.
[So] Source:Biochemistry;56(37):4940-4950, 2017 Sep 19.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CmlI catalyzes the six-electron oxidation of an aryl-amine precursor (NH -CAM) to the aryl-nitro group of chloramphenicol (CAM). The active site of CmlI contains a (hydr)oxo- and carboxylate-bridged dinuclear iron cluster. During catalysis, a novel diferric-peroxo intermediate P is formed and is thought to directly effect oxygenase chemistry. Peroxo intermediates can facilitate at most two-electron oxidations, so the biosynthetic pathway of CmlI must involve at least three steps. Here, kinetic techniques are used to characterize the rate and/or dissociation constants for each step by taking advantage of the remarkable stability of P in the absence of substrates (decay t = 3 h at 4 °C) and the visible chromophore of the diiron cluster. It is found that diferrous CmlI (CmlI ) can react with NH -CAM and O in either order to form a P-NH -CAM intermediate. P-NH -CAM undergoes rapid oxygen transfer to form a diferric CmlI (CmlI ) complex with the aryl-hydroxylamine [NH(OH)-CAM] pathway intermediate. CmlI -NH(OH)-CAM undergoes a rapid internal redox reaction to form a CmlI -nitroso-CAM (NO-CAM) complex. O binding results in formation of P-NO-CAM that converts to CmlI -CAM by enzyme-mediated oxygen atom transfer. The kinetic analysis indicates that there is little dissociation of pathway intermediates as the reaction progresses. Reactions initiated by adding pathway intermediates from solution occur much more slowly than those in which the intermediate is generated in the active site as part of the catalytic process. Thus, CmlI is able to preserve efficiency and specificity while avoiding adventitious chemistry by performing the entire six-electron oxidation in one active site.
[Mh] Termos MeSH primário: Antibacterianos/biossíntese
Proteínas de Bactérias/metabolismo
Cloranfenicol/biossíntese
Modelos Moleculares
Ferroproteínas não Heme/metabolismo
Oxigenases/metabolismo
Streptomyces/enzimologia
[Mh] Termos MeSH secundário: Antibacterianos/química
Proteínas de Bactérias/química
Biocatálise
Domínio Catalítico
Cloranfenicol/análogos & derivados
Cloranfenicol/química
Meia-Vida
Cinética
Ferroproteínas não Heme/química
Oxirredução
Oxigênio
Oxigenases/química
Espectroscopia de Mossbauer
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Bacterial Agents); 0 (Bacterial Proteins); 0 (Nonheme Iron Proteins); 66974FR9Q1 (Chloramphenicol); EC 1.13.- (Oxygenases); S88TT14065 (Oxygen)
[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:170822
[St] Status:MEDLINE
[do] DOI:10.1021/acs.biochem.7b00695


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[PMID]:28505283
[Au] Autor:Dunham J; Bauer J; Campbell GR; Mahad DJ; van Driel N; van der Pol SMA; 't Hart BA; Lassmann H; Laman JD; van Horssen J; Kap YS
[Ad] Endereço:From the Department of Immunobiology, Biomedical Primate Research Centre, Rijswijk, The Netherlands (JD, NvD, BAH, YSK); Department of Neuroscience, University Medical Center, University of Groningen, Groningen, The Netherlands (JD, BAH, JDL); Medical University of Vienna, Center for Brain Research,
[Ti] Título:Oxidative Injury and Iron Redistribution Are Pathological Hallmarks of Marmoset Experimental Autoimmune Encephalomyelitis.
[So] Source:J Neuropathol Exp Neurol;76(6):467-478, 2017 Jun 01.
[Is] ISSN:1554-6578
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Oxidative damage and iron redistribution are associated with the pathogenesis and progression of multiple sclerosis (MS), but these aspects are not entirely replicated in rodent experimental autoimmune encephalomyelitis (EAE) models. Here, we report that oxidative burst and injury as well as redistribution of iron are hallmarks of the MS-like pathology in the EAE model in the common marmoset. Active lesions in the marmoset EAE brain display increased expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (p22phox, p47phox, and gp91phox) and inducible nitric oxide synthase immunoreactivity within lesions with active inflammation and demyelination, coinciding with enhanced expression of mitochondrial heat-shock protein 70 and superoxide dismutase 1 and 2. The EAE lesion-associated liberation of iron (due to loss of iron-containing myelin) was associated with altered expression of the iron metabolic markers FtH1, lactoferrin, hephaestin, and ceruloplasmin. The enhanced expression of oxidative damage markers in inflammatory lesions indicates that the enhanced antioxidant enzyme expression could not counteract reactive oxygen and nitrogen species-induced cellular damage, as is also observed in MS brains. This study demonstrates that oxidative injury and aberrant iron distribution are prominent pathological hallmarks of marmoset EAE thus making this model suitable for therapeutic intervention studies aimed at reducing oxidative stress and associated iron dysmetabolism.
