Homocysteine Thiolactone: Metabolic Origin and Protein Homocysteinylation in Humans

Abstract

Homocysteine thiolactone, an intramolecular thioester of homocysteine, is synthesized by methionyl-tRNA synthetase in an error-editing reaction that prevents translational incorporation of homocysteine into proteins. The synthesis of thiolactone occurs in all human cell types investigated. An increase in homocysteine levels leads to elevation of thiolactone levels in human cells. In cultured human cells and in human serum, homocysteine thiolactone reacts with proteins by a mechanism involving homocysteinylation of protein lysine residues. The homocysteinylation leads to protein damage. A calcium-dependent homocysteine thiolactonase, tightly associated with HDL in human serum, may prevent protein damage by detoxifying thiolactone.