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International Journal of Molecular... May 2017Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique... (Review)
Review
Metallothionein-3 (MT-3), a member of the mammalian metallothionein (MT) family, is mainly expressed in the central nervous system (CNS). MT-3 possesses a unique neuronal growth inhibitory activity, and the levels of this intra- and extracellularly occurring metalloprotein are markedly diminished in the brain of patients affected by a number of metal-linked neurodegenerative disorders, including Alzheimer's disease (AD). In these pathologies, the redox cycling of copper, accompanied by the production of reactive oxygen species (ROS), plays a key role in the neuronal toxicity. Although MT-3 shares the metal-thiolate clusters with the well-characterized MT-1 and MT-2, it shows distinct biological, structural and chemical properties. Owing to its anti-oxidant properties and modulator function not only for Zn, but also for Cu in the extra- and intracellular space, MT-3, but not MT-1/MT-2, protects neuronal cells from the toxicity of various Cu(II)-bound amyloids. In recent years, the roles of zinc dynamics and MT-3 function in neurodegeneration are slowly emerging. This short review focuses on the recent developments regarding the chemistry and biology of MT-3.
Topics: Animals; Copper; Humans; Metallothionein; Metallothionein 3; Models, Molecular; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Protein Conformation; Reactive Oxygen Species; Zinc
PubMed: 28538697
DOI: 10.3390/ijms18061117 -
Molecular Brain Aug 2020Transition metals, such as iron, copper, and zinc, play a very important role in life as the regulators of various physiochemical reactions in cells. Abnormal... (Review)
Review
Transition metals, such as iron, copper, and zinc, play a very important role in life as the regulators of various physiochemical reactions in cells. Abnormal distribution and concentration of these metals in the body are closely associated with various diseases including ischemic seizure, Alzheimer's disease, diabetes, and cancer. Iron and copper are known to be mainly involved in in vivo redox reaction. Zinc controls a variety of intracellular metabolism via binding to lots of proteins in cells and altering their structure and function. Metallothionein-3 (MT3) is a representative zinc binding protein predominant in the brain. Although the role of MT3 in other organs still needs to be elucidated, many reports have suggested critical roles for the protein in the control of a variety of cellular homeostasis. Here, we review various biological functions of MT3, focusing on different cellular molecules and diseases involving MT3 in the body.
Topics: Amino Acid Sequence; Animals; Apoptosis; Autophagy; Cells; Disease; Humans; Metallothionein; Reactive Oxygen Species
PubMed: 32843100
DOI: 10.1186/s13041-020-00654-w -
World Journal of Surgical Oncology May 2011The Metallothionein (MT) is a protein which has several interesting biological effects and has been demonstrated increase focus on the role of MT in various biological... (Review)
Review
The Metallothionein (MT) is a protein which has several interesting biological effects and has been demonstrated increase focus on the role of MT in various biological systems in the past three decades. The studies on the role of MT were limited with few areas like apoptosis and antioxidants in selected organs even fifty years after its discovery. Now acknowledge the exploration of various isoforms of MT such as MT-I, MT-II, MT-III and MT-IV and other isoforms in various biological systems.Strong evidence exists that MT modulates complex diseases and the immune system in the body but the primary function of MT still remains unknown. This review's main objective is to explore the capability to specifically manipulate MT levels in cells and in animals to provide answers regarding how MT could impact those complex disease scenarios.The experimental result mentioned in this review related among MT, zinc, cadmium, diabetic, heart disease, bone retardation, neuro toxicity, kidney dysfunction, cancer, and brain suggest novel method for exploration and contribute significantly to the growing scientist to research further in this field.
Topics: Animals; Bone Diseases, Developmental; Central Nervous System; Diabetes Mellitus; Heart Diseases; Humans; Kidney Diseases; Metallothionein; Neoplasms; Oxidative Stress; Protein Isoforms
PubMed: 21599891
DOI: 10.1186/1477-7819-9-54 -
International Journal of Molecular... Dec 2022Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron-regulatory hormone, is a 25-amino-acid peptide with four intramolecular disulfide bonds circulating in blood. Its hormonal...
