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

J. Biol. Chem., Vol. 280, Issue 3, 1754-1763, January 21, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/3/1754    most recent M405726200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Foltyn, V. N. Articles by Wolosker, H. Search for Related Content PubMed PubMed Citation Articles by Foltyn, V. N. Articles by Wolosker, H. Social Bookmarking                      What's this?

Serine Racemase Modulates Intracellular D-Serine Levels through an ,-Elimination Activity^*

Veronika N. Foltyn, Inna Bendikov, Joari De Miranda, Rogerio Panizzutti, Elena Dumin, Maria Shleper, Pu Li¶, Michael D. Toney¶, Elena Kartvelishvily, and Herman Wolosker||

From the Department of Biochemistry, Technion-Israel Institute of Technology, The B. Rappaport Faculty of Medicine, Haifa 31096, Israel, the Department of Biochemistry, Federal University of Rio de Janeiro, Rio de Janeiro RJ 21941-590, Brazil, and the ^¶Department of Chemistry, University of California, Davis, California 95616

Mammalian brain contains high levels of D-serine, an endogenous co-agonist of N-methyl D-aspartate type of glutamate receptors. D-Serine is synthesized by serine racemase, a brain enriched enzyme converting L- to D-serine. Degradation of D-serine is achieved by D-amino acid oxidase, but this enzyme is not present in forebrain areas that are highly enriched in D-serine. We now report that serine racemase catalyzes the degradation of cellular D-serine itself, through the ,-elimination of water. The enzyme also catalyzes water ,-elimination with L-serine and L-threonine. ,-Elimination with these substrates is observed both in vitro and in vivo. To investigate further the role of ,-elimination in regulating cellular D-serine, we generated a serine racemase mutant displaying selective impairment of ,-elimination activity (Q155D). Levels of D-serine synthesized by the Q155D mutant are several-fold higher than the wild-type both in vitro and in vivo. This suggests that the ,-elimination reaction limits the achievable D-serine concentration in vivo. Additional mutants in vicinal residues (H152S, P153S, and N154F) similarly altered the partition between the ,-elimination and racemization reactions. ,-Elimination also competes with the reverse serine racemase reaction in vivo. Although the formation of L- from D-serine is readily detected in Q155D mutant-expressing cells incubated with physiological D-serine concentrations, reversal with wild-type serine racemase-expressing cells required much higher D-serine concentration. We propose that ,-elimination provides a novel mechanism for regulating intracellular D-serine levels, especially in brain areas that do not possess D-amino acid oxidase activity. Extracellular D-serine is more stable toward ,-elimination, likely due to physical separation from serine racemase and its elimination activity.

Received for publication, May 24, 2004 , and in revised form, October 12, 2004.

^* This work was supported by the Israel Science Foundation, Mallat Family Fund, and Gabriel and Matilda Barnett Foundation (to H. W.) and by National Institutes of Health Grant GM54779 (to M. D. T.). 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.

^|| To whom correspondence should be addressed: Tel.: 972-4-829-5386; Fax: 972-4-829-5384; E-mail: hwolosker{at}tx.technion.ac.il.

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

This article has been cited by other articles:

				H. Tanaka, A. Yamamoto, T. Ishida, and K. Horiike D-Serine Dehydratase from Chicken Kidney: A Vertebral Homologue of the Cryptic Enzyme from Burkholderia cepacia J. Biochem., January 1, 2008; 143(1): 49 - 57. [Abstract] [Full Text] [PDF]

				O. B. Bleijerveld, J. F. H. M. Brouwers, A. B. Vaandrager, J. B. Helms, and M. Houweling The CDP-ethanolamine Pathway and Phosphatidylserine Decarboxylation Generate Different Phosphatidylethanolamine Molecular Species J. Biol. Chem., September 28, 2007; 282(39): 28362 - 28372. [Abstract] [Full Text] [PDF]

				A. K. Mustafa, M. Kumar, B. Selvakumar, G. P. H. Ho, J. T. Ehmsen, R. K. Barrow, L. M. Amzel, and S. H. Snyder Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of D-serine formation PNAS, February 20, 2007; 104(8): 2950 - 2955. [Abstract] [Full Text] [PDF]

				H. Wolosker D-Serine Regulation of NMDA Receptor Activity Sci. Signal., October 10, 2006; 2006(356): pe41 - pe41. [Abstract] [Full Text] [PDF]

				E. Dumin, I. Bendikov, V. N. Foltyn, Y. Misumi, Y. Ikehara, E. Kartvelishvily, and H. Wolosker Modulation of D-Serine Levels via Ubiquitin-dependent Proteasomal Degradation of Serine Racemase J. Biol. Chem., July 21, 2006; 281(29): 20291 - 20302. [Abstract] [Full Text] [PDF]

				E. Kartvelishvily, M. Shleper, L. Balan, E. Dumin, and H. Wolosker Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors J. Biol. Chem., May 19, 2006; 281(20): 14151 - 14162. [Abstract] [Full Text] [PDF]