What is Metallothionein and Role of Metallothionein in Oxidative Stress

What Is Metallothionein: Metallothionein (MT) is a low molecular weight protein and it is a family of cysteine-rich, They’re localized to the membrane of the Golgi apparatus. Therefore, Metallothioneins have the capacity to bind both xenobiotic (like cadmium, silver, arsenic, mercury) and physiological (like copper, zinc, selenium) heavy metals through the thiol group of its cysteine residues, that represent nearly thirty percent (30%) of its constituent amino acid residues.

Metallothioneins are small proteins that bind heavy metals, like copper, zinc, nickel, cadmium, etc. it is a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds. Furthermore, an empirical classification into three classes has been proposed by coworkers and Kojima and Fowler. Therefore, the members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B and include mammalian MTs as well as from crustaceans and Molluscs. furthermore, class II groups Metallothioneins from a variety of species, including sea urchins, insects, fungi, and cyanobacteria. Class III Metallothioneins are atypical polypeptides composed of gamma-Glutamylcysteinyl units.

This original classification system has been found to be limited, which means that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Therefore, subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which essentially proposes an MT family for each main taxonomic group of organisms. These entries compsise MT from vertebrates and MT-10 type metallothioneins from aquatic molluscs.

Biological Process: None
Molecular Function: Metal ion binding (GO:0046872)
Cellular Component: None

Metallothionein plays an important role in the protection against metal toxicity and oxidative stress and is involved in zinc (Zn) and copper regulation. Basically four main isoforms expressed in humans (see the table chart): MT1 (subtypes A, B, E, F, G, H, L, M, X), MT2, MT3, and MT4. In the human body, large quantities are synthesized primarily in the kidneys and liver. Furthermore, Their production is dependent on the availability of dietary minerals such as copper, selenium, and zinc, as well as the amino acids histidine and cysteine.

MTs are rich in thiols, causing them to bind a number of trace metals. MT binds several Zn ions. One of few eukaryotic proteins distinguished as having a role in substantial metal Zinc detoxification. Cadmium and Metallothionein Zinc are tetrahedrally coordinated to cysteine residues, each metallothionein protein molecule might bind up to 7 atoms of Cd or Zn. The biosynthesis of metallothionein appeared to have increased by several-fold throughout oxidative stress to shield the cells against cytotoxicity and Deoxyribonucleic acid (DNA) damage. MT biosynthesis can also be induced by certain agents or conditions, such as for example, alcohols, pharmaceuticals, hormones, other substance treatments, and many more. Therefore, metallothionein is a cytoplasmic protein, in an adult liver, Furthermore, it’s localized basically in the cytoplasm and in the human fetus, metallothionein is localized in hepatocyte nuclei.

Metallothionein Structure And Classification

Metallothionein is present in a vast range of taxonomic groups, ranging from prokaryotes like that the cyanobacteria Synechococcus sp., protozoa, plants (like Triticum durum, Pisum sativum, Quercus suber, or Zea mays) yeast (such as Saccharomyces cerevisiae or Candida albicans), vertebrates (like the chicken Gallus gallus, or Mus musculus or the mammalian Homo sapiens) and invertebrates (like insect Drosophila melanogaster, nematode Caenorhabditis elegans, or the echinoderm Strongylocentrotus purpuratus).

The Metallothioneins (MTs) from this diverse taxonomic range describe the high-heterogeneity sequence (regarding relative molecular weight and number and distribution of Cys residues) and don’t show the homology, furthermore, in spite of this, homology is underlie inside some taxonomic groups.

From their primary structure, MTs are classified by different strategies. The 1st one dates from 1987, when Fowler et al., established 3 classes of MTs:
Class I- In the class 1st including the MTs that show homology with horse MT,
Class II- In the class 2nd including the rest of the MTs with no homology with horse MT
Class III- Which includes phytochelatins, Cys-rich enzymatically synthesized peptides.

