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1.
Molecules ; 26(21)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34771023

RESUMO

Zinc is the second most abundant trace element in the human body, and it plays a fundamental role in human physiology, being an integral component of hundreds of enzymes and transcription factors. The discovery that zinc atoms may compete with copper for their absorption in the gastrointestinal tract let to introduce zinc in the therapy of Wilson's disease, a congenital disorder of copper metabolism characterized by a systemic copper storage. Nowadays, zinc salts are considered one of the best therapeutic approach in patients affected by Wilson's disease. On the basis of the similarities, at histological level, between Wilson's disease and non-alcoholic liver disease, zinc has been successfully introduced in the therapy of non-alcoholic liver disease, with positive effects both on insulin resistance and oxidative stress. Recently, zinc deficiency has been indicated as a possible factor responsible for the susceptibility of elderly patients to undergo infection by SARS-CoV-2, the coronavirus responsible for the COVID-19 pandemic. Here, we present the data correlating zinc deficiency with the insurgence and progression of Covid-19 with low zinc levels associated with severe disease states. Finally, the relevance of zinc supplementation in aged people at risk for SARS-CoV-2 is underlined, with the aim that the zinc-based drug, classically used in the treatment of copper overload, might be recorded as one of the tools reducing the mortality of COVID-19, particularly in elderly people.


Assuntos
Fígado/efeitos dos fármacos , Fígado/lesões , Zinco/farmacologia , COVID-19/complicações , COVID-19/tratamento farmacológico , Quelantes/metabolismo , Cobre/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/tratamento farmacológico , Degeneração Hepatolenticular/metabolismo , Humanos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/metabolismo , SARS-CoV-2/patogenicidade , Zinco/deficiência , Zinco/metabolismo
2.
Molecules ; 26(21)2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34771072

RESUMO

The synthesis of nanoparticles is most important in the context of cancer therapy, particularly copper nanoparticles, which are widely used. In this work, copper(II)-tyrosinase was isolated from potato peel powder. Copper nanoparticles (Tyr-Cu(II)-AEEA NPs) were synthesized via the reaction of tyrosinase with N-aminoethylethanolamine to produce Cu(II)-NPs and these were characterized by means of FT-IR, UV-Spectroscopy, XRD, SEM, TEM and a particle size analyzer. These Tyr-Cu(II)-AEEA NPs were tested as anticancer agents against MCF-7 breast cancer cells. Fluorescence microscopy and DNA fragmentation were also performed, which revealed the inhibiting potentials of Cu(II)-AEEA NPs and consequent cell death; Tyr-Cu(II)-AEEA NPs show potential cytotoxicity activity and this nano material could be contemplated as an anticancer medicament in future investigations.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/farmacologia , Etanolaminas/farmacologia , Nanopartículas Metálicas/química , Monofenol Mono-Oxigenase/metabolismo , Solanum tuberosum/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Complexos de Coordenação/metabolismo , Cobre/química , Cobre/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Etanolaminas/química , Etanolaminas/metabolismo , Feminino , Humanos , Células MCF-7 , Microscopia de Fluorescência , Solanum tuberosum/química
3.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638871

RESUMO

In order to analyze the mechanisms involved in copper accumulation in Ulva compressa, algae were collected at control sites of central and northern Chile, and at two copper-polluted sites of northern Chile. The level of intracellular copper, reduced glutathione (GSH), phytochelatins (PCs), PC2 and PC4, and transcripts encoding metallothioneins (MTs) of U. compressa, UcMT1, UcMT2 and UcMT3, were determined. Algae of control sites contained around 20 µg of copper g-1 of dry tissue (DT) whereas algae of copper-polluted sites contained 260 and 272 µg of copper g-1 of DT. Algae of control sites and copper-polluted sites did not show detectable amounts of GSH, the level of PC2 did not change among sites whereas PC4 was increased in one of the copper-polluted sites. The level of transcripts of UcMT1 and UcMT2 were increased in algae of copper-polluted sites, but the level of UcMT3 did not change. Algae of a control site and a copper-polluted site were visualized by transmission electron microscopy (TEM) and the existence of copper in electrodense particles was analyzed using energy dispersive x-ray spectroscopy (EDXS). Algae of copper-polluted sites showed electrodense nanoparticles containing copper in the chloroplasts, whereas algae of control sites did not. Algae of a control site, Cachagua, were cultivated without copper (control) and with 10 µM copper for 5 days and they were analyzed by TEM-EDXS. Algae cultivated with copper showed copper-containing nanoparticles in the chloroplast whereas control algae did not. Thus, U. compressa from copper-polluted sites exhibits intracellular copper accumulation, an increase in the level of PC4 and expression of UcMTs, and the accumulation of copper-containing particles in chloroplasts.


