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Protein N-homocysteinylation: implications for atherosclerosis
1Department of Microbiology & Molecular Genetics, UMDNJ-New Jersey Medical School, Newark 07103, USA. jakubows@umdnj.edu
Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|November 1, 2001
Summary
Elevated homocysteine (Hcy) can damage cells through protein N-homocysteinylation. This occurs via translational or post-translational pathways, influenced by factors linked to cardiovascular disease.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Elevated homocysteine (Hcy) is linked to cardiovascular disease, but the exact mechanism of cellular damage is unclear.
- Protein N-homocysteinylation, the incorporation of Hcy into proteins, is a proposed mechanism for Hcy-induced cell damage.
- This process can occur through both translational and post-translational pathways.
Purpose of the Study:
- To elucidate the mechanisms by which homocysteine damages cells.
- To investigate the pathways of protein N-homocysteinylation.
- To identify factors influencing Hcy levels and protein modification in cardiovascular disease.
Main Methods:
- Described two pathways for protein N-homocysteinylation: a translational pathway involving S-nitrosylation and aminoacylation, and a post-translational pathway involving Hcy thiolactone.
- Investigated the role of methionyl-tRNA synthetase (MetRS) in Hcy metabolism and protein modification.
- Examined the influence of Hcy/methionine ratio, folic acid, and HDL on Hcy thiolactone and N-homocysteinylated protein levels in vascular endothelial cells.
Main Results:
- Identified a translational pathway where S-nitroso-Hcy is incorporated into proteins via tRNAMet.
- Identified a post-translational pathway where Hcy thiolactone acylates protein lysine residues.
- Demonstrated that Hcy/Met ratio, folic acid, and HDL levels affect N-homocysteinylated protein and Hcy thiolactone levels.
- Highlighted the protective role of HDL-associated Hcy thiolactonase/paraoxonase in hydrolyzing Hcy thiolactone.
Conclusions:
- Protein N-homocysteinylation is a significant mechanism for homocysteine-induced cellular damage.
- The interplay between Hcy metabolism, protein modification pathways, and factors like HDL is crucial in Hcy-associated cardiovascular disease.
- Variations in Hcy thiolactonase activity may contribute to the risk of cardiovascular pathologies linked to elevated homocysteine.