Glutathionylation Of Proteins – Thesis Example

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INTRODUCTIONThe current advances in modern science have greatly enhanced the understanding of modification of proteins and its impact on the cellular microenvironment along with its association with various diseases. Even though protein folding and re-folding are important steps in the synthesis of proteins the modification of these proteins are of prime importance since they provide the structural and functional diversity of the proteins. Post-translational modification of proteins influences a variety of cellular functions such as DNA repair, enzyme activity, protein-protein interactions, etc. ‘Oxidative stress’ is a condition in which the intracellular per oxidant – anti-oxidant ratio scale tips in the favour of per oxidants, which leads to the accumulation of oxygen radicals and other oxygen-derived species within the cells which in turn leads to conditions like ageing or a variety of human diseases such as cancer.

ATP synthesis in a Eukaryotic cell generally produces superoxide anion free radicals and other active oxygen species such as OH ions or H2O2. Even though there are several mechanisms to prevent their accumulation at times the system may get overwhelmed leading to toxic cell damage. Glutathione is an important component in providing the cellular defences against oxidative stress.

During oxidative stress the cell is known to produce increased glutathione. Its role against active oxygen species and reactive intermediates are quite unique. They not only act as reductants for hydrogen peroxides and organic hydrogen peroxides but also act as a nucleophile which conjugates electrophilic molecules. The reaction is catalysed by glutathione peroxidise. The excess glutathione disulphide produced due to the reaction is effectively removed by glutathione reductase [35]. After extensive research it has been proved that cell death due to conditions of oxidative stress may be caused due to depletion of glutathione in the cell.

But the exact mechanism of cell death and glutathione depletion has not yet been clarified. To maintain the intracellular redox balance glutathione is attached to proteins by a thiol group. Protein – SSG + GSH → Protein – SH + GSSGThe reaction is catalysed by thiol transferase. It has been noted that loss of protein thiols leads to glutathione depletion eventually leading to cell death. Thus glutathionylation of proteins is important to prevent cell death and damage.

Deficiency of glutathione is reported as an autosomal recessive disorder which is found to be hereditary to certain group of people [30]. Glutathione is also known to protect the Eukaryotic cell from oxidative stress caused due to excessive exposure of metals [17]. GLUTATHIONEGlutathione is a tri-peptide with a simple sulphur compound. It is one of the most common non-protein thiol group found in most of the organisms. The most important function of glutathione is redox - haemostatic buffering. It also acts as a transducer for the cellular network for environmental signals.

StructureGlutathione is a thiol tri-peptide with an amino acid sequence of ɣ-L-glutamyl, L-cysteinyl-glycine [27]. Glutathione in nature exists in two forms the thiol-reduced glutathione (GSH) and the disulphide oxidised form (GSSG). GSH is the most predominant form and is found in most of the mammalian tissue where as the GSSG form only occupies 1% of the total amount of glutathione. The cytosol, mitochondria and the endoplasmic reticulum are the 3 major reservoirs of glutathione in the eukaryotic cell. One of the unique features of glutathione is the peptide bond linking the glutamate and cysteine of the GSH by the ɣ-carboxyl group which can be subjected to hydrolysis only by the enzyme ɣ-glutamyltranspeptidase.

The ɣ-glutamyltranspeptidase is present only on the outer surface of the cells which makes the GSH resistant to intracellular degradation making it possible to be metabolised only extracellularly by the organs with the particular enzyme.

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