Assuntos
Cloroplastos/metabolismo , Cobre/metabolismo , Regulação da Expressão Gênica de Plantas , Metalotioneína/biossíntese , Nanopartículas/metabolismo , Proteínas de Plantas/biossíntese , Ulva/metabolismo , Poluentes Químicos da Água/metabolismo , Chile , Poluição Ambiental
4.
Int J Mol Sci ; 22(19)2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34639045

RESUMO

Angiogenesis plays a key role in the wound healing process, involving the migration, growth, and differentiation of endothelial cells. Angiogenesis is controlled by a strict balance of different factors, and among these, the angiogenin protein plays a relevant role. Angiogenin is a secreted protein member of the ribonuclease superfamily that is taken up by cells and translocated to the nucleus when the process of blood vessel formation has to be promoted. However, the chemical signaling that activates the protein, normally present in the plasma, and the transport pathways through which the protein enters the cell are still largely unclear. Copper is also an angiogenic factor that regulates angiogenin expression and participates in the activation of common signaling pathways. The interaction between angiogenin and copper could be a relevant mechanism in regulating the formation of new blood vessel pathways and paving the way to the development of new drugs for chronic non-healing wounds.


Assuntos
Cobre/metabolismo , Ribonuclease Pancreático/metabolismo , Cicatrização/fisiologia , Animais , Ativação Enzimática , Expressão Gênica , Humanos , Neovascularização Fisiológica/genética , Ribonuclease Pancreático/química , Ribonuclease Pancreático/genética , Relação Estrutura-Atividade
5.
Molecules ; 26(20)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34684707

RESUMO

Cerebral ischemia results in increased oxidative stress in the affected brain. Accumulating evidence suggests that quercetin possesses anti-oxidant and anti-inflammatory properties. The essential elements magnesium (Mg), zinc (Zn), selenium (Se), and transition metal iron (Fe), copper (Cu), and antioxidants superoxide dismutase (SOD) and catalase (CAT) are required for brain functions. This study investigates whether the neuroprotective effects of quercetin on the ipsilateral brain cortex involve altered levels of essential trace metals, the Cu/Zn ratio, and antioxidant activity. Rats were intraperitoneally administered quercetin (20 mg/kg) once daily for 10 days before ischemic surgery. Cerebral ischemia was induced by ligation of the right middle cerebral artery and the right common carotid artery for 1 h. The ipsilateral brain cortex was homogenized and the supernatant was collected for biochemical analysis. Results show that rats pretreated with quercetin before ischemia significantly increased Mg, Zn, Se, SOD, and CAT levels, while the malondialdehyde, Fe, Cu, and the Cu/Zn ratio clearly decreased as compared to the untreated ligation subject. Taken together, our findings suggest that the mechanisms underlying the neuroprotective effects of quercetin during cerebral ischemic injury involve the modulation of essential elements, transition metals, Cu/Zn ratio, and antioxidant activity.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Quercetina/farmacologia , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Catalase , Cobre/metabolismo , Glutationa Peroxidase/metabolismo , Ferro , Peroxidação de Lipídeos/efeitos dos fármacos , Magnésio , Masculino , Malondialdeído , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Quercetina/metabolismo , Ratos , Ratos Sprague-Dawley , Selênio , Superóxido Dismutase , Zinco/metabolismo
6.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576306