Hepcidin (DTHFPICIFCCGCCHRSKCGMCCKT), an iron-regulatory hormone, is a 25-amino-acid peptide with four intramolecular disulfide bonds circulating in blood. Its hormonal activity is indirect and consists of marking ferroportin-1 (an iron exporter) for degradation. Hepcidin biosynthesis involves the N-terminally extended precursors prepro-hepcidin and pro-hepcidin, processed by peptidases to the final 25-peptide form. A sequence-specific formation of disulfide bonds and export of the oxidized peptide to the bloodstream follows. In this study we considered the fact that prior to export, reduced hepcidin may function as an octathiol ligand bearing some resemblance to the N-terminal part of the α-domain of metallothioneins. Consequently, we studied its ability to bind Zn(II) and Cd(II) ions using the original peptide and a model for prohepcidin extended N-terminally with a stretch of five arginine residues (5R-hepcidin). We found that both form equivalent mononuclear complexes with two Zn(II) or Cd(II) ions saturating all eight Cys residues. The average affinity at pH 7.4, determined from pH-metric spectroscopic titrations, is 10 M for Zn(II) ions; Cd(II) ions bind with affinities of 10 M and 10 M. Using mass spectrometry and 5R-hepcidin we demonstrated that hepcidin can compete for Cd(II) ions with metallothionein-2, a cellular cadmium target. This study enabled us to conclude that hepcidin binds Zn(II) and Cd(II) sufficiently strongly to participate in zinc physiology and cadmium toxicity under intracellular conditions.
Topics: Cadmium; Hepcidins; Peptides; Iron; Disulfides; Metallothionein
PubMed: 36555126
DOI: 10.3390/ijms232415483 -
Chemical Reviews Dec 2021The 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...
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.
Topics: Animals; Chemistry, Bioinorganic; Humans; Mammals; Metallothionein; Metals; Zinc
PubMed: 34652893
DOI: 10.1021/acs.chemrev.1c00371 -
International Journal of Molecular... Oct 2017Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals.... (Review)
Review
Metallothioneins (MTs) are a family of metal-binding proteins virtually expressed in all organisms including prokaryotes, lower eukaryotes, invertebrates and mammals. These proteins regulate homeostasis of zinc (Zn) and copper (Cu), mitigate heavy metal poisoning, and alleviate superoxide stress. In recent years, MTs have emerged as an important, yet largely underappreciated, component of the immune system. Innate and adaptive immune cells regulate MTs in response to stress stimuli, cytokine signals and microbial challenge. Modulation of MTs in these cells in turn regulates metal ion release, transport and distribution, cellular redox status, enzyme function and cell signaling. While it is well established that the host strictly regulates availability of metal ions during microbial pathogenesis, we are only recently beginning to unravel the interplay between metal-regulatory pathways and immunological defenses. In this perspective, investigation of mechanisms that leverage the potential of MTs to orchestrate inflammatory responses and antimicrobial defenses has gained momentum. The purpose of this review, therefore, is to illumine the role of MTs in immune regulation. We discuss the mechanisms of MT induction and signaling in immune cells and explore the therapeutic potential of the MT-Zn axis in bolstering immune defenses against pathogens.
Topics: Animals; Cytokines; Humans; Immune System; Infections; Metallothionein; Metals; Signal Transduction
PubMed: 29065550
DOI: 10.3390/ijms18102197 -
Arhiv Za Higijenu Rada I Toksikologiju Mar 2020Human metallothioneins are a superfamily of low molecular weight intracellular proteins, whose synthesis can be induced by essential elements (primarily Zn and Cu),... (Review)
Review
Human metallothioneins are a superfamily of low molecular weight intracellular proteins, whose synthesis can be induced by essential elements (primarily Zn and Cu), toxic elements and chemical agents, and stress-producing conditions. Of the four known isoforms in the human body MT2 is the most common. The expression of metallothioneins is encoded by a multigene family of linked genes and can be influenced by single nucleotide polymorphisms (SNPs) in these genes. To date, 24 SNPs in the MT2A gene have been identified with the incidence of about 1 % in various population groups, and three of them were shown to affect physiological and pathophysiological processes. This review summarises current knowledge about these three SNPs in the MT2A gene and their associations with element concentrations in the body of healthy and diseased persons. The most investigated SNP is rs28366003 (MT2A -5 A/G). Reports associate it with longevity, cancer (breast, prostate, laryngeal, and in paranasal sinuses), and chronic renal disease. The second most investigated SNP, rs10636 (MT2A +838G/C), is associated with breast cancer, cardiovascular disease, and type 2 diabetes. Both are also associated with several metal/metalloid concentrations in the organism. The third SNP, rs1610216 (MT2A -209A/G), has been studied for association with type 2 diabetes, cardiomyopathy, hyperglycaemia, and Zn concentrations. Metallothionein concentrations and MT2A polymorphisms have a potential to be used as biomarkers of metal exposure and clinical markers of a number of chronic diseases. This potential needs to be studied and verified in a large number of well-defined groups of participants (several hundreds and thousands) with a focus on particular physiological or pathological condition and taking into consideration other contributing factors, such as environmental exposure and individual genetic and epigenetic makeup.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Breast Neoplasms; Diabetes Mellitus, Type 2; Female; Genetic Predisposition to Disease; Humans; Male; Metallothionein; Middle Aged; Polymorphism, Single Nucleotide; Trace Elements
PubMed: 32597135
DOI: 10.2478/aiht-2020-71-3349 -
Chimia 2012Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function... (Review)
Review
Multinuclear and multidimensional nuclear magnetic resonance (NMR) spectroscopy is applied in our groups to gain insights into the role of metal ions for the function and structure of large biomolecules. Specifically, NMR is used i) to investigate how metal ions bind to nucleic acids and thereby control the folding and structure of RNAs, ii) to characterize how metal ions are able to stabilize modified nucleic acids to be used as potential nanowires, and iii) to characterize the formation, structure, and role of the diverse metal clusters within plant metallothioneins. In this review we summarize the various NMR experiments applied and the information obtained, demonstrating the important and fascinating part NMR spectroscopy plays in the field of bioinorganic chemistry.
