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1.
Biochem Soc Trans ; 52(1): 269-278, 2024 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-38372426

RESUMEN

Recent evidence highlights the importance of trace metal micronutrients such as zinc (Zn) in coronary and vascular diseases. Zn2+ plays a signalling role in modulating endothelial nitric oxide synthase and protects the endothelium against oxidative stress by up-regulation of glutathione synthesis. Excessive accumulation of Zn2+ in endothelial cells leads to apoptotic cell death resulting from dysregulation of glutathione and mitochondrial ATP synthesis, whereas zinc deficiency induces an inflammatory phenotype, associated with increased monocyte adhesion. Nuclear factor-E2-related factor 2 (NRF2) is a transcription factor known to target hundreds of different genes. Activation of NRF2 affects redox metabolism, autophagy, cell proliferation, remodelling of the extracellular matrix and wound healing. As a redox-inert metal ion, Zn has emerged as a biomarker in diagnosis and as a therapeutic approach for oxidative-related diseases due to its close link to NRF2 signalling. In non-vascular cell types, Zn has been shown to modify conformations of the NRF2 negative regulators Kelch-like ECH-associated Protein 1 (KEAP1) and glycogen synthase kinase 3ß (GSK3ß) and to promote degradation of BACH1, a transcriptional suppressor of select NRF2 genes. Zn can affect phosphorylation signalling, including mitogen-activated protein kinases (MAPK), phosphoinositide 3-kinases and protein kinase C, which facilitate NRF2 phosphorylation and nuclear translocation. Notably, several NRF2-targeted proteins have been suggested to modify cellular Zn concentration via Zn exporters (ZnTs) and importers (ZIPs) and the Zn buffering protein metallothionein. This review summarises the cross-talk between reactive oxygen species, Zn and NRF2 in antioxidant responses of vascular cells against oxidative stress and hypoxia/reoxygenation.


Asunto(s)
Factor 2 Relacionado con NF-E2 , Zinc , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Zinc/metabolismo , Células Endoteliales/metabolismo , Estrés Oxidativo , Oxidación-Reducción , Glutatión/metabolismo
2.
Chem Rev ; 121(23): 14594-14648, 2021 12 08.
Artículo en Inglés | MEDLINE | ID: mdl-34652893

RESUMEN

The functions, purposes, and roles of metallothioneins have been the subject of speculations since the discovery of the protein over 60 years ago. This article guides through the history of investigations and resolves multiple contentions by providing new interpretations of the structure-stability-function relationship. It challenges the dogma that the biologically relevant structure of the mammalian proteins is only the one determined by X-ray diffraction and NMR spectroscopy. The terms metallothionein and thionein are ambiguous and insufficient to understand biological function. The proteins need to be seen in their biological context, which limits and defines the chemistry possible. They exist in multiple forms with different degrees of metalation and types of metal ions. The homoleptic thiolate coordination of mammalian metallothioneins is important for their molecular mechanism. It endows the proteins with redox activity and a specific pH dependence of their metal affinities. The proteins, therefore, also exist in different redox states of the sulfur donor ligands. Their coordination dynamics allows a vast conformational landscape for interactions with other proteins and ligands. Many fundamental signal transduction pathways regulate the expression of the dozen of human metallothionein genes. Recent advances in understanding the control of cellular zinc and copper homeostasis are the foundation for suggesting that mammalian metallothioneins provide a highly dynamic, regulated, and uniquely biological metal buffer to control the availability, fluctuations, and signaling transients of the most competitive Zn(II) and Cu(I) ions in cellular space and time.