RESUMO

Streptomycetes are important biotechnological bacteria that produce several clinically bioactive compounds. They have a complex development, including hyphae differentiation and sporulation. Cytosolic copper is a well-known modulator of differentiation and secondary metabolism. The interruption of the Streptomyces coelicolor SCO2730 (copper chaperone, SCO2730::Tn5062 mutant) blocks SCO2730 and reduces SCO2731 (P-type ATPase copper export) expressions, decreasing copper export and increasing cytosolic copper. This mutation triggers the expression of 13 secondary metabolite clusters, including cryptic pathways, during the whole developmental cycle, skipping the vegetative, non-productive stage. As a proof of concept, here, we tested whether the knockdown of the SCO2730/31 orthologue expression can enhance secondary metabolism in streptomycetes. We created a SCO2730/31 consensus antisense mRNA from the sequences of seven key streptomycetes, which helped to increase the cytosolic copper in S. coelicolor, albeit to a lower level than in the SCO2730::Tn5062 mutant. This antisense mRNA affected the production of at least six secondary metabolites (CDA, 2-methylisoborneol, undecylprodigiosin, tetrahydroxynaphtalene, α-actinorhodin, ε-actinorhodin) in the S. coelicolor, and five (phenanthroviridin, alkylresorcinol, chloramphenicol, pikromycin, jadomycin G) in the S. venezuelae; it also helped to alter the S. albus metabolome. The SCO2730/31 consensus antisense mRNA designed here constitutes a tool for the knockdown of SCO2730/31 expression and for the enhancement of Streptomyces' secondary metabolism.


Assuntos
Proteínas de Bactérias/metabolismo , ATPases Transportadoras de Cobre/metabolismo , Chaperonas Moleculares/metabolismo , Metabolismo Secundário , Streptomyces coelicolor/metabolismo , Proteínas de Bactérias/genética , Cobre/metabolismo , ATPases Transportadoras de Cobre/genética , Chaperonas Moleculares/genética , Streptomyces coelicolor/genética
7.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502369

RESUMO

The aim of the present review is to discuss traditional hypotheses on the etiopathogenesis of Alzheimer's disease (AD), as well as the role of metabolic-syndrome-related mechanisms in AD development with a special focus on advanced glycation end-products (AGEs) and their role in metal-induced neurodegeneration in AD. Persistent hyperglycemia along with oxidative stress results in increased protein glycation and formation of AGEs. The latter were shown to possess a wide spectrum of neurotoxic effects including increased Aß generation and aggregation. In addition, AGE binding to receptor for AGE (RAGE) induces a variety of pathways contributing to neuroinflammation. The existing data also demonstrate that AGE toxicity seems to mediate the involvement of copper (Cu) and potentially other metals in AD pathogenesis. Specifically, Cu promotes AGE formation, AGE-Aß cross-linking and up-regulation of RAGE expression. Moreover, Aß glycation was shown to increase prooxidant effects of Cu through Fenton chemistry. Given the role of AGE and RAGE, as well as metal toxicity in AD pathogenesis, it is proposed that metal chelation and/or incretins may slow down oxidative damage. In addition, selenium (Se) compounds seem to attenuate the intracellular toxicity of the deranged tau and Aß, as well as inhibiting AGE accumulation and metal-induced neurotoxicity.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Produtos Finais de Glicação Avançada/metabolismo , Peptídeos beta-Amiloides/metabolismo , Quelantes/farmacologia , Cobre/metabolismo , Índice Glicêmico/fisiologia , Humanos , Ferro/metabolismo , Metabolismo dos Lipídeos/fisiologia , Síndrome Metabólica/fisiopatologia , Metais/farmacologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/farmacologia , Selênio/metabolismo
8.
Int J Mol Sci ; 22(17)2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34502389

RESUMO

Metal-oxide nanoparticles (MO-NPs), such as the highly bioreactive copper-based nanoparticles (CuO-NPs), are widely used in manufacturing of hundreds of commercial products. Epidemiological studies correlated levels of nanoparticles in ambient air with a significant increase in lung disease. CuO-NPs, specifically, were among the most potent in a set of metal-oxides and carbons studied in parallel regarding DNA damage and cytotoxicity. Despite advances in nanotoxicology research and the characterization of their toxicity, the exact mechanism(s) of toxicity are yet to be defined. We identified chlorination toxicity as a damaging consequence of inflammation and myeloperoxidase (MPO) activation, resulting in macromolecular damage and cell damage/death. We hypothesized that the inhalation of CuO-NPs elicits an inflammatory response resulting in chlorination damage in cells and lung tissues. We further tested the protective action of LGM2605, a synthetic small molecule with known scavenging properties for reactive oxygen species (ROS), but most importantly, for active chlorine species (ACS) and an inhibitor of MPO. CuO-NPs (15 µg/bolus) were instilled intranasally in mice and the kinetics of the inflammatory response in lungs was evaluated 1, 3, and 7 days later. Evaluation of the protective action of LGM2605 was performed at 24 h post-challenge, which was selected as the peak acute inflammatory response to CuO-NP. LGM2605 was given daily via gavage to mice starting 2 days prior to the time of the insult (100 mg/kg). CuO-NPs induced a significant inflammatory influx, inflammasome-relevant cytokine release, and chlorination damage in mouse lungs, which was mitigated by the action of LGM2605. Preventive action of LGM2605 ameliorated the adverse effects of CuO-NP in lung.


