Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels

ABSTRACT Homocysteine thiolactone, a cyclic thioester, is synthesized by certain aminoacyl‐tRNA synthetases in editing or proofreading reactions that prevent translational incorporation of homocysteine into proteins. Although homocysteine thiolactone is expected to acylate amino groups in proteins,...

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Bibliographic Details
Published in:The FASEB journal 1999-12, Vol.13 (15), p.2277-2283
Main Author: JAKUBOWSKI, HIERONIM
Format: Article
Language:English
Subjects:
atherosclerosis
Blood Proteins - metabolism
Escherichia coli
Homocysteine - analogs & derivatives
Homocysteine - blood
Homocysteine - metabolism
homocysteine thiolactone
Humans
In Vitro Techniques
Kinetics
Protein Denaturation
Sulfur Radioisotopes
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Summary:ABSTRACT Homocysteine thiolactone, a cyclic thioester, is synthesized by certain aminoacyl‐tRNA synthetases in editing or proofreading reactions that prevent translational incorporation of homocysteine into proteins. Although homocysteine thiolactone is expected to acylate amino groups in proteins, virtually nothing is known regarding reactivity of the thiolactone. Here it is shown that reactions of the thiolactone with protein lysine residues were robust under physiological conditions. In human serum incubated with homocysteine thiolactone, protein homocysteinylation was a major reaction that could be observed with as little as 10 nM thiolactone. Individual proteins were homocysteinylated at rates proportional to their lysine contents. Homocysteinylation led to protein damage, manifested as multimerization and precipitation of extensively modified proteins. Model enzymes, such as methionyl‐tRNA synthetase and trypsin, were inactivated by homocysteinylation. Metabolic conversion of homocysteine to the thiolactone, protein homocysteinylation, and resulting protein damage may underlie involvement of Hcy in the pathology of vascular disease.—Jakubowski, H. Protein homocysteinylation: possible mechanism underlying pathological consequences of elevated homocysteine levels. FASEB J. 13, 2277–2283 (1999)
ISSN:0892-6638
1530-6860
DOI:10.1096/fasebj.13.15.2277