Abstract
Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state—an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity.
Highlights
Homocysteine is a sulfur containing toxic metabolite produced as a byproduct in methionine metabolism pathway
We have investigated the effect of protein N-homocysteinylation on three different proteins having different physico-chemical properties
The result suggests that hydrodynamic diameter of different proteins increases at different time intervals depending on the homocysteine thiolactone (HTL) concentration
Summary
Homocysteine is a sulfur containing toxic metabolite produced as a byproduct in methionine metabolism pathway. This toxic homocysteine is known to metabolize to methionine by remethylation or to cystiene by trans-sulfurylation [1]. It has been demonstrated that HTL preferentially forms amide bonds with e-amino group of lysine residues of protein in a nonenzymatic mechanism; a process referred to as ‘‘protein Nhomocysteinylation’’ [13] which results in various kinds of toxic effects on macromolecules including loss of enzymatic activity, generation of oxidative stress within the cell and autoimmune response generation against N-homocysteinylated self proteins [14]
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