Assuntos
Butileno Glicóis/farmacologia , Glucosídeos/farmacologia , Inflamação/tratamento farmacológico , Animais , Líquido da Lavagem Broncoalveolar/citologia , Butileno Glicóis/metabolismo , Cloro/metabolismo , Cobre/metabolismo , Cobre/toxicidade , Dano ao DNA/efeitos dos fármacos , Feminino , Glucosídeos/metabolismo , Inflamassomos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Nanopartículas Metálicas/efeitos adversos , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Óxidos/farmacologia , Peroxidase/farmacologia , Espécies Reativas de Oxigênio/farmacologia
9.
Int J Mol Sci ; 22(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34502439

RESUMO

The angiogenin protein (ANG) is one of the most potent endogenous angiogenic factors. In this work we characterized by means of potentiometric, spectroscopic and voltammetric techniques, the copper complex species formed with peptide fragments derived from the N-terminal domain of the protein, encompassing the sequence 1-17 and having free amino, Ang1-17, or acetylated N-terminus group, AcAng1-17, so to explore the role of amino group in metal binding and cellular copper uptake. The obtained data show that amino group is the main copper anchoring site for Ang1-17. The affinity constant values, metal coordination geometry and complexes redox-potentials strongly depend, for both peptides, on the number of copper equivalents added. Confocal laser scanning microscope analysis on neuroblastoma cells showed that in the presence of one equivalent of copper ion, the free amino Ang1-17 increases cellular copper uptake while the acetylated AcAng1-17 strongly decreases the intracellular metal level. The activity of peptides was also compared to that of the protein normally present in the plasma (wtANG) as well as to the recombinant form (rANG) most commonly used in literature experiments. The two protein isoforms bind copper ions but with a different coordination environment. Confocal laser scanning microscope data showed that the wtANG induces a strong increase in intracellular copper compared to control while the rANG decreases the copper signal inside cells. These data demonstrate the relevance of copper complexes' geometry to modulate peptides' activity and show that wtANG, normally present in the plasma, can affect cellular copper uptake.


Assuntos
Cobre/metabolismo , Ribonuclease Pancreático/química , Linhagem Celular Tumoral , Espectroscopia de Ressonância de Spin Eletrônica , Escherichia coli , Humanos , Ribonuclease Pancreático/metabolismo
10.
Int J Mol Sci ; 22(17)2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34502449

RESUMO

As an essential nutrient, copper (Cu) scarcity causes a decrease in agricultural production. Cu deficiency responses include the induction of several microRNAs, known as Cu-miRNAs, which are responsible for degrading mRNAs from abundant and dispensable cuproproteins to economize copper when scarce. Cu-miRNAs, such as miR398 and miR408 are conserved, as well as the signal transduction pathway to induce them under Cu deficiency. The Arabidopsis thaliana SQUAMOSA-PROMOTER BINDING PROTEIN-LIKE (SPL) family member SPL7 binds to the cis-regulatory motifs present in the promoter regions of genes expressed under Cu deficiency, including Cu-miRNAs. The expression of several other SPL transcription factor family members is regulated by miR156. This regulatory miR156-SPL module plays a crucial role in developmental phase transitions while integrating internal and external cues. Here, we show that Cu deficiency also affects miR156 expression and that SPL3 overexpressing plants, resistant to miR156 regulation, show a severe decrease in SPL7-mediated Cu deficiency responses. These include the expression of Cu-miRNAs and their targets and is probably due to competition between SPL7 and miR156-regulated SPL3 in binding to cis-regulatory elements in Cu-miRNA promoters. Thus, the conserved SPL7-mediated Cu-miRNA pathway could generally be affected by the miR156-SPL module, thereby underscoring the integration of the Cu-miRNA pathway with developmental and environmental stress responses in Arabidopsis thaliana.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Cobre/metabolismo , Proteínas de Ligação a DNA/metabolismo , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo , Arabidopsis/crescimento & desenvolvimento , Desenvolvimento Vegetal , Estresse Fisiológico
11.
Biochemistry ; 60(38): 2845-2850, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34510894