[Mh] Termos MeSH primário: Callithrix
Encefalomielite Autoimune Experimental/metabolismo
Encefalomielite Autoimune Experimental/patologia
Ferro/metabolismo
Estresse Oxidativo
[Mh] Termos MeSH secundário: Animais
Doenças Desmielinizantes/patologia
Feminino
Proteínas de Choque Térmico HSP70/metabolismo
Imuno-Histoquímica
Masculino
Bainha de Mielina/metabolismo
NADPH Oxidases/metabolismo
Óxido Nítrico Sintase Tipo II/metabolismo
Ferroproteínas não Heme/metabolismo
Superóxido Dismutase/metabolismo
Distribuição Tecidual
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HSP70 Heat-Shock Proteins); 0 (Nonheme Iron Proteins); E1UOL152H7 (Iron); EC 1.14.13.39 (Nitric Oxide Synthase Type II); EC 1.15.1.1 (Superoxide Dismutase); EC 1.6.3.- (NADPH Oxidases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170516
[St] Status:MEDLINE
[do] DOI:10.1093/jnen/nlx034


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[PMID]:28219079
[Au] Autor:Suga M; Akita F; Sugahara M; Kubo M; Nakajima Y; Nakane T; Yamashita K; Umena Y; Nakabayashi M; Yamane T; Nakano T; Suzuki M; Masuda T; Inoue S; Kimura T; Nomura T; Yonekura S; Yu LJ; Sakamoto T; Motomura T; Chen JH; Kato Y; Noguchi T; Tono K; Joti Y; Kameshima T; Hatsui T; Nango E; Tanaka R; Naitow H; Matsuura Y; Yamashita A; Yamamoto M; Nureki O; Yabashi M; Ishikawa T; Iwata S; Shen JR
[Ad] Endereço:Research Institute for Interdisciplinary Science and Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushima Naka, Okayama 700-8530, Japan.
[Ti] Título:Light-induced structural changes and the site of O=O bond formation in PSII caught by XFEL.
[So] Source:Nature;543(7643):131-135, 2017 03 02.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Photosystem II (PSII) is a huge membrane-protein complex consisting of 20 different subunits with a total molecular mass of 350 kDa for a monomer. It catalyses light-driven water oxidation at its catalytic centre, the oxygen-evolving complex (OEC). The structure of PSII has been analysed at 1.9 Å resolution by synchrotron radiation X-rays, which revealed that the OEC is a Mn CaO cluster organized in an asymmetric, 'distorted-chair' form. This structure was further analysed with femtosecond X-ray free electron lasers (XFEL), providing the 'radiation damage-free' structure. The mechanism of O=O bond formation, however, remains obscure owing to the lack of intermediate-state structures. Here we describe the structural changes in PSII induced by two-flash illumination at room temperature at a resolution of 2.35 Å using time-resolved serial femtosecond crystallography with an XFEL provided by the SPring-8 ångström compact free-electron laser. An isomorphous difference Fourier map between the two-flash and dark-adapted states revealed two areas of apparent changes: around the Q /non-haem iron and the Mn CaO cluster. The changes around the Q /non-haem iron region reflected the electron and proton transfers induced by the two-flash illumination. In the region around the OEC, a water molecule located 3.5 Å from the Mn CaO cluster disappeared from the map upon two-flash illumination. This reduced the distance between another water molecule and the oxygen atom O4, suggesting that proton transfer also occurred. Importantly, the two-flash-minus-dark isomorphous difference Fourier map showed an apparent positive peak around O5, a unique µ -oxo-bridge located in the quasi-centre of Mn1 and Mn4 (refs 4,5). This suggests the insertion of a new oxygen atom (O6) close to O5, providing an O=O distance of 1.5 Å between these two oxygen atoms. This provides a mechanism for the O=O bond formation consistent with that proposed previously.
