Glutathione S-Transferase

Glutathione S-Transferase, commonly abbreviated GST, are a family of multifunctional proteins that work both as important enzymes of detoxification and intra-cellular binding proteins. Glutathione S-transferase employ glutathione in many reactions that bring about the change of several compounds such as carcinogens, therapeutic drugs and products involved in oxidative stress.

Glutathione S Transferase

   

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Because of the dual function of GST, it has been the research interest of several scientists, including pharmacologists, biochemists, physiologists, toxicologists, and cell biologists. In their enzymatic reaction, they catalyze the reaction between the nucleophile reduced glutathione (GSH) and a large number of electrophilic compounds.


Glutathione-S-TransferaseGST family of purifying enzymes consists of many microsomal, mitochondrial and cytosolic proteins, which make significant parts of the enzyme body. They occur in eukaryotes and prokaryotes where they are crucial in catalyzing the different reactions and at the same time accept xenobiotic and endogenous substrates.

Multiple GST isoenzymes that are bound by cytosolic and membranes are found in eukaryotic species. Each possess unique catalytic and non-catalytic binding characteristics.


GST bind a number of amphipathic compounds that they do not metabolize (non-substrate ligands) and have been suggested to act as intracellular transport proteins for compounds that have partial solubility in water.


Glutathione S-Transferase Function


Glutathione S-Transferase contain up to 10 percent cytosolic elements in some organs. GST catalyze the mechanism of conjugation of glutathione to electrophilic regions through sulfhydryl group. The purpose is to increase the solubility of compounds. In the process, some compounds are detoxified, including peroxidized lipids and compounds and xenobiotics are broken down.

Another important function carried out by glutathione S-Transferase is the binding of toxins, which also serves as a mechanism for transporting proteins. That is why glutathione S-transferase are referred to as ligands.


Structure of Glutathione S transferase


Glutathione S transferase has a super family structure made of cytosolic-dimer enzymes that are categorized into six classes: pi, omega, zeta, theta, mu and alpha.


Relation between Glutathione S-Transferase and GSH and Their Purpose


Acclaimed research shows that glutathione s-transferase plays a critical role in the determination of cell sensitivity to a wide scope of harmful chemicals. The key functions of GSTs are highly dependant on frequent supply of glutathione (GSH) which is from two synthetic enzymes gamma glutamylcysteine and glutathione synthetase. This association is related to other functions provided by defined transporters that aid in the removal of GSH conjugates from the cells.

 The Important role carried by glutathione s transferase (GST) is to catalyze nucleophilic attack order to bring about detoxification of xenobiotics. This is performed by GSH which works under electrophilic carbon, sulfur or atoms of nitrogen. This full mechanism prevent an interaction with cellular proteins and nucleic acids.

Thus, the purpose of GSTs can be said to be two-way:

 

  • Bind substrate at hydrophobic H-region and adjacent GSH (hydrophilic G-site) so as to create and activate region for the enzyme.
  • Enables nucleophilic attack on substrate to activate thiol glutathione (GSH) group


Furthermore, glutathione s-transferase are able to bind cell signaling process with non-substrate ligands. Some glutathione s transferase enzymes belonging in diverse categories are known to show characteristics of kinase which is involved in MAPK pathway, as a result controlling cell death and cell proliferation. They constrain the role played by kinase in cascading signals.


Role of glutathione s transferase in Cell Signaling


Glutathione s transferases are best known for their capability to conjugate xenobiotics to GSH and therefore purify cellular movements. But they are also capable of sticking non-substrate ligands, with important cell signaling associations.

A number of GST isozymes from different categories have been shown to prevent the function of a kinase involved in the MAPK pathway that controls cell proliferation and death, which inhibit the kinase from carrying out its role in facilitating the signaling cascade.


Glutathione S-Transferase and Cancer Resistance


There is strong evidence supporting the role of glutathione s-transferase in anti-cancer drug resistance, more so GSTP, in cancer development and chemotherapeutic resistance. The relation between GSTP and cancer is more evident in the overexpression of GSTP in many cancers.


Role of Glutathione S-Transferase in Treatment of Brain Disorders


Glutathione s-transferase gene controls brain disorders including the onset of Alzheimer’s and Parkinson’s disease and determines when we get these diseases, according to research by genetics researchers. Previously, it has been linked to the risk of Parkinson’s disease among people who used pesticides.


Relation of Alzheimer’s Disease and Glutathione s transferase


The primary cause of Alzheimer’s disease is known to be free radicals and oxidative damage in neurons. When amyloid-peptide accumulates in senile plaques, it leads to neuronal degeneration; part of cause of Alzheimer’s disease. When amyloid-peptide encroaches the brain, it increases the production of free radicals, or oxidative stress.

Vitamin C and E (antioxidants) eliminate the damaging free radicals. Glutathione components or associations, including Glutathione s-transferase can prevent death of brain cells induced by amyloid plaques in Alzheimer’s disease, while substances that eliminate glutathione increase death of cells.


Studies show the Indian spice, curcumin, has neuroprotective effects because of its capability to induce the enzyme, hemeoxygenase-1, which protects neurons exposed to oxidant stress. Curcumin increases expression of hemeoxygenase-1 protein as well as glutathione s transferase, thus is used in treatment of brain cells called astrocytes.


Glutathione s transferase and Mood Disorders


Studies show that expression of the genes that make glutathione s-transferase is regulated by valproate, a mood stabilizing drug used to treat epilepsy and bi-polar disorder. Another mood stabilizing drug, lithium, also increases levels of glutathione s transferase. This indications led researchers to believe that glutathione s transferase may be a unique target for mood stabilizing drugs.


Release of Glutathione S Transferase an Indication of Organ Damage


GST can be used as indicators of cell damage since the high intracellular concentrations of GSTs in addition to their cell-specific cellular distribution allows them to function as biomarkers for localizing and monitoring injury in defined cell types. For example, hepatocytes, which contain high levels of alpha GST and serum GST is used as an indicator of hepatocyte injury in viral infections, transplantation and toxicity. Glutathione s transferases are implicated in a variety of diseases by virtue of their involvement with GSH, in addition to the roles they play in cancer development and chemotherapeutic drug resistance. Diabetes, a disease that involves oxidative damage, is a potential target for treatment by GSTs.

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