RESUMO

Methanobactins (Mbns) are ribosomally produced, post-translationally modified peptidic natural products that bind copper with high affinity. Methanotrophic bacteria use Mbns to acquire copper needed for enzymatic methane oxidation. Despite the presence of Mbn operons in a range of methanotroph and other bacterial genomes, few Mbns have been isolated and structurally characterized. Here we report the isolation of a novel Mbn from the methanotroph Methylosinus (Ms.) sp. LW3. Mass spectrometric and nuclear magnetic resonance spectroscopic data indicate that this Mbn, the largest characterized to date, consists of a 13-amino acid backbone modified to include pyrazinedione/oxazolone rings and neighboring thioamide groups derived from cysteine residues. The pyrazinedione ring is more stable to acid hydrolysis than the oxazolone ring and likely protects the Mbn from degradation. The structure corresponds exactly to that predicted on the basis of the Ms. sp. LW3 Mbn operon content, providing support for the proposed role of an uncharacterized biosynthetic enzyme, MbnF, and expanding the diversity of known Mbns.


Assuntos
Cobre/metabolismo , Methylosinus/enzimologia , Methylosinus/metabolismo , Sequência de Aminoácidos/genética , Proteínas de Bactérias/metabolismo , Produtos Biológicos/metabolismo , Quelantes/química , Cobre/química , Expressão Gênica/genética , Regulação Bacteriana da Expressão Gênica/genética , Genoma Bacteriano/genética , Imidazóis/metabolismo , Metano/metabolismo , Methylosinus/genética , Methylosinus trichosporium/enzimologia , Methylosinus trichosporium/genética , Methylosinus trichosporium/metabolismo , Oligopeptídeos/metabolismo , Óperon/genética , Oxirredução , Peptídeos/metabolismo
12.
FASEB J ; 35(9): e21810, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390520

RESUMO

Copper (Cu) is an essential micronutrient required for the activity of redox-active enzymes involved in critical metabolic reactions, signaling pathways, and biological functions. Transporters and chaperones control Cu ion levels and bioavailability to ensure proper subcellular and systemic Cu distribution. Intensive research has focused on understanding how mammalian cells maintain Cu homeostasis, and how molecular signals coordinate Cu acquisition and storage within organs. In humans, mutations of genes that regulate Cu homeostasis or facilitate interactions with Cu ions lead to numerous pathologic conditions. Malfunctions of the Cu+ -transporting ATPases ATP7A and ATP7B cause Menkes disease and Wilson disease, respectively. Additionally, defects in the mitochondrial and cellular distributions and homeostasis of Cu lead to severe neurodegenerative conditions, mitochondrial myopathies, and metabolic diseases. Cu has a dual nature in carcinogenesis as a promotor of tumor growth and an inducer of redox stress in cancer cells. Cu also plays role in cancer treatment as a component of drugs and a regulator of drug sensitivity and uptake. In this review, we provide an overview of the current knowledge of Cu metabolism and transport and its relation to various human pathologies.


Assuntos
Cobre/metabolismo , Homeostase/fisiologia , Animais , Transporte Biológico/fisiologia , ATPases Transportadoras de Cobre/metabolismo , Humanos , Doenças Metabólicas/metabolismo , Doenças Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo
13.
Plant Physiol Biochem ; 167: 459-469, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34418592

RESUMO

The moss Physcomitrium (Physcomitrella) patens is a bryophyte that provides genetic information about the adaptation to the life on land by early Embryophytes and is a reference organism for comparative evolutionary studies in plants. Copper is an essential micronutrient for every living organism, its transport across the plasma membrane is achieved by the copper transport protein family COPT/CTR. Two genes related to the COPT family were identified in Physcomitrella patens, PpaCOPT1 and PpaCOPT2. Homology modelling of both proteins showed the presence of three putative transmembrane domains (TMD) and the Mx3M motif, constituting a potential Cu + selectivity filter present in other members of this family. Functional characterization of PpaCOPT1 and PpaCOPT2 in the yeast mutant ctr1Δctr3Δ restored its growth on medium with non-fermentable carbon sources at micromolar Cu concentrations, providing support that these two moss proteins function as high affinity Cu + transporters. Localization of PpaCOPT1 and PpaCOPT2 in yeast cells was observed at the tonoplast and plasma membrane, respectively. The heterologous expression of PpaCOPT2 in tobacco epidermal cells co-localized with the plasma membrane marker. Finally, only PpaCOPT1 was expressed in seven-day old protonema and was influenced by extracellular copper levels. This evidence suggests different roles of PpaCOPT1 and PpaCOPT2 in copper homeostasis in Physcomitrella patens.


