D-Serine is an endogenous coagonist for the N-methyl-D-as-partate receptor and is involved in excitatory neurotransmission in the brain. Mammalian pyridoxal 5 -phosphate-dependent serine racemase, which is localized in the mammalian brain, catalyzes the racemization of L-serine to yield D-serine and vice versa. The enzyme also catalyzes the dehydration of D-and L-serine. Both reactions are enhanced by Mg⅐ATP in vivo. We have determined the structures of the following three forms of the mammalian enzyme homolog from Schizosaccharomyces pombe: the wild-type enzyme, the wild-type enzyme in the complex with an ATP analog, and the modified enzyme in the complex with serine at 1.7, 1.9, and 2.2 Å resolution, respectively. On binding of the substrate, the small domain rotates toward the large domain to close the active site. The ATP binding site was identified at the domain and the subunit interface. Computer graphics models of the wild-type enzyme complexed with L-serine and D-serine provided an insight into the catalytic mechanisms of both reactions. Lys-57 and Ser-82 located on the protein and solvent sides, respectively, with respect to the cofactor plane, are acid-base catalysts that shuttle protons to the substrate. The modified enzyme, which has a unique "lysino-D-alanyl" residue at the active site, also exhibits catalytic activities. The crystal-soaking experiment showed that the substrate serine was actually trapped in the active site of the modified enzyme, suggesting that the lysino-D-alanyl residue acts as a catalytic base in the same manner as inherent Lys-57 of the wildtype enzyme.D-Serine, which is present at a high level in the mammalian brain, serves as an endogenous coagonist for the N-methyl-Daspartate (NMDA) 5 receptor selectively localized on the postsynaptic membrane of the excitatory synapse (1-5) and is involved in excitatory neurotransmission and higher brain functions such as learning and memory (3, 6, 7). Stimulation of the NMDA receptor requires the binding of D-serine as well as the agonist L-glutamate. The major enzyme for D-serine synthesis from L-serine in the brain is considered to be pyridoxal 5Ј-phosphate (PLP)-dependent serine racemase (SR) (8 -10). D-Serine and SR are localized on protoplasmic astrocytes that have the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor. Glutamate released from presynaptic neurons approaches and activates the ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, which in turn induces SR to produce D-serine and is followed by D-serine release from astrocytes that act on the NMDA receptor. Recently, it was shown that not only glia but also neurons synthesize and release D-serine involved in signaling (11). SR also catalyzes ␣,-elimination of water from D-or L-serine to form pyruvate and ammonia as well as the conversion of L-serine into D-serine and vice versa and is presumed to link D-serine synthesis and energy metabolism of astrocytes (12) and to control the D-serine level (13). Mg⅐ATP, which is fully bound to SR under physiologi...
Serine racemase synthesizes d-serine, a physiological agonist of the NMDA receptor in mammalian brains. Schizosaccharomyces pombe produces serine racemase (spSR) that is highly similar to the brain enzyme. Our mass-spectrometric and X-ray studies revealed that spSR is modified with its natural substrate serine. spSR remains partially active even though its essential Lys57 inherently forming a Schiff base with the coenzyme pyridoxal 5'-phosphate is converted to N(6)-(R-2-amino-2-carboxyethyl)-l-lysyl (lysino-d-alanyl) residue. This indicates that the alpha-amino group of the d-alanyl moiety of the lysino-d-alanyl residue serves as a catalytic base in the same manner as the epsilon-amino group of Lys57 of the original spSR.
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