[Mh] Termos MeSH primário: Cristalografia/métodos
Elétrons
Lasers
Luz
Oxigênio/química
Oxigênio/efeitos da radiação
Complexo de Proteína do Fotossistema II/química
Complexo de Proteína do Fotossistema II/efeitos da radiação
[Mh] Termos MeSH secundário: Biocatálise/efeitos da radiação
Cianobactérias/química
Transporte de Elétrons/efeitos da radiação
Análise de Fourier
Manganês/química
Manganês/metabolismo
Modelos Moleculares
Ferroproteínas não Heme/química
Ferroproteínas não Heme/metabolismo
Ferroproteínas não Heme/efeitos da radiação
Oxigênio/metabolismo
Complexo de Proteína do Fotossistema II/metabolismo
Prótons
Temperatura Ambiente
Fatores de Tempo
Água/química
Água/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Nonheme Iron Proteins); 0 (Photosystem II Protein Complex); 0 (Protons); 059QF0KO0R (Water); 42Z2K6ZL8P (Manganese); S88TT14065 (Oxygen)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170221
[St] Status:MEDLINE
[do] DOI:10.1038/nature21400


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[PMID]:27941874
[Au] Autor:Bogoevska V; Wolters-Eisfeld G; Hofmann BT; El Gammal AT; Mercanoglu B; Gebauer F; Vashist YK; Bogoevski D; Perez D; Gagliani N; Izbicki JR; Bockhorn M; Güngör C
[Ad] Endereço:Cardiologicum Hamburg Research and Study Center, Hamburg, Germany.
[Ti] Título:HRG/HER2/HER3 signaling promotes AhR-mediated Memo-1 expression and migration in colorectal cancer.
[So] Source:Oncogene;36(17):2394-2404, 2017 Apr 27.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Colorectal cancer (CRC) is a complex disease with still unsatisfactory prognosis even in western societies, although substantial progress has been made in pre-screening programs, surgical techniques and targeted therapy options. Mediator of motility-1 (Memo-1) was previously recognized as an important effector of cell migration downstream of receptor tyrosine kinase signaling in breast cancer. This study identified Memo-1 as frequently overexpressed in CRC and established a close link between extracellular HER2 activation, AhR/ARNT transcriptional activity and Memo-1 expression. Dissection of the hMemo-1 gene promoter using reporter assays and chromatin IP techniques revealed recruitment of Aryl hydrocarbon receptor (AhR)/Aryl hydrocarbon receptor nuclear-translocator (ARNT) complex, which positively influenced Memo-1 expression in cancer cells. We found that Memo-1 depletion negatively influenced the cellular actin network and that its expression is required for HER2-mediated cell migration and invasion. Moreover, analyses of Memo-1 expression in primary CRC revealed correlation with clinical parameters that point to Memo-1 as a new prognostic factor of aggressive disease in CRC patients. Altogether, these observations demonstrate that Memo-1 is an important downstream regulator of HER2-driven CRC cell migration and invasion through connecting extracellular signals from membrane to the cytoskeletal actin network.
[Mh] Termos MeSH primário: Neoplasias Colorretais/patologia
Regulação Neoplásica da Expressão Gênica
Ferroproteínas não Heme/genética
Proteínas/metabolismo
Receptor ErbB-2/metabolismo
Receptor ErbB-3/metabolismo
Receptores de Hidrocarboneto Arílico/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular Tumoral
Movimento Celular
Progressão da Doença
Seres Humanos
Invasividade Neoplásica
Regiões Promotoras Genéticas/genética
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MEMO1 protein, human); 0 (Nonheme Iron Proteins); 0 (Proteins); 0 (Receptors, Aryl Hydrocarbon); 0 (histidine-rich proteins); EC 2.7.10.1 (ERBB2 protein, human); EC 2.7.10.1 (ERBB3 protein, human); EC 2.7.10.1 (Receptor, ErbB-2); EC 2.7.10.1 (Receptor, ErbB-3)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170901
[Lr] Data última revisão:
170901
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161213
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.390


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[PMID]:27792301
[Au] Autor:Solomon EI; Goudarzi S; Sutherlin KD
[Ad] Endereço:Department of Chemistry, Stanford University , Stanford, California 94305, United States.
[Ti] Título:O Activation by Non-Heme Iron Enzymes.
[So] Source:Biochemistry;55(46):6363-6374, 2016 Nov 22.
