3ZNQ

IN VITRO AND IN VIVO INHIBITION OF HUMAN D-AMINO ACID OXIDASE: REGULATION OF D-SERINE CONCENTRATION IN THE BRAIN

Summary for 3ZNQ

• Entry DOI: 10.2210/pdb3znq/pdb
• Related: 3ZNN 3ZNO 3ZNP
• Descriptor: D-AMINO-ACID OXIDASE, FLAVIN-ADENINE DINUCLEOTIDE, 3-PHENETHYL-4H-FURO[3,2-B]PYRROLE-5-CARBOXYLIC ACID, ... (4 entities in total)
• Functional Keywords: oxidoreductase, neurotransmission
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Peroxisome: P14920
• Total number of polymer chains: 2
• Total formula weight: 80866.17

Authors

Hopkins, S.C.,Heffernan, M.L.R.,Saraswat, L.D.,Bowen, C.A.,Melnick, L.,Hardy, L.W.,Orsini, M.A.,Allen, M.S.,Koch, P.,Spear, K.L.,Foglesong, R.J.,Soukri, M.,Chytil, M.,Fang, Q.K.,Jones, S.W.,Varney, M.A.,Panatier, A.,Oliet, S.H.R.,Pollegioni, L.,Piubelli, L.,Molla, G.,Nardini, M.,Large, T.H. (deposition date: 2013-02-15, release date: 2013-05-15, Last modification date: 2023-12-20)

Primary citation

Hopkins, S.C.,Heffernan, M.L.R.,Saraswat, L.D.,Bowen, C.A.,Melnick, L.,Hardy, L.W.,Orsini, M.A.,Allen, M.S.,Koch, P.,Spear, K.L.,Foglesong, R.J.,Soukri, M.,Chytil, M.,Fang, Q.K.,Jones, S.W.,Varney, M.A.,Panatier, A.,Oliet, S.H.R.,Pollegioni, L.,Piubelli, L.,Molla, G.,Nardini, M.,Large, T.H.
Structural, Kinetic, and Pharmacodynamic Mechanisms of D-Amino Acid Oxidase Inhibition by Small Molecules.
J.Med.Chem., 56:3710-, 2013

PubMed Abstract: We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 μM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.

PubMed: 23631755
DOI: 10.1021/JM4002583

Experimental method

X-RAY DIFFRACTION (2.75 Å)