The Structure of Mammalian Serine Racemase

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.