Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 98, Issue 9, Pages 5294-5299Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.091002298
Keywords
glutamate receptors; L-serine O-sulfate
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Serine racemase is a brain-enriched enzyme that synthesizes D-serine. an endogenous modulator of the glycine site of N-methyl-D-aspartate (NMDA) receptors, We now report that serine racemase catalyzes an elimination reaction toward a nonphysiological substrate that provides a powerful tool to study its neurobiological role and will be useful to develop selective enzyme inhibitors. Serine racemase catalyzes robust elimination of L-serine O-sulfate that is 500 times faster than the physiological racemization reaction, generating sulfate, ammonia, and pyruvate, This reaction provides the most simple and sensitive assay to detect the enzyme activity so far. We establish stable cell lines expressing serine racemase and show that serine racemase can also be converted into a powerful eliminase in cultured cells, while the racemization of L-serine is inhibited. Likewise, L-serine O-sulfate inhibits the synthesis of D-serine in primary astrocyte cultures, We conclude that the synthetic compound I-serine O-sulfate is a better substrate than L-serine as well as an inhibitor of D-serine synthesis. Inhibition of serine racemase provides a new strategy to selectively decrease NMDA receptor coactivation and may be useful in conditions in which overstimulation of NMDA receptors plays a pathological role.
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