Asunto(s)
Química Bioinorgánica , Metalotioneína , Animales , Humanos , Mamíferos/metabolismo , Metalotioneína/química , Metalotioneína/genética , Metalotioneína/metabolismo , Metales/metabolismo , Zinc/química , Zinc/metabolismo
3.
Nature ; 608(7921): 38-39, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35918525
4.
Cell Mol Life Sci ; 78(4): 1781-1798, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32797246

RESUMEN

Zinc has been known to be essential for cell division for over 40 years but the molecular pathways involved remain elusive. Cellular zinc import across biological membranes necessitates the help of zinc transporters such as the SLC39A family of ZIP transporters. We have discovered a molecular process that explains why zinc is required for cell division, involving two highly regulated zinc transporters, as a heteromer of ZIP6 and ZIP10, providing the means of cellular zinc entry at a specific time of the cell cycle that initiates a pathway resulting in the onset of mitosis. Crucially, when the zinc influx across this heteromer is blocked by ZIP6 or ZIP10 specific antibodies, there is no evidence of mitosis, confirming the requirement for zinc influx as a trigger of mitosis. The zinc that influxes into cells to trigger mitosis additionally changes the phosphorylation state of STAT3 converting it from a transcription factor to a protein that complexes with this heteromer and pS38Stathmin, the form allowing microtubule rearrangement as required in mitosis. This discovery now explains the specific cellular role of ZIP6 and ZIP10 and how they have special importance in the mitosis process compared to other ZIP transporter family members. This finding offers new therapeutic opportunities for inhibition of cell division in the many proliferative diseases that exist, such as cancer.


Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión/genética , Mitosis/genética , Factor de Transcripción STAT3/genética , Regulación de la Expresión Génica , Humanos , Células MCF-7 , Fosforilación/genética , Multimerización de Proteína/genética , Transducción de Señal/genética , Zinc/química , Zinc/metabolismo
5.
Br J Nutr ; 125(1): 71-78, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-32660679

RESUMEN

The present study reports on first-trimester reference ranges of plasma mineral Se/Zn/Cu concentration in relation to free thyroxine (FT4), thyrotropin (TSH) and thyroid peroxidase antibodies (TPO-Ab), assessed at 12 weeks' gestation in 2041 pregnant women, including 544 women not taking supplements containing Se/Zn/Cu. The reference range (2·5th-97·5th percentiles) in these 544 women was 0·72-1·25 µmol/l for Se, 17·15-35·98 µmol/l for Cu and 9·57-16·41 µmol/l for Zn. These women had significantly lower mean plasma Se concentration (0·94 (sd 0·12) µmol/l) than those (n 1479) taking Se/Zn/Cu supplements (1·03 (sd 0·14) µmol/l; P < 0·001), while the mean Cu (26·25 µmol/l) and Zn (12·55 µmol/l) concentrations were almost identical in these sub-groups. Women with hypothyroxinaemia (FT4 below reference range with normal TSH) had significantly lower plasma Zn concentrations than euthyroid women. After adjusting for covariates including supplement intake, plasma Se (negatively), Zn and Cu (positively) concentrations were significantly related to logFT4; Se and Cu (but not Zn) were positively and significantly related to logTSH. Women taking additional Se/Zn/Cu supplements were 1·46 (95 % CI 1·09, 2·04) times less likely to have elevated titres of TPO-Ab at 12 weeks of gestation. We conclude that first-trimester Se reference ranges are influenced by Se-supplement intake, while Cu and Zn ranges are not. Plasma mineral Se/Zn/Cu concentrations are associated with thyroid FT4 and TSH concentrations. Se/Zn/Cu supplement intake affects TPO-Ab status. Future research should focus on the impact of trace mineral status during gestation on thyroid function.


Asunto(s)
Cobre/sangre , Primer Trimestre del Embarazo/sangre , Selenio/sangre , Hormonas Tiroideas/sangre , Oligoelementos/sangre , Zinc/sangre , Adulto , Suplementos Dietéticos/estadística & datos numéricos , Femenino , Humanos , Embarazo , Complicaciones del Embarazo/sangre , Valores de Referencia , Enfermedades de la Tiroides/sangre , Pruebas de Función de la Tiroides
8.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799326

