Abstract
Serine racemase (SR) generates D-serine, a coagonist with glutamate at NMDA receptors. We show that SR is physiologically S-nitrosylated leading to marked inhibition of enzyme activity. Inhibition involves interactions with the cofactor ATP reflecting juxtaposition of the ATP-binding site and cysteine-113 (C113), the site for physiological S-nitrosylation. NMDA receptor physiologically enhances SR S-nitrosylation by activating neuronal nitric-oxide synthase (nNOS). These findings support a model whereby postsynaptic stimulation of nitric-oxide (NO) formation feeds back to presynaptic cells to S-nitrosylate SR and decrease D-serine availability to postsynaptic NMDA receptors.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Animals
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Coenzymes / metabolism
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Cysteine / metabolism
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Enzyme Activation / drug effects
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Feedback, Physiological / drug effects*
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Humans
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Mice
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Models, Molecular
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Models, Neurological
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Molecular Sequence Data
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Nitric Oxide / pharmacology*
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Nitric Oxide Synthase Type I / metabolism
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Racemases and Epimerases / chemistry
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Racemases and Epimerases / metabolism*
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Receptors, N-Methyl-D-Aspartate / metabolism
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S-Nitrosoglutathione / pharmacology*
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Serine / biosynthesis*
Substances
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Coenzymes
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Receptors, N-Methyl-D-Aspartate
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Nitric Oxide
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Serine
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S-Nitrosoglutathione
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Adenosine Triphosphate
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Nitric Oxide Synthase Type I
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Racemases and Epimerases
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serine racemase
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Cysteine