title: Chemical biology of homocysteine thiolactone and related metabolites.
abstract: Protein-related homocysteine (Hcy) metabolism produces Hcy-thiolactone, N-Hcy-protein, and N epsilon-homocysteinyl-lysine (N epsilon-Hcy-Lys). Hcy-thiolactone is generated in an error-editing reaction in protein biosynthesis when Hcy is erroneously selected in place of methionine by methionyl-tRNA synthetase. Hcy-thiolactone, an intramolecular thioester, is chemically reactive and forms isopeptide bonds with protein lysine residues in a process called N-homocysteinylation, which impairs or alters the protein's biological function. The resulting protein damage is exacerbated by a thiyl radical-mediated oxidation. N-Hcy-proteins undergo structural changes leading to aggregation and amyloid formation. These structural changes generate proteins, which are toxic and which induce an autoimmune response. Proteolytic degradation of N-Hcy-proteins generates N epsilon-Hcy-Lys. Levels of Hcy-thiolactone, N-Hcy-protein, and N epsilon-Hcy-Lys increase under pathological conditions in humans and mice and have been linked to cardiovascular and brain disorders. This chapter reviews fundamental biological chemistry of Hcy-thiolactone, N-Hcy-protein, and N epsilon-Hcy-Lys and discusses their clinical significance.
authors: Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, New Jersey, USA. jakubows@umdnj.edu
authors: Hieronim
authors: H
authors: Jakubowski
authors: Rafał
authors: R
authors: Głowacki
mesh_terms: D000682:Amyloid / Q000096:biosynthesis*; D000818:Animals; D001927:Brain Diseases / Q000378:metabolism* / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology; D004151:Dipeptides / Q000097:blood; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008715:Methionine / Q000378:metabolism; D008718:Methionine-tRNA Ligase / Q000378:metabolism; D051379:Mice; D014176:Protein Biosynthesis; D011506:Proteins / Q000032:analysis / Q000378:metabolism; D059748:Proteolysis
chemical_list: D000682:Amyloid; D004151:Dipeptides; C556024:N(epsilon)-homocysteinyl-lysine; D011506:Proteins; D006710:Homocysteine; D008715:Methionine; C007957:homocysteine thiolactone; D008718:Methionine-tRNA Ligase