The second classification was performed by Binz and Kagi in 2001 and takes into account taxonomic parameters and therefore, the patterns of distribution of Cys residues along the MT sequence. furthermore, in a classification of Fifteen (15) families for proteinaceous MTs. Therefore, family 15 contains the plant MTs, that in 2002 and has been classified by Cobbet and Goldsbrough into four (4) Types (1, 2, 3, and 4), which depending on the division of their Cys residues and Cys-devoid regions (this is also called spacers) characteristic of plant MTs.

Metallothioneins are described by a profusion of cysteine residues and a lack of generic secondary structure motifs. Furthermore, yeast Metallothionein (MT) is also an alternatively named, Copper metallothionein (CUP). Furthermore, yeast metallothionein coordinates much more strongly to Cu+ than Cu2+.

This MT protein functions in primary metal storage, transport, and Zinc detoxification. MT stores copper thus, therefore, it protects the cell against the Cu toxicity by tightly chelating copper ions. Furthermore, the first forty residues in the protein, the polypeptide wraps around the metal by forming 2 large parallel loops which will be separated by a deep cleft containing the metal cluster.

Function

Control Of Oxidative Stress

Cysteine residues from Metallothioneins can capture harmful oxidant radicals such as superoxide and hydroxyl radicals. during this reaction, cysteine is oxidized to cystine, and the metal ions which were bound to cysteine are released to the media. Therefore, this Zn can activate the synthesis of additional MTs. it is a very important mechanism in the control of oxidative stress by Metallothioneins. The role of MTs in reducing oxidative stress has been confirmed by MT Knockout mutants, furthermore, however, some experiments propose also a prooxidant role for MTs.

MT also plays an important role in hematopoietic cell differentiation and proliferation, as well as the prevention of apoptosis of early differentiated cells. Therefore, induced MT levels were adversely associated with sensitivity to etoposide-induced apoptosis, signifying that MT is a potential negative controller of apoptosis.

Expression And Regulation

Metallothionein gene expression is induced by a high variety of stimuli, as metal exposure, glucocorticoids, Vitamin D, oxidative stress, hydric stress, fasting, exercise, etc. Furthermore, the level of the response to these inducers depends on the MT gene. thus MT genes will be existing in their promoters specific sequences and for the regulation of the expression, glucocorticoid response elements, elements as metal response elements, thyroid response elements and GC-rich boxes, basal level elements.

Metallothionein And Disease

Autism

Heavy metal toxicity has been planned as a hypothetical etiology of autism, and dysfunction of MT synthesis. Many heavy metals, including lead, mercury, and arsenic has been linked to symptoms that resemble the neurological symptoms of autism. However, MT dysfunction has not been linked to autistic spectrum disorders. In the study 2006, investigating children exposed to the vaccine preservative (metallothionein supplements) thiomersal found that levels of MT and antibodies to MT in autistic kids did not differ significantly from the non-autistic kids.

Low zinc (Zn) to copper ratio has been seen as a biomarker for autism and suggested as a sign that the Metallothionein system has been affected.

Further, there’s a sign that the mother’s zinc levels can affect the developing baby’s immunological state which may lead to autism, and could be again an indication that the Metallothionein system has been affected.

Cancer

Metallothioneins (MTs) played important role in the transcription factor regulation, and defects in Metallothionein (MT) function or expression can lead to malignant transformation of cells and ultimately cancer.

Therefore, studies have found enhanced expression of MTs in few cancers of the breast, kidney, colon, liver, skin (melanoma), nasopharynx, ovary, prostate, mouth, lung, salivary gland, testes, thyroid, and urinary bladder. furthermore, they have also found lower levels of MT expression in liver adenocarcinoma and hepatocellular carcinoma. Furthermore, there is evidence to suggest that higher levels of MT expression might also cause also lead to resistance to chemotherapeutic drugs.

REFERENCES

1. Article Reference Taken From Metallothionein Wikipedia:
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