Functional inhibition of redox regulated heme proteins: A novel mechanism towards oxidative stress induced by homocysteine

Homocysteine (Hcy) is a sulfur containing non-protein toxic amino acid synthesized from methionine. Elevated level of Hcy is associated with cardiovascular complications and neurodegeneration. Hcy is believed to induce organ damage and apoptosis via oxidative stress. The pro-oxidant nature of Hcy is considered to originate from the metal-induced oxidation of thiol group-containing molecules forming disulfides (Hcy-Hcy, Hcy-cysteine, Hcy-glutathione, etc) or with free cysteine residues of proteins (a process called protein S-homocysteinylation). Formation of such disulfides indeed results in the generation of reactive oxygen species (ROS) which eventually leads to loss of cellular integrity. In the present manuscript, we performed systematic investigation of the effect of Hcy on iron containing proteins. We discover a novel mechanism of Hcy toxicity wherein Hcy oxidation is linked with the functional loss of the protein with iron as cofactors. Our results indicate that redox regulated heme proteins might be primarily involved in the Hcy toxicity and associated oxidative stress.