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Papers In Press, published online ahead of print May 31, 2005
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2
Corresponding Author: dennis.vance{at}ualberta.ca
Genetic ablation of phosphatidylethanolamine N-methyltransferase (PEMT) in mice causes a 50% reduction in plasma homocysteine (Hcy) levels. Since hyperhomocysteinemia is an independent risk factor for cardiovascular disease, resolution of the molecular basis for this reduction is of significant clinical interest. The PEMT pathway is a metabolically channeled process localized to the endoplasmic reticulum (ER). To assess the importance of PEMT localization for Hcy homeostasis, we identified and ablated the minimal ER targeting motif. Mutagenesis of a conserved, C terminal lysine residue (197) re-localized the enzyme to the Golgi, demonstrating that Lys-197 is essential for targeting PEMT to the ER. To evaluate the functional significance of PEMT localization, hepatoma cell lines were generated that stably express either ER- or Golgi-localized PEMT only. Intriguingly, stable expression of PEMT in either the ER or the Golgi caused increased Hcy secretion. Moreover, PEMT-mediated Hcy secretion correlated with the methyltransferase activity of the enzyme, independent of subcellular localization. Thus, our data suggest that Hcy homeostasis is regulated concomitantly with PEMT activity, but independently of PEMT localization.
J. Biol. Chem, 10.1074/jbc.M504658200
Submitted on April 28, 2005
Revised on May 27, 2005
Accepted on May 31, 2005
Localization-independent regulation of homocysteine secretion by phosphatidylethanolamine N-methyltransferase
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