Abstract
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.
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Acknowledgments
This work was supported in part by grants from the American Heart Association (0855919D) and the Ministry of Science and Higher Education, Poland (NN 401 230634, N401 065 32/1504, POIG.01.03.01-00-097/08).
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Głowacki, R., Bald, E. & Jakubowski, H. Identification and origin of Nε-homocysteinyl-lysine isopeptide in humans and mice. Amino Acids 39, 1563–1569 (2010). https://doi.org/10.1007/s00726-010-0627-y
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DOI: https://doi.org/10.1007/s00726-010-0627-y