[Is] ISSN:1520-4995
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The non-heme Fe enzymes are ubiquitous in nature and perform a wide range of functions involving O activation. These had been difficult to study relative to heme enzymes; however, spectroscopic methods that provide significant insight into the correlation of structure with function have now been developed. This Current Topics article summarizes both the molecular mechanism these enzymes use to control O activation in the presence of cosubstrates and the oxygen intermediates these reactions generate. Three types of O activation are observed. First, non-heme reactivity is shown to be different from heme chemistry where a low-spin Fe -OOH non-heme intermediate directly reacts with substrate. Also, two subclasses of non-heme Fe enzymes generate high-spin Fe ═O intermediates that provide both σ and π frontier molecular orbitals that can control selectivity. Finally, for several subclasses of non-heme Fe enzymes, binding of the substrate to the Fe site leads to the one-electron reductive activation of O to an Fe -superoxide capable of H atom abstraction and electrophilic attack.
[Mh] Termos MeSH primário: Dioxigenases/química
Enzimas/química
Ferroproteínas não Heme/química
Oxigênio/química
[Mh] Termos MeSH secundário: Domínio Catalítico
Dicroísmo Circular/métodos
Dioxigenases/metabolismo
Enzimas/metabolismo
Ligações de Hidrogênio
Cinética
Modelos Químicos
Modelos Moleculares
Ferroproteínas não Heme/metabolismo
Oxirredução
Oxigênio/metabolismo
Ligação Proteica
Especificidade por Substrato
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzymes); 0 (Nonheme Iron Proteins); EC 1.13.11.- (Dioxygenases); S88TT14065 (Oxygen)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171122
[Lr] Data última revisão:
171122
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161030
[St] Status:MEDLINE


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[PMID]:27586346
[Au] Autor:Chino M; Leone L; Maglio O; Lombardi A
[Ad] Endereço:University of Napoli Federico II, Napoli, Italy.
[Ti] Título:Designing Covalently Linked Heterodimeric Four-Helix Bundles.
[So] Source:Methods Enzymol;580:471-99, 2016.
[Is] ISSN:1557-7988
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:De novo design has proven a powerful methodology for understanding protein folding and function, and for mimicking or even bettering the properties of natural proteins. Extensive progress has been made in the design of helical bundles, simple structural motifs that can be nowadays designed with a high degree of precision. Among helical bundles, the four-helix bundle is widespread in nature, and is involved in numerous and fundamental processes. Representative examples are the carboxylate bridged diiron proteins, which perform a variety of different functions, ranging from reversible dioxygen binding to catalysis of dioxygen-dependent reactions, including epoxidation, desaturation, monohydroxylation, and radical formation. The "Due Ferri" (two-irons; DF) family of proteins is the result of a de novo design approach, aimed to reproduce in minimal four-helix bundle models the properties of the more complex natural diiron proteins, and to address how the amino acid sequence modulates their functions. The results so far obtained point out that asymmetric metal environments are essential to reprogram functions, and to achieve the specificity and selectivity of the natural enzymes. Here, we describe a design method that allows constructing asymmetric four-helix bundles through the covalent heterodimerization of two different α-helical harpins. In particular, starting from the homodimeric DF3 structure, we developed a protocol for covalently linking the two α2 monomers by using the Cu(I) catalyzed azide-alkyne cycloaddition. The protocol was then generalized, in order to include the construction of several linkers, in different protein positions. Our method is fast, low cost, and in principle can be applied to any couple of peptides/proteins we desire to link.
[Mh] Termos MeSH primário: Metaloproteínas/química
Ferroproteínas não Heme/química
Engenharia de Proteínas/métodos
Relação Estrutura-Atividade
[Mh] Termos MeSH secundário: Sequência de Aminoácidos/genética
Dicroísmo Circular
Metaloproteínas/metabolismo
Modelos Moleculares
Ferroproteínas não Heme/síntese química
Ferroproteínas não Heme/genética
Conformação Proteica em alfa-Hélice
Dobramento de Proteína
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Metalloproteins); 0 (Nonheme Iron Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170807
[Lr] Data última revisão:
170807
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160903
[St] Status:MEDLINE


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[PMID]:27369780
[Au] Autor:Solomon EI; Park K
[Ad] Endereço:Department of Chemistry, Stanford University, Stanford, CA, 94305-5080, USA. edward.solomon@stanford.edu.
[Ti] Título:Structure/function correlations over binuclear non-heme iron active sites.
