The Mechanism and Consequences of Homocysteine Incorporation Into Protein in Humans

Abstract

Protein-related homocysteine (Hcy) metabolism generates Hcy-thiolactone thioester (1), N-Hcy-protein adducts (2), and Nϵ-Hcy-Lys) isopeptide (3). (1) is generated in an enzymatic error-editing reaction in protein biosynthesis when Hcy is erroneously selected in place of methionine by methionyl-tRNA synthetase. The Hcy editing reaction and the biosynthesis of (1) are universally conserved from bacteria to humans. (2) is formed in a chemical reaction of (1) with ϵ-amino groups of protein lysine residues in mice and humans. (3) is a product of proteolytic degradation of (2) that occurs in mice and humans. Chemical biology and pathophysiology of these metabolites is summarized in this review.

GRAPHICAL ABSTRACT

Keywords:

• Homocysteine thiolactone
• protein modification
• genetic & nutritional hyperhomocysteinemia
• cardiovascular disease
• neurodegenerative disease

Acknowledgments

Supported in part by grants 2011/01/B/NZ1/03417 and 2011/02/A/NZ1/00010 from the National Science Center, Poland.