A new strategy to decrease N-methyl-D-aspartate (NMDA) receptor coactivation: inhibition of D-serine synthesis by converting serine racemase into an eliminase.
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 l-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.
Panizzutti
R
R
Departamento de Bioquimica Medica, Instituto de Ciencias Biomedicas, and Center for Neurodegenerative Diseases, Departamento de Anatomia, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21491-590, Brazil.
De Miranda
J
J
Ribeiro
C S
CS
Engelender
S
S
Wolosker
H
H
D000641:Ammonia / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D051379:Mice; D019289:Pyruvic Acid / Q000737:chemistry / Q000378:metabolism; D019998:Racemases and Epimerases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D000099300:Serine Racemase
D000641:Ammonia; D019289:Pyruvic Acid; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D012694:Serine; D000099300:Serine Racemase; C036040:serine O-sulfate