RESUMEN

The human zinc transporter ZnT8 provides the granules of pancreatic ß-cells with zinc (II) ions for assembly of insulin hexamers for storage. Until recently, the structure and function of human ZnTs have been modelled on the basis of the 3D structures of bacterial zinc exporters, which form homodimers with each monomer having six transmembrane α-helices harbouring the zinc transport site and a cytosolic domain with an α,ß structure and additional zinc-binding sites. However, there are important differences in function as the bacterial proteins export an excess of zinc ions from the bacterial cytoplasm, whereas ZnT8 exports zinc ions into subcellular vesicles when there is no apparent excess of cytosolic zinc ions. Indeed, recent structural investigations of human ZnT8 show differences in metal binding in the cytosolic domain when compared to the bacterial proteins. Two common variants, one with tryptophan (W) and the other with arginine (R) at position 325, have generated considerable interest as the R-variant is associated with a higher risk of developing type 2 diabetes. Since the mutation is at the apex of the cytosolic domain facing towards the cytosol, it is not clear how it can affect zinc transport through the transmembrane domain. We expressed the cytosolic domain of both variants of human ZnT8 and have begun structural and functional studies. We found that (i) the metal binding of the human protein is different from that of the bacterial proteins, (ii) the human protein has a C-terminal extension with three cysteine residues that bind a zinc(II) ion, and (iii) there are small differences in stability between the two variants. In this investigation, we employed nickel(II) ions as a probe for the spectroscopically silent Zn(II) ions and utilised colorimetric and fluorimetric indicators for Ni(II) ions to investigate metal binding. We established Ni(II) coordination to the C-terminal cysteines and found differences in metal affinity and coordination in the two ZnT8 variants. These structural differences are thought to be critical for the functional differences regarding the diabetes risk. Further insight into the assembly of the metal centres in the cytosolic domain was gained from potentiometric investigations of zinc binding to synthetic peptides corresponding to N-terminal and C-terminal sequences of ZnT8 bearing the metal-coordinating ligands. Our work suggests the involvement of the C-terminal cysteines, which are part of the cytosolic domain, in a metal chelation and/or acquisition mechanism and, as now supported by the high-resolution structural work, provides the first example of metal-thiolate coordination chemistry in zinc transporters.


Asunto(s)
Proteínas Portadoras/ultraestructura , Insulina/genética , Relación Estructura-Actividad , Transportador 8 de Zinc/ultraestructura , Proteínas Portadoras/química , Proteínas Portadoras/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patología , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Conformación Molecular , Níquel/química , Conformación Proteica en Hélice alfa/genética , Dominios Proteicos/genética , Zinc/química , Transportador 8 de Zinc/química , Transportador 8 de Zinc/genética
9.
Toxicol Mech Methods ; 31(9): 690-698, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34320920

RESUMEN

Tungsten has no known function in humans and is a relatively new contaminant, whereas molybdenum, its congener in the periodic table, is a nutritionally essential element. In addition to early studies on molybdosis in ruminants, their toxic effects in the form of tungstate and molybdate have been addressed primarily in rodents and are predominantly mediated by inducing oxidative stress in various tissues. The purpose of this study was to evaluate the differences between tungstate and molybdate in human liver (HepG2) and kidney (HEK293) cell lines in terms of retention in cells, effect on reactive oxygen species, and activities of xanthine oxidase and phosphatases. The cell lines were exposed to tungstate or molybdate (1 µM to 10 mM) for 24 h, lysed and analyzed for the above biochemical parameters. Despite the chemical similarity of the two anions, cell-specific differential effects were observed. At all concentrations, tungstate was retained more in HEK293 cells while molybdate was retained more in HepG2 cells. HepG2 cells were more sensitive to tungstate than molybdate, showing reduced viability at concentrations as low as 10 µM. Exposure to either anion resulted in the inhibition of protein tyrosine phosphatases at 1 mM and an increased production of reactive oxygen species (ROS) at 100 µM despite their inhibition of the ROS-producing molybdenum enzyme xanthine oxidase. In conclusion, the results indicate that excess of nutritionally essential molybdate or non-essential tungstate causes toxicity by affecting ROS- and phosphorylation-dependent signaling pathways and ensuing gene expression.