Assuntos
Bryopsida , Sequência de Aminoácidos , Bryopsida/genética , Bryopsida/metabolismo , Cobre/metabolismo , Proteínas de Transporte de Cobre , Homeostase
14.
Biophys J ; 120(20): 4600-4607, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34461106

RESUMO

ATP7A and ATP7B are structurally similar but functionally distinct active copper transporters that regulate copper levels in the human cells and deliver copper to the biosynthetic pathways. Both proteins have a chain of six cytosolic metal-binding domains (MBDs) believed to be involved in the copper-dependent regulation of the activity and intracellular localization of these enzymes. Although all the MBDs are quite similar in structure, their spacing differs markedly between ATP7A and ATP7B. We show by NMR that the long polypeptide between MBD1 and MBD2 of ATP7A forms an additional seventh metastable domain, which we called HMA1A (heavy metal associated domain 1A). The structure of HMA1A resembles the MBDs but contains no copper-binding site. The HMA1A domain, which is unique to ATP7A, may modulate regulatory interactions between MBD1-3, contributing to the distinct functional properties of ATP7A and ATP7B.


Assuntos
ATPases Transportadoras de Cobre , Cobre , Sítios de Ligação , Cobre/metabolismo , ATPases Transportadoras de Cobre/genética , Humanos , Domínios Proteicos
15.
Biomolecules ; 11(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34439909

RESUMO

WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer's ratio. As these amino acids are linked to the urea-Krebs' cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD.


Assuntos
Inteligência Artificial , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/genética , Adulto , Algoritmos , Encéfalo/embriologia , Ceruloplasmina/metabolismo , Cobre/metabolismo , ATPases Transportadoras de Cobre/biossíntese , DNA Mitocondrial/metabolismo , Diagnóstico por Computador , Feminino , Lógica Fuzzy , Ácido Glutâmico/metabolismo , Degeneração Hepatolenticular/fisiopatologia , Humanos , Fígado/metabolismo , Masculino , Informática Médica/métodos , Pessoa de Meia-Idade , Mutação , Redes Neurais de Computação , Fenótipo , Análise de Componente Principal
16.
Biochim Biophys Acta Gen Subj ; 1865(11): 129979, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34364973

RESUMO

BACKGROUND: Copper and lipid metabolism are intimately linked, sharing a complex, inverse relationship in the periphery (outside of the central nervous system), which remains to be fully elucidated. SCOPE: Copper and lipids have independently been implicated in the pathogenesis of diseases involving dyslipidaemia, including obesity, cardiovascular disease and non-alcoholic fatty liver disease and also in Wilson disease, an inherited disorder of copper overload. Here we review the relationship between copper and lipid regulatory pathways, which are potential druggable targets for therapeutic intervention. MAJOR CONCLUSIONS: While the inverse relationship between copper and lipids is apparent, tissue-specific roles for the copper regulatory protein, ATP7B provide further insight into the association between copper and lipid metabolism. GENERAL SIGNIFICANCE: Understanding the relationship between copper and lipid metabolism is important for identifying druggable targets for diseases with disrupted copper and/or lipid metabolism; and may reveal similar connections within the brain and in neurological diseases with impaired copper and lipid transport.


Assuntos
Cobre/metabolismo , Animais , Humanos , Metabolismo dos Lipídeos
17.
J Biol Chem ; 297(3): 101078, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34400169

RESUMO

Bacteria require a precise balance of copper ions to ensure that essential cuproproteins are fully metalated while also avoiding copper-induced toxicity. The Gram-positive bacterium Bacillus subtilis maintains appropriate copper homeostasis in part through the ycn operon. The ycn operon comprises genes encoding three proteins: the putative copper importer YcnJ, the copper-dependent transcriptional repressor YcnK, and the uncharacterized Domain of Unknown Function 1775 (DUF1775) containing YcnI. DUF1775 domains are found across bacterial phylogeny, and bioinformatics analyses indicate that they frequently neighbor domains implicated in copper homeostasis and transport. Here, we investigated whether YcnI can interact with copper and, using electron paramagnetic resonance and inductively coupled plasma-MS, found that this protein can bind a single Cu(II) ion. We determine the structure of both the apo and copper-bound forms of the protein by X-ray crystallography, uncovering a copper-binding site featuring a unique monohistidine brace ligand set that is highly conserved among DUF1775 domains. These data suggest a possible role for YcnI as a copper chaperone and that DUF1775 domains in other bacterial species may also function in copper homeostasis.


