The N-methyl D-aspartate receptor glycine site and D-serine metabolism: An evolutionary perspective

Michael J. Schell

Research output: Contribution to journalArticle

Abstract

The N-methyl D-aspartate (NMDA) type of glutamate receptor requires two distinct agonists to operate. Glycine is assumed to be the endogenous ligand for the NMDA receptor glycine site, but this notion has been challenged by the discovery of high levels of endogenous D-serine in the mammalian forebrain. I have outlined an evolutionary framework for the appearance of a glycine site in animals and the metabolic events leading to high levels of D-serine in brain. Sequence alignments of the glycine-binding regions, along with the scant experimental data available, suggest that the properties of invertebrate NMDA receptor glycine sites are probably different from those in vertebrates. The synthesis of D-serine in brain is due to a pyridoxal-5′-phosphate (B 6)-requiring serine racemase in glia. Although it remains unknown when serine racemase first evolved, data concerning the evolution of B 6 enzymes, along with the known occurrences of serine racemases in animals, point to D-serine synthesis arising around the divergence time of arthropods. D-Serine catabolism occurs via the ancient peroxisomal enzyme D-amino acid oxidase (DAO), whose ontogenetic expression in the hindbrain of mammals is delayed until the postnatal period and absent from the forebrain. The phylogeny of D-serine metabolism has relevance to our understanding of brain ontogeny, schizophrenia and neurotransmitter dynamics.

Original languageEnglish (US)
Pages (from-to)943-964
Number of pages22
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume359
Issue number1446
DOIs
StatePublished - Jun 29 2004
Externally publishedYes

Fingerprint

aspartic acid
N-Methyl-D-Aspartate Receptors
Metabolism
Glycine
serine
Serine
brain
metabolism
enzyme
Brain
catabolism
animal
Prosencephalon
ontogeny
arthropod
ligand
vertebrate
Animals
phylogeny
mammal

Keywords

  • D-amino acid
  • D-serine
  • Glutamate
  • Glycine
  • Racemase
  • Schizophrenia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Agricultural and Biological Sciences (miscellaneous)

Cite this

The N-methyl D-aspartate receptor glycine site and D-serine metabolism : An evolutionary perspective. / Schell, Michael J.

In: Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 359, No. 1446, 29.06.2004, p. 943-964.

Research output: Contribution to journalArticle

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