Proline reduces half‐life of homocysteine thiolactone

Abstract

Homocysteine (Hcy) is a sulfur containing toxic amino acid synthesized from sulfur metabolism pathway. Elevated level of Hcy is associated with various cardiovascular complications including atherosclerosis. One of the likely mechanisms underlying harmful effects of Hcy is the chemical modification of proteins by homocysteine thiolactone (HTL), a highly reactive cyclic thioester of Hcy. HTL preferentially forms amide bonds with ɛ‐ amino group of protein lysine, arginine or histidine residues in a non‐enzymatic mechanism; a process referred to as “protein N‐homocysteinylation resulting in the impairment of protein functions. Therefore, novel approaches that could inhibit or delay protein N‐homocysteinylation would be therapeutically important to curb hyperhomocysteinemia. In the present communication, we screened for different cellular molecules produced under stressful insults for their ability to suppress covalent modification of proteins by HTL. We found that out of several molecules, proline has the potential to inhibit protein N‐homocysteinylation in a non‐enzymatic fashion. We also discovered that proline treatment increases Hcy levels in HeLa cells and induces cell cycle arrest. Our study highlights the importance of proline treatment in reducing toxicity load in hyperhomocysteinemic/homocystinuric patients.