Assuntos
Bacillus subtilis/metabolismo , Cobre/metabolismo , Bacillus subtilis/genética , Proteínas de Bactérias/metabolismo , Sítios de Ligação/genética , Quelantes/metabolismo , Cristalografia por Raios X/métodos , Regulação Bacteriana da Expressão Gênica/genética , Homeostase , Ligantes , Modelos Moleculares , Chaperonas Moleculares/metabolismo , Óperon/genética , Ligação Proteica/genética , Domínios Proteicos/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo
18.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202166

RESUMO

Copper (Cu) has been implicated in the progression of Alzheimer's disease (AD), and aggregation of Cu and amyloid ß peptide (Aß) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aß aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aß aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aß aggregation and Aß production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aß aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aß by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteínas de Transporte/metabolismo , Cobre/metabolismo , Peptídeos/metabolismo , Agregados Proteicos , Mapeamento de Interação de Proteínas , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Animais , Proteínas de Transporte/química , Técnicas de Visualização da Superfície Celular , Humanos , Camundongos , Oxirredução , Estresse Oxidativo , Peptídeos/química , Agregação Patológica de Proteínas/metabolismo , Mapeamento de Interação de Proteínas/métodos
19.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208680

RESUMO

In this paper, we present studies on the influence of the disulfide bridge on the copper (II) ions' binding abilities by the cyclic His4-peptide. The studied ligand HKHPHRHC-S-S-C consists of nine amino acids. The cyclic structure was obtained through a disulfide bridge between two cysteinyl groups. Moreover, this peptide is characterized by the presence of four His residues in the sequence, which makes it an interesting ligand for transition metal ions. The potentiometric and spectroscopic (UV-Vis spectroscopy and circular dichroism spectroscopy (CD)) studies were carried out in various molar ligand to metal ratios: 2:1, 1:1, and 1:2, in the pH range of 2.5-11 at 25 °C. The results showed that the cyclic His4-peptide promotes dinuclear complexes in each of these systems and forms the final dinuclear species with the {NIm, 3N-amide}{NIm, 3N-amide} coordination mode. The obtained data shows that cyclization by the formation of the disulfide bond has an impact on the peptide chain flexibility and appearance of additional potential donors for metal ions and influences the copper (II) ions' coordination.


Assuntos
Cobre/metabolismo , Histidina/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Cátions , Dissulfetos/química , Histidina/química , Concentração de Íons de Hidrogênio , Ligantes , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos , Ligação Proteica , Análise Espectral
20.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299316

RESUMO

Redox-active metal ions, Cu(I/II) and Fe(II/III), are essential biological molecules for the normal functioning of the brain, including oxidative metabolism, synaptic plasticity, myelination, and generation of neurotransmitters. Dyshomeostasis of these redox-active metal ions in the brain could cause Alzheimer's disease (AD). Thus, regulating the levels of Cu(I/II) and Fe(II/III) is necessary for normal brain function. To control the amounts of metal ions in the brain and understand the involvement of Cu(I/II) and Fe(II/III) in the pathogenesis of AD, many chemical agents have been developed. In addition, since toxic aggregates of amyloid-ß (Aß) have been proposed as one of the major causes of the disease, the mechanism of clearing Aß is also required to be investigated to reveal the etiology of AD clearly. Multiple metalloenzymes (e.g., neprilysin, insulin-degrading enzyme, and ADAM10) have been reported to have an important role in the degradation of Aß in the brain. These amyloid degrading enzymes (ADE) could interact with redox-active metal ions and affect the pathogenesis of AD. In this review, we introduce and summarize the roles, distributions, and transportations of Cu(I/II) and Fe(II/III), along with previously invented chelators, and the structures and functions of ADE in the brain, as well as their interrelationships.


Assuntos
Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Encéfalo/metabolismo , Proteína ADAM10/metabolismo , Doença de Alzheimer/etiologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Quelantes/metabolismo , Cobre/metabolismo , Humanos , Insulisina/metabolismo , Ferro/metabolismo , Proteínas de Membrana/metabolismo , Metais/metabolismo , Neprilisina/metabolismo , Oxirredução , Proteólise
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