[So] Source:J Biol Inorg Chem;21(5-6):575-88, 2016 Sep.
[Is] ISSN:1432-1327
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Binuclear non-heme iron enzymes activate O2 to perform diverse chemistries. Three different structural mechanisms of O2 binding to a coupled binuclear iron site have been identified utilizing variable-temperature, variable-field magnetic circular dichroism spectroscopy (VTVH MCD). For the µ-OH-bridged Fe(II)2 site in hemerythrin, O2 binds terminally to a five-coordinate Fe(II) center as hydroperoxide with the proton deriving from the µ-OH bridge and the second electron transferring through the resulting µ-oxo superexchange pathway from the second coordinatively saturated Fe(II) center in a proton-coupled electron transfer process. For carboxylate-only-bridged Fe(II)2 sites, O2 binding as a bridged peroxide requires both Fe(II) centers to be coordinatively unsaturated and has good frontier orbital overlap with the two orthogonal O2 π* orbitals to form peroxo-bridged Fe(III)2 intermediates. Alternatively, carboxylate-only-bridged Fe(II)2 sites with only a single open coordination position on an Fe(II) enable the one-electron formation of Fe(III)-O2 (-) or Fe(III)-NO(-) species. Finally, for the peroxo-bridged Fe(III)2 intermediates, further activation is necessary for their reactivities in one-electron reduction and electrophilic aromatic substitution, and a strategy consistent with existing spectral data is discussed.
[Mh] Termos MeSH primário: Ferroproteínas não Heme/química
Ferroproteínas não Heme/metabolismo
[Mh] Termos MeSH secundário: Domínio Catalítico
Teoria Quântica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Nonheme Iron Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160703
[St] Status:MEDLINE
[do] DOI:10.1007/s00775-016-1372-9


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[PMID]:27364958
[Au] Autor:Proos Vedin N; Lundberg M
[Ad] Endereço:Department of Chemistry-Ångström Laboratory, Uppsala University, Box 518, 751 20, Uppsala, Sweden.
[Ti] Título:Protein effects in non-heme iron enzyme catalysis: insights from multiscale models.
[So] Source:J Biol Inorg Chem;21(5-6):645-57, 2016 Sep.
[Is] ISSN:1432-1327
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Many non-heme iron enzymes have similar sets of ligands but still catalyze widely different reactions. A key question is, therefore, the role of the protein in controlling reactivity and selectivity. Examples from multiscale simulations, primarily QM/MM, of both mono- and binuclear non-heme iron enzymes are used to analyze the stability of these models and what they reveal about the protein effects. Consistent results from QM/MM modeling are the importance of the hydrogen bond network to control reactivity and electrostatic stabilization of electron transfer from second-sphere residues. The long-range electrostatic effects on reaction barriers are small for many systems. In the systems where large electrostatic effects have been reported, these lead to higher barriers. There is thus no evidence of any significant long-range electrostatic effects contributing to the catalytic efficiency of non-heme iron enzymes. However, the correct evaluation of electrostatic contributions is challenging, and the correlation between calculated residue contributions and the effects of mutation experiments is not very strong. The largest benefits of QM/MM models are thus the improved active-site geometries, rather than the calculation of accurate energies. Reported differences in mechanistic predictions between QM and QM/MM models can be explained by differences in hydrogen bonding patterns in and around the active site. Correctly constructed cluster models can give results with similar accuracy as those from multiscale models, but the latter reduces the risk of drawing the wrong mechanistic conclusions based on incorrect geometries and are preferable for all types of modeling, even when using very large QM parts.
[Mh] Termos MeSH primário: Simulação de Dinâmica Molecular
Ferroproteínas não Heme/metabolismo
[Mh] Termos MeSH secundário: Biocatálise
Ferroproteínas não Heme/química
Teoria Quântica
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Nonheme Iron Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160702
[St] Status:MEDLINE
[do] DOI:10.1007/s00775-016-1374-7


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[PMID]:27331785
[Au] Autor:Han M; Chang J; Kim J
[Ad] Endereço:Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts, USA.
[Ti] Título:Loss of divalent metal transporter 1 function promotes brain copper accumulation and increases impulsivity.
[So] Source:J Neurochem;138(6):918-28, 2016 Sep.
