Nitric oxide S-nitrosylates serine racemase, mediating feedback inhibition of D-serine formation.
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.
Mustafa
Asif K
AK
Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Kumar
Manish
M
Selvakumar
Balakrishnan
B
Ho
Gary P H
GP
Ehmsen
Jeffrey T
JT
Barrow
Roxanne K
RK
Amzel
L Mario
LM
Snyder
Solomon H
SH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D003067:Coenzymes / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D025461:Feedback, Physiological / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000494:pharmacology*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D019998:Racemases and Epimerases / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D026422:S-Nitrosoglutathione / Q000494:pharmacology*; D012694:Serine / Q000096:biosynthesis*; D000099300:Serine Racemase
D000255:Adenosine Triphosphate; D003067:Coenzymes; D003545:Cysteine; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; D019998:Racemases and Epimerases; D016194:Receptors, N-Methyl-D-Aspartate; D026422:S-Nitrosoglutathione; D012694:Serine; D000099300:Serine Racemase