Journal
FASEB JOURNAL
Volume 24, Issue 3, Pages 931-936Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-144410
Keywords
cystathionine; beta-synthase deficiency; enzymatic activities of high-density lipoprotein; homocysteine-thiolactonase; protein modification by homocysteine-thiolactone
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Funding
- American Heart Association [0855919D]
- Ministry of Science and Higher Education, Warsaw, Poland [NN 401 230634, N401 065 32/1504, POIG.01.03.01-00-097/08]
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Genetic or nutritional disorders in homocysteine (Hcy) or folate metabolism elevate plasma Hcy-thiolactone and lead to vascular and/or brain pathologies. Hcy-thiolactone has the ability to form isopeptide bonds with protein lysine residues, which generates N-Hcy-protein with autoimmunogenic and prothrombotic properties. Paraoxonase (PON1), carried on high-density lipoproteins (HDLs) in the blood, hydrolyzes Hcy-thiolactone and protects against the accumulation of N-Hcy-protein in vitro. To determine its role in vivo, we studied how natural variation in Hcy-thiolactonase activity of PON1 affects plasma N-Hcy-protein levels in cystathionine beta-synthase-deficient patients (n = 28). We found that plasma N-Hcy-protein was negatively correlated with serum Hcy-thiolactonase activity (r = -0.43, P = 0.01), i.e., the higher the Hcy-thiolactonase activity, the lower N-Hcy protein levels. This relation was faithfully replicated in vitro in experiments with radiolabeled Hcy-thiolactone. We also found that enzymatic activities of the PON1 protein measured with artificial substrates correlated less strongly (r = -0.36, P = 0.025 for paraoxonase activity) or did not correlate at all (phenylacetate hydrolase and TBLase activities) with plasma N-Hcy protein. These findings provide evidence that the Hcy-thiolactonase activity of PON1 is a determinant of plasma N-Hcy-protein levels and that Hcy-thiolactonase/PON1 protects proteins against N-homocysteinylation in vivo, a novel mechanism likely to contribute to atheroprotective roles of HDL in humans.-Perla-Kajan, J., Jakubowski, H. Paraoxonase 1 protects against protein N-homocysteinylation in humans. FASEB J. 24, 931-936 (2010). www.fasebj.org
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