Serine racemase: A glial enzyme synthesizing d -serine to regulate glutamate- N -methyl- d -aspartate neurotransmission

Serine racemase: A glial enzyme synthesizing d-serine to regulate glutamate-N-methyl-d-aspartate neurotransmission

Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry, The Johns Hopkins University, School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205

Contributed by Solomon H. Snyder

Abstract

Although d amino acids are prominent in bacteria, they generally are thought not to occur in mammals. Recently, high levels of d-serine have been found in mammalian brain where it activates glutamate/N-methyl-d-aspartate receptors by interacting with the “glycine site” of the receptor. Because amino acid racemases are thought to be restricted to bacteria and insects, the origin of d-serine in mammals has been puzzling. We now report cloning and expression of serine racemase, an enzyme catalyzing the formation of d-serine from l-serine. Serine racemase is a protein representing an additional family of pyridoxal-5′ phosphate-dependent enzymes in eukaryotes. The enzyme is enriched in rat brain where it occurs in glial cells that possess high levels of d-serine in vivo. Occurrence of serine racemase in the brain demonstrates the conservation of d-amino acid metabolism in mammals with implications for the regulation of N-methyl-d-aspartate neurotransmission through glia-neuronal interactions.

Footnotes

↵ * Present address: Departamento de Bioquimica, ICB/CCS, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21941–590, Brazil.
↵ † Present address: Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115.
↵ ‡ To whom reprint requests should be addressed. E-mail: ssnyder{at}jhmi.edu.
Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. AF148321).
Abbreviations:

NMDA,

N-methyl-d-aspartate;

EST,

expressed sequence tag;

GFAP,

glial fibrillary acidic protein