Topics: Chemistry, Bioinorganic; Magnetic Resonance Spectroscopy; Metallothionein; Models, Molecular; Nucleic Acids; RNA, Catalytic
PubMed: 23146267
DOI: 10.2533/chimia.2012.791 -
Arhiv Za Higijenu Rada I Toksikologiju Dec 2019Metallothioneins are peculiar cysteine rich, heat resistant, small cellular plasma proteins expressed through almost all life forms. The currently established biological... (Review)
Review
Metallothioneins are peculiar cysteine rich, heat resistant, small cellular plasma proteins expressed through almost all life forms. The currently established biological functions of metallothioneins are the homeostasis of essential metals and protection against toxic transitional metals (TM) alongside defence from oxidative stress by direct scavenging of reactive oxygen and nitrogen species (ROS and RNS). In mammals, among the four main evolutionary conserved forms, only the ubiquitously expressed metallothionein 1 and 2 (here abbreviated as MT) are inducible by TM, oxidative stress, glucocorticoids and starvation among various other stimuli. However, more than sixty years after being discovered, metallothioneins still bear unresolved issues about their possible physiological function and regulation. The biological function of MTs has still not been associated with the in vitro-demonstrated capacity of MT interaction with cellular molecules glutathione (GSH) or adenosine triphosphate (ATP), or with the possibility of direct iron-MT binding in the reducing intracellular environment of some organelles, e.g. lysosomes. Iron as the most abundant cellular TM is also one of the main physiological sources of ROS. Moreover, iron exhibits strain, sex and age differences that reflected ROS generation and MT induction in (patho)physiology and toxicology studies. A recent study showed that iron sex differences follows expression of both ferritin and MT leading to wide implications from essential TM interconnectivity to aging. This review places emphasis on biochemically proven but physiologically ignored interactions of MT with iron to stimulate advanced research for establishing a wide frame of the biological roles of MTs important for health and longevity.
Topics: Animals; Fishes; Hazardous Substances; Heavy Metal Poisoning; Humans; Mammals; Metallothionein; Molecular Structure; Oxidative Stress
PubMed: 32623859
DOI: 10.2478/aiht-2019-70-3317 -
World Journal of Gastroenterology Feb 2007Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that... (Review)
Review
Metallothioneins (MTs) were discovered in 1957 by Margoshes and Vallee and identified as low-molecular weight and sulphydryl rich proteins. It is not surprising that most mammalian tissues contain age related basal levels of MTs since they are involved in metalloregulatory processes that include cell growth and multiplication. In an effort to understand the biology of this intriguing tumor, various biomarkers such as oncogenes, p53 tumor suppressor gene, waf 1 protein, proliferating cell nuclear antigen, telomerase, microsatellite markers and cytogenetic changes have been examined. One biomarker which has recently shown to be expressed in various human tumors but still less reported in carcinoma is MT. Immunohistochemical detection of MT proteins in cold acetone-fixed paraffin embedded liver sections was performed by the streptavidin-avidin-biotin immuno-peroxidase complex method.
Topics: Animals; Antioxidants; Biomarkers, Tumor; Carcinoma; Gene Expression Regulation, Neoplastic; Humans; Liver; Liver Neoplasms; Metabolic Detoxication, Phase I; Metallothionein; Mice
PubMed: 17373731
DOI: 10.3748/wjg.v13.i7.993