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J Biol Chem, Vol. 275, Issue 6, 3957-3962, February 11, 2000
From the Department of Microbiology and Molecular Genetics,
University of Medicine and Dentistry of New Jersey, New Jersey
Medical School, Newark, New Jersey 07103
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.
Calcium-dependent Human Serum Homocysteine
Thiolactone Hydrolase
A PROTECTIVE MECHANISM AGAINST PROTEIN
N-HOMOCYSTEINYLATION*
*
This work was supported by National Science Foundation Grant
MCB-972-4929.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Microbiology
and Molecular Genetics, UMDNJ-New Jersey Medical School, 185 S. Orange
Ave., Newark, NJ 07103. Tel.: 973-972-4679; Fax: 973-972-3644; E-mail:
jakubows@umdnj.edu.
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