title: Structural basis of D-DOPA oxidation by D-amino acid oxidase: alternative pathway for dopamine biosynthesis.
abstract: D-amino acid oxidase (DAO) degrades the gliotransmitter