[Is] ISSN:1471-4159
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The divalent metal transporter 1 (DMT1) is a major iron transporter required for iron absorption and erythropoiesis. Loss of DMT1 function results in microcytic anemia. While iron plays an important role in neural function, the behavioral consequences of DMT1 deficiency are largely unexplored. The goal of this study was to define the neurobehavioral and neurochemical phenotypes of homozygous Belgrade (b/b) rats that carry DMT1 mutation and explore potential mechanisms of these phenotypes. The b/b rats (11-12 weeks old) and their healthy littermate heterozygous (+/b) Belgrade rats were subject to elevated plus maze tasks. The b/b rats spent more time in open arms, entered open arms more frequently and traveled more distance in the maze than +/b controls, suggesting increased impulsivity. Impaired emotional behavior was associated with down-regulation of GABA in the hippocampus in b/b rats. Also, b/b rats showed increased GABAA receptor α1 and GABA transporter, indicating altered GABAergic function. Furthermore, metal analysis revealed that b/b rats have decreased total iron, but normal non-heme iron, in the brain. Interestingly, b/b rats exhibited unusually high copper levels in most brain regions, including striatum and hippocampus. Quantitative PCR analysis showed that both copper importer copper transporter 1 and exporter copper-transporting ATPase 1 were up-regulated in the hippocampus from b/b rats. Finally, b/b rats exhibited increased 8-isoprostane levels and decreased glutathione/glutathione disulfide ratio in the hippocampus, reflecting elevated oxidative stress. Combined, our results suggest that copper loading in DMT1 deficiency could induce oxidative stress and impair GABA metabolism, which promote impulsivity-like behavior. Iron-copper model: Mutations in the divalent metal transporter 1 (DMT1) decrease body iron status and up-regulate copper absorption, which leads to copper loading in the brain and consequently increases metal-induced oxidative stress. This event disrupts GABAergic neurotransmission and promotes impulsivity-like behavior. Our model provides better understanding of physiological risks associated with imbalanced metal metabolism in mental function and, more specifically, the interactions with GABA and redox control in the treatment of emotional disorders.
[Mh] Termos MeSH primário: Química Encefálica/genética
Proteínas de Transporte de Cátions/genética
Proteínas de Transporte de Cátions/fisiologia
Cobre/metabolismo
Comportamento Impulsivo
[Mh] Termos MeSH secundário: Adenosina Trifosfatases/metabolismo
Animais
Ansiedade/genética
Ansiedade/psicologia
Comportamento Animal
Proteínas de Transporte de Cátions/metabolismo
Regulação para Baixo
Emoções/fisiologia
Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo
Hipocampo/metabolismo
Ferro/metabolismo
Masculino
Metionina/análogos & derivados
Mutação/genética
Ferroproteínas não Heme/metabolismo
Ratos
Ratos Endogâmicos F344
Receptores de GABA-A/genética
Ácido gama-Aminobutírico/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (2-(2'-(methylthio)ethyl)methionine); 0 (Cation Transport Proteins); 0 (GABA Plasma Membrane Transport Proteins); 0 (Nonheme Iron Proteins); 0 (Receptors, GABA-A); 0 (copper transporter 1); 0 (solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2); 56-12-2 (gamma-Aminobutyric Acid); 789U1901C5 (Copper); AE28F7PNPL (Methionine); E1UOL152H7 (Iron); EC 3.6.1.- (Adenosine Triphosphatases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170902
[Lr] Data última revisão:
170902
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160623
[St] Status:MEDLINE
[do] DOI:10.1111/jnc.13717


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[PMID]:27229513
[Au] Autor:Rokob TA; Chalupský J; Bím D; Andrikopoulos PC; Srnec M; Rulísek L
[Ad] Endereço:Institute of Organic Chemistry, Research Centre for Natural Sciences, HAS, P.O.Box 286, Budapest, 1519, Hungary.
[Ti] Título:Mono- and binuclear non-heme iron chemistry from a theoretical perspective.
[So] Source:J Biol Inorg Chem;21(5-6):619-44, 2016 Sep.
[Is] ISSN:1432-1327
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:In this minireview, we provide an account of the current state-of-the-art developments in the area of mono- and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represents a challenge for experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems. After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry, which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods.
[Mh] Termos MeSH primário: Ferroproteínas não Heme/química
Teoria Quântica
[Mh] Termos MeSH secundário: Seres Humanos
Ferroproteínas não Heme/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Nonheme Iron Proteins)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160528
[St] Status:MEDLINE
[do] DOI:10.1007/s00775-016-1357-8



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