HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 29, 27339-27344, July 22, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/29/27339    most recent M504658200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shields, D. J. Articles by Vance, D. E. Search for Related Content PubMed PubMed Citation Articles by Shields, D. J. Articles by Vance, D. E. Social Bookmarking                      What's this?

Localization-independent Regulation of Homocysteine Secretion by Phosphatidylethanolamine N-Methyltransferase^*

David J. Shields, Susanne Lingrell, Luis B. Agellon, John T. Brosnan¶||, and Dennis E. Vance**

From the Department of Biochemistry and Canadian Institutes of Health Research Group on Molecular & Cell Biology of Lipids, University of Alberta, Edmonton, Alberta T6G 2S2, Canada and ^¶Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada

Genetic ablation of phosphatidylethanolamine N-methyltransferase (PEMT) in mice causes a 50% reduction in plasma homocysteine (Hcy) levels. Because 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) relocalized 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 expressed 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, independently of subcellular localization. Thus, our data suggest that Hcy homeostasis is regulated concomitantly with PEMT activity but independently of PEMT localization.

Received for publication, April 28, 2005 , and in revised form, May 27, 2005.

^* This research was supported in part by grants from the Canadian Institutes for Health Research (CIHR) and the Canadian Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a studentship from the Alberta Heritage Foundation for Medical Research. Current address: The Scripps Research Institute, 10550 N. Torrey Pines Rd. (IMM-24), La Jolla, CA 92037.

^|| CIHR Senior Investigator.

^** Canada Research Chair in Molecular and Cell Biology of Lipids and Heritage Medical Scientist of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: 328 HMRC, Dept. of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Tel.: 780-492-8286; E-mail: Dennis.Vance{at}ualberta.ca.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. Aktas and F. Narberhaus In Vitro Characterization of the Enzyme Properties of the Phospholipid N-Methyltransferase PmtA from Agrobacterium tumefaciens J. Bacteriol., April 1, 2009; 191(7): 2033 - 2041. [Abstract] [Full Text] [PDF]

				C.J. Carter Schizophrenia Susceptibility Genes Directly Implicated in the Life Cycles of Pathogens: Cytomegalovirus, Influenza, Herpes simplex, Rubella, and Toxoplasma gondii Schizophr Bull, June 13, 2008; (2008) sbn054v1. [Abstract] [Full Text] [PDF]

				D. E. Vance, Z. Li, and R. L. Jacobs Hepatic Phosphatidylethanolamine N-Methyltransferase, Unexpected Roles in Animal Biochemistry and Physiology J. Biol. Chem., November 16, 2007; 282(46): 33237 - 33241. [Full Text] [PDF]

				K. T. Williams and K. L. Schalinske New Insights into the Regulation of Methyl Group and Homocysteine Metabolism J. Nutr., February 1, 2007; 137(2): 311 - 314. [Abstract] [Full Text] [PDF]

				S H. Mudd, J. T Brosnan, M. E Brosnan, R. L Jacobs, S. P Stabler, R. H Allen, D. E Vance, and C. Wagner Methyl balance and transmethylation fluxes in humans Am. J. Clinical Nutrition, January 1, 2007; 85(1): 19 - 25. [Abstract] [Full Text] [PDF]

				C. S. Hartz, K. M. Nieman, R. L. Jacobs, D. E. Vance, and K. L. Schalinske Hepatic Phosphatidylethanolamine N-Methyltransferase Expression Is Increased in Diabetic Rats J. Nutr., December 1, 2006; 136(12): 3005 - 3009. [Abstract] [Full Text] [PDF]

				K. M. Nieman, C. S. Hartz, S. S. Szegedi, T. A. Garrow, J. D. Sparks, and K. L. Schalinske Folate status modulates the induction of hepatic glycine N-methyltransferase and homocysteine metabolism in diabetic rats Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1235 - E1242. [Abstract] [Full Text] [PDF]