Asunto(s)
Molibdeno , Compuestos de Tungsteno , Células HEK293 , Humanos , Riñón , Hígado , Molibdeno/toxicidad , Compuestos de Tungsteno/toxicidad
10.
Biochem Biophys Res Commun ; 528(4): 698-705, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32517868

RESUMEN

Zinc transporters of the ZIP (Slc39, importers) and ZnT (Slc30, exporters) protein families have evolutionary conserved roles in biology. The aim of the present study was to explore the role of zinc, and zinc transporters Zip10 and Znt1a in zebrafish hatching gland development and larval hatching. In the study, knockdown of genes for Zip10 and Znt1a in zebrafish embryos was achieved using morpholino-modified oligonucleotides. A partial loss-of-function Znt1a mutant (Znt1asa17) allowed comparison with the Znt1a morphant. Free Zn2+ in embryos and apoptosis were investigated using fluorescent dyes whereas gene expression was investigated by whole-mount in situ hybridization (WISH). The results showed high levels of free Zn2+ in the hatching gland cells (HGC) along with abundant expression of zip10 and znt1a in normal embryo. Knockdown of zip10 reduced free Zn2+ in HGC, ceased their normal developmental apoptosis, and resulted in displacement and later disappearance of hatching glands and hatching enzymes he1a and catL1b, and inability to hatch. Conversely, knockdown of znt1a or the Znt1asa17 mutation accelerated hatching and coincided with high expression of hatching enzymes and free Zn2+ in the HGC. Thus, Zip10 and free Zn2+ in the HGC are required both for their development and function. This study also demonstrated the opposite functions of the two zinc transporters, ZIP10 and ZnT1 as well as shedding light on the role of Zn2+ in regulation of the human hatching enzyme homologue, ovastacin, which is activated by zinc and cleaves the zona pellucida protein, ZP2, to prevent polyspermy.


Asunto(s)
Pez Cebra/embriología , Zinc/metabolismo , Animales , Regulación del Desarrollo de la Expresión Génica , Mutación con Pérdida de Función , Regulación hacia Arriba , Pez Cebra/genética , Pez Cebra/metabolismo
12.
Int J Mol Sci ; 20(21)2019 Nov 04.
Artículo en Inglés | MEDLINE | ID: mdl-31690008

RESUMEN

The zinc transporter ZnT8 (SLC30A8) localises to insulin secretory granules of ß-cells where it facilitates zinc uptake for insulin crystallisation. ZnT8 abundance has been linked to ß-cell survival and functional phenotype. However, the consequences of ZnT8 haploinsufficiency for ß-cell zinc trafficking and function remain unclear. Since investigations in human populations have shown SLC30A8 truncating polymorphisms to decrease the risk of developing Type 2 Diabetes, we hypothesised that ZnT8 haploinsufficiency would improve ß-cell function and maintain the endocrine phenotype. We used CRISPR/Cas9 technology to generate ZnT8 haploinsufficient mouse MIN6 ß-cells and showed that ZnT8 haploinsufficiency is associated with downregulation of mRNAs for Slc39a8 and Slc39a14, which encode for the zinc importers, Znt- and Irt-related proteins 8 (ZIP8) and 14 (ZIP14), and with lowered total cellular zinc content. ZnT8 haploinsufficiency disrupts expression of a distinct array of important ß-cell markers, decreases cellular proliferation via mitogen-activated protein (MAP) kinase cascades and downregulates insulin gene expression. Thus, ZnT8 cooperates with zinc importers of the ZIP family to maintain ß-cell zinc homeostasis. In contrast to the hypothesis, lowered ZnT8 expression reduces MIN6 cell survival by affecting zinc-dependent transcription factors that control the ß-cell phenotype.


