Structure of Mammalian Serine Racemase: EVIDENCE FOR CONFORMATIONAL CHANGES UPON INHIBITOR BINDING

Serine racemase is responsible for the synthesis of D-serine, an endogenous co-agonist for N-methyl-D-aspartate receptor-type glutamate receptors (NMDARs). This pyridoxal 5'-phosphate-dependent enzyme is involved both in the reversible conversion of L- to D-serine and serine catabolism by α,β-e...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-04, Vol.285 (17), p.12873-12881
Main Authors: Smith, Myron A, Mack, Volker, Ebneth, Andreas, Moraes, Isabel, Felicetti, Brunella, Wood, Michael, Schonfeld, Dorian, Mather, Owen, Cesura, Andrea, Barker, John
Format: Article
Language:English
Subjects:
Animals
Catalytic Domain
Crystallography, X-Ray
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - metabolism
Enzymology
Humans
Malonates - chemistry
Malonates - metabolism
Protein Binding
Protein Multimerization
Protein Structure and Folding
Protein Structure, Quaternary
Protein Structure, Tertiary
Pyridoxal Phosphate - chemistry
Pyridoxal Phosphate - genetics
Pyridoxal Phosphate - metabolism
Racemases and Epimerases - chemistry
Racemases and Epimerases - genetics
Racemases and Epimerases - metabolism
Rats
Receptors, N-Methyl-D-Aspartate - genetics
Receptors, N-Methyl-D-Aspartate - metabolism
Serine - biosynthesis
Serine - genetics
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Summary:Serine racemase is responsible for the synthesis of D-serine, an endogenous co-agonist for N-methyl-D-aspartate receptor-type glutamate receptors (NMDARs). This pyridoxal 5'-phosphate-dependent enzyme is involved both in the reversible conversion of L- to D-serine and serine catabolism by α,β-elimination of water, thereby regulating D-serine levels. Because D-serine affects NMDAR signaling throughout the brain, serine racemase is a promising target for the treatment of disorders related to NMDAR dysfunction. To provide a molecular basis for rational drug design the x-ray crystal structures of human and rat serine racemase were determined at 1.5- and 2.1-Å resolution, respectively, and in the presence and absence of the orthosteric inhibitor malonate. The structures revealed a fold typical of β-family pyridoxal 5'-phosphate enzymes, with both a large domain and a flexible small domain associated into a symmetric dimer, and indicated a ligand-induced rearrangement of the small domain that organizes the active site for specific turnover of the substrate.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.050062