Identification and origin of Nε-homocysteinyl-lysine isopeptide in humans and mice.
Homocysteine (Hcy) metabolites, Hcy-thiolactone and N-Hcy-proteins, have been linked to the pathology of human cardiovascular and neurodegenerative diseases. Hcy-thiolactone is generated in an error-editing reaction in protein biosynthesis when Hcy is selected in place of methionine by methionyl-tRNA synthetase. N-Hcy-protein, in which Hcy is linked via isopeptide bond to ε-amino group of a protein lysine residue, forms in a post-translational reaction of Hcy-thiolactone with proteins. Here, we identify a novel metabolite, Nε-Hcy-Lys, in human and mouse plasma, and show that this metabolite is elevated in genetic (cystathionine β-synthase deficiency in humans and mice, methylenetetrahydrofolate reductase deficiency in mice) or dietary (high Met diet in mice) deficiencies in Hcy metabolism. We also show that Nε-Hcy-Lys is generated by proteolytic degradation of N-Hcy-protein in mouse liver extracts. Our data indicate that free Nε-Hcy-Lys is an important pathology-related component of Hcy metabolism in humans and mice.
Department of Environmental Chemistry, Łódź University, 90-236, Łódź, Poland.
Rafał
R
Głowacki
Edward
E
Bald
Hieronim
H
Jakubowski
D000818:Animals; D004151:Dipeptides / Q000097:blood* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D010455:Peptides / Q000097:blood*
D004151:Dipeptides; C556024:N(epsilon)-homocysteinyl-lysine; D010455:Peptides