Asunto(s)
Células Secretoras de Insulina/metabolismo , Transportador 8 de Zinc/genética , Zinc/metabolismo , Animales , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Línea Celular , Regulación hacia Abajo , Haploinsuficiencia , Sistema de Señalización de MAP Quinasas , Ratones , Fenotipo
13.
J Am Chem Soc ; 140(12): 4446-4454, 2018 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-29512390

RESUMEN

While the majority of phosphatases are metalloenzymes, the prevailing model for the reactions catalyzed by protein tyrosine phosphatases does not involve any metal ion, yet both metal cations and oxoanions affect their enzymatic activity. Mg2+ and Zn2+ activate and inhibit, respectively, protein tyrosine phosphatase 1B (PTP1B). Molecular dynamics simulations, metadynamics, and quantum chemical calculations in combination with experimental investigations demonstrate that Mg2+ and Zn2+ compete for the same binding site in the active site only in the closed conformation of the enzyme in its phosphorylated state. The two cations have different effects on the arrangements and activities of water molecules that are necessary for the hydrolysis of the phosphocysteine intermediate in the second catalytic step of the reaction. Remarkable differences between the established structural enzymology of PTP1B investigated ex vivo and the function of PTP1B in vivo become evident. Different reaction pathways are viable when the presence of metal ions and their cellular concentrations are considered. The findings suggest that the substrate delivers the inhibitory Zn2+ ion to the active site. The inhibition and activation can be ascribed to the different coordination chemistries of Zn2+ and Mg2+ ions and the orientation of the metal-coordinated water molecules. Metallochemistry adds an additional dimension to the regulation of PTP1B and presumably other members of this enzyme family.

14.
Adv Exp Med Biol ; 1055: 1-20, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29884959

RESUMEN

Metallomics, a discipline integrating sciences that address the biometals and biometalloids, provides new opportunities for discoveries. As part of a systems biology approach, it draws attention to the importance of many chemical elements in biochemistry. Traditionally, biochemistry has treated life as organic chemistry, separating it from inorganic chemistry, considered a field reserved for investigating the inanimate world. However, inorganic chemistry is part of the chemistry of life, and metallomics contributes by showing the importance of a neglected fifth branch of building blocks in biochemistry. Metallomics adds chemical elements/metals to the four building blocks of biomolecules and the fields of their studies: carbohydrates (glycome), lipids (lipidome), proteins (proteome), and nucleotides (genome). The realization that non-essential elements are present in organisms in addition to essential elements represents a certain paradigm shift in our thinking, as it stipulates inquiries into the functional implications of virtually all the natural elements. This article discusses opportunities arising from metallomics for a better understanding of human biology and health. It looks at a biological periodic system of the elements as a sum of metallomes and focuses on the major roles of metals in about 30-40% of all proteins, the metalloproteomes. It emphasizes the importance of zinc and iron biology and discusses why it is important to investigate non-essential metal ions, what bioinformatics approaches can contribute to understanding metalloproteins, and why metallomics has a bright future in the many dimensions it covers.


Asunto(s)
Metabolismo de los Hidratos de Carbono , Metabolismo de los Lípidos , Metaloides/metabolismo , Metaloproteínas/metabolismo , Metales/metabolismo , Ácidos Nucleicos/metabolismo , Animales , Humanos
15.
BMC Genomics ; 18(1): 719, 2017 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-28893192

RESUMEN

BACKGROUND: Pancreatic ß-cells require a constant supply of zinc to maintain normal insulin secretory function. Following co-exocytosis with insulin, zinc is replenished via the Zrt- and Irt-like (ZIP; SLC39A) family of transporters. However the ZIP paralogues of particular importance for zinc uptake, and associations with ß-cell function and Type 2 Diabetes remain largely unexplored. We retrieved and statistically analysed publically available microarray and RNA-seq datasets to perform a systematic review on the expression of ß-cell SLC39A paralogues. We complemented results with experimental data on expression profiling of human islets and mouse ß-cell derived MIN6 cells, and compared transcriptomic and proteomic sequence conservation between human, mouse and rat. RESULTS: The 14 ZIP paralogues have 73-98% amino sequence conservation between human and rodents. We identified 18 datasets for ß-cell SLC39A analysis, which compared relative expression to non-ß-cells, and expression in response to PDX-1 activity, cytokines, glucose and type 2 diabetic status. Published expression data demonstrate enrichment of transcripts for ZIP7 and ZIP9 transporters within rodent ß-cells and of ZIP6, ZIP7 and ZIP14 within human ß-cells, with ZIP1 most differentially expressed in response to cytokines and PDX-1 within rodent, and ZIP6 in response to diabetic status in human and glucose in rat. Our qPCR expression profiling data indicate that SLC39A6, -9, -13, and - 14 are the highest expressed paralogues in human ß-cells and Slc39a6 and -7 in MIN6 cells. CONCLUSIONS: Our systematic review, expression profiling and sequence alignment reveal similarities and potentially important differences in ZIP complements between human and rodent ß-cells. We identify ZIP6, ZIP7, ZIP9, ZIP13 and ZIP14 in human and rodent and ZIP1 in rodent as potentially biologically important for ß-cell zinc trafficking. We propose ZIP6 and ZIP7 are key functional orthologues in human and rodent ß-cells and highlight these zinc importers as important targets for exploring associations between zinc status and normal physiology of ß-cells and their decline in Type 2 Diabetes.


Asunto(s)
Proteínas de Transporte de Catión/genética , Perfilación de la Expresión Génica , Células Secretoras de Insulina/metabolismo , Animales , Humanos
16.
Biometals ; 30(4): 517-527, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28540523

RESUMEN

Protein tyrosine phosphatases are not considered to be metalloenzymes. Yet, they are inhibited by zinc cations and metal and non-metal oxyanions that are chemical analogues of phosphate, e.g. vanadate. Metal inhibition is generally not recognized as these enzymes are purified, supplied, and assayed with buffers containing chelating and reducing agents. We screened a series of cations and anions for their capacity to inhibit protein tyrosine phosphatase 1B and discuss the ensuing general issues with inhibition constants reported in the scientific literature. In contrast to zinc, which binds to the phosphocysteine intermediate in the closed conformation of protein tyrosine phosphatase 1B when the catalytic aspartate has moved into the active site, other divalent cations such as cadmium and copper may also bind to the enzyme in the open conformation. Inhibition by both anions and cations, conditions such as pH, the presence of metal ligands such as glutathione, and the existence of multiple conformational states of protein tyrosine phosphatases in the reaction cycle establish a complex pattern of inhibition of these important regulatory enzymes with implications for the physiology, pharmacology and toxicology of metal ions.


Asunto(s)
Cadmio/química , Cobre/química , Inhibidores Enzimáticos/química , Proteína Tirosina Fosfatasa no Receptora Tipo 1/química , Zinc/química , Arseniatos/química , Cationes Bivalentes , Pruebas de Enzimas , Glutatión/química , Humanos , Concentración de Iones de Hidrógeno , Cinética , Molibdeno/química , Nitratos/química , Unión Proteica , Proteínas Recombinantes/química , Soluciones , Compuestos de Tungsteno/química , Vanadatos/química
17.
Int J Mol Sci ; 18(11)2017 Oct 31.
Artículo en Inglés | MEDLINE | ID: mdl-29088067

RESUMEN

In the last decade, we witnessed discoveries that established Zn2+ as a second major signalling metal ion in the transmission of information within cells and in communication between cells. Together with Ca2+ and Mg2+, Zn2+ covers biological regulation with redox-inert metal ions over many orders of magnitude in concentrations. The regulatory functions of zinc ions, together with their functions as a cofactor in about three thousand zinc metalloproteins, impact virtually all aspects of cell biology. This article attempts to define the regulatory functions of zinc ions, and focuses on the nature of zinc signals and zinc signalling in pathways where zinc ions are either extracellular stimuli or intracellular messengers. These pathways interact with Ca2+, redox, and phosphorylation signalling. The regulatory functions of zinc require a complex system of precise homeostatic control for transients, subcellular distribution and traffic, organellar homeostasis, and vesicular storage and exocytosis of zinc ions.


Asunto(s)
Transducción de Señal , Zinc/metabolismo , Animales , Proteínas de Unión al ADN/metabolismo , Humanos , Metalotioneína/metabolismo , Factores de Transcripción/metabolismo , Factor de Transcripción MTF-1
18.
Int J Mol Sci ; 18(6)2017 Jun 09.
Artículo en Inglés | MEDLINE | ID: mdl-28598392

RESUMEN

Recent discoveries in zinc biology provide a new platform for discussing the primary physiological functions of mammalian metallothioneins (MTs) and their exquisite zinc-dependent regulation. It is now understood that the control of cellular zinc homeostasis includes buffering of Zn2+ ions at picomolar concentrations, extensive subcellular re-distribution of Zn2+, the loading of exocytotic vesicles with zinc species, and the control of Zn2+ ion signalling. In parallel, characteristic features of human MTs became known: their graded affinities for Zn2+ and the redox activity of their thiolate coordination environments. Unlike the single species that structural models of mammalian MTs describe with a set of seven divalent or eight to twelve monovalent metal ions, MTs are metamorphic. In vivo, they exist as many species differing in redox state and load with different metal ions. The functions of mammalian MTs should no longer be considered elusive or enigmatic because it is now evident that the reactivity and coordination dynamics of MTs with Zn2+ and Cu⁺ match the biological requirements for controlling-binding and delivering-these cellular metal ions, thus completing a 60-year search for their functions. MT represents a unique biological principle for buffering the most competitive essential metal ions Zn2+ and Cu⁺. How this knowledge translates to the function of other families of MTs awaits further insights into the specifics of how their properties relate to zinc and copper metabolism in other organisms.


Asunto(s)
Cobre/metabolismo , Metalotioneína/metabolismo , Zinc/metabolismo , Animales , Transporte Biológico , Regulación de la Expresión Génica , Humanos , Metalotioneína/química , Metalotioneína/genética , Metales/metabolismo , Oxidación-Reducción , Unión Proteica , Transducción de Señal , Relación Estructura-Actividad
19.
Coord Chem Rev ; 327-328: 70-83, 2016 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-27890939

RESUMEN

A new paradigm in metallobiochemistry describes the activation of inactive metalloenzymes by metal ion removal. Protein tyrosine phosphatases (PTPs) do not seem to require a metal ion for enzymatic activity. However, both metal cations and metal anions modulate their enzymatic activity. One binding site is the phosphate binding site at the catalytic cysteine residue. Oxyanions with structural similarity to phosphate, such as vanadate, inhibit the enzyme with nanomolar to micromolar affinities. In addition, zinc ions (Zn2+) inhibit with picomolar to nanomolar affinities. We mapped the cation binding site close to the anion binding site and established a specific mechanism of inhibition occurring only in the closed conformation of the enzyme when the catalytic cysteine is phosphorylated and the catalytic aspartate moves into the active site. We discuss this dual inhibition by anions and cations here for PTP1B, the most thoroughly investigated protein tyrosine phosphatase. The significance of the inhibition in phosphorylation signaling is becoming apparent only from the functions of PTP1B in the biological context of metal cations as cellular signaling ions. Zinc ion signals complement redox signals but provide a different type of control and longer lasting inhibition on a biological time scale owing to the specificity and affinity of zinc ions for coordination environments. Inhibitor design for PTP1B and other PTPs is a major area of research activity and interest owing to their prominent roles in metabolic regulation in health and disease, in particular cancer and diabetes. Our results explain the apparent dichotomy of both cations (Zn2+) and oxyanions such as vanadate inhibiting PTP1B and having insulin-enhancing ("anti-diabetic") effects and suggest different approaches, namely targeting PTPs in the cell by affecting their physiological modulators and considering a metallodrug approach that builds on the knowledge of the insulin-enhancing effects of both zinc and vanadium compounds.

20.
Arch Biochem Biophys ; 611: 3-19, 2016 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-27117234

RESUMEN

The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the "mobile" zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn2+ without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn2+ differs from s-block cations such as Ca2+ with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol.


Asunto(s)
Química Bioinorgánica , Zinc/química , Aniones , Tampones (Química) , Catálisis , Cationes , Quelantes/química , Humanos , Concentración de Iones de Hidrógeno , Ligandos , Oxidación-Reducción , Proteínas/química , Transducción de Señal , Solubilidad , Temperatura
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