Calcium-dependent human serum homocysteine thiolactone hydrolase. A protective mechanism against protein N-homocysteinylation

Homocysteine thiolactone is formed in all cell types studied thus far as a result of editing reactions of some aminoacyl-tRNA synthetases. Because inadvertent reactions of thiolactone with proteins are potentially harmful, the ability to detoxify homocysteine thiolactone is essential for biological...

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Bibliographic Details
Published in:The Journal of biological chemistry 2000-02, Vol.275 (6), p.3957-3962
Main Author: Jakubowski, H
Format: Article
Language:English
Subjects:
Amino Acids - pharmacology
Arteriosclerosis - metabolism
Aryldialkylphosphatase
Calcium - metabolism
Enzyme Inhibitors - pharmacology
Esterases - blood
Esterases - chemistry
Esterases - isolation & purification
Homocysteine - analogs & derivatives
Homocysteine - blood
Homocysteine - metabolism
homocysteine thiolactone
Humans
Kinetics
Lipoproteins, HDL - metabolism
paraoxonase
Penicillamine - pharmacology
Sequence Analysis
Substrate Specificity
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Summary:Homocysteine thiolactone is formed in all cell types studied thus far as a result of editing reactions of some aminoacyl-tRNA synthetases. Because inadvertent reactions of thiolactone with proteins are potentially harmful, the ability to detoxify homocysteine thiolactone is essential for biological integrity. This work shows that a single specific enzyme, present in mammalian but not in avian sera, hydrolyzes thiolactone to homocysteine. Human serum thiolactonase, a 45-kDa protein component of high density lipoprotein, requires calcium for activity and stability and is inhibited by isoleucine and penicillamine. Substrate specificity studies suggest that homocysteine thiolactone is a likely natural substrate of this enzyme. However, thiolactonase also hydrolyzes non-natural substrates, such as phenyl acetate, p-nitrophenyl acetate, and the organophospate paraoxon. N-terminal amino acid sequence of pure thiolactonase is identical with that of human paraoxonase. These and other data indicate that paraoxonase, an organophosphate-detoxifying enzyme whose natural substrate and function remained unknown up to now, is in fact homocysteine thiolactonase. By detoxifying homocysteine thiolactone, the thiolactonase/paraoxonase would protect proteins against homocysteinylation, a potential contributing factor to atherosclerosis.
ISSN:0021-9258
DOI:10.1074/jbc.275.6.3957