Serine racemase modulates intracellular D-serine levels through an α,β-elimination activity

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

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151 Scopus citations

Abstract

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 α,β-elimination of water. The enzyme also catalyzes water α,β-elimination with L-serine and L-threonine. α,β- Elimination with these substrates is observed both in vitro and in vivo. To investigate further the role of α,β-elimination in regulating cellular D-serine, we generated a serine racemase mutant displaying selective impairment of α,β-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 α,β-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 α,β-elimination and racemization reactions. α,β-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 α,β-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 α,β-elimination, likely due to physical separation from serine racemase and its elimination activity.

Original languageEnglish (US)
Pages (from-to)1754-1763
Number of pages10
JournalJournal of Biological Chemistry
Volume280
Issue number3
DOIs
StatePublished - Jan 21 2005

ASJC Scopus subject areas

  • Biochemistry

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    Foltyn, V. N., Bendikov, I., De Miranda, J., Panizzutti, R., Dumin, E., Shleper, M., Li, P., Toney, M. D., Kartvelishvily, E., & Wolosker, H. (2005). Serine racemase modulates intracellular D-serine levels through an α,β-elimination activity. Journal of Biological Chemistry, 280(3), 1754-1763. https://doi.org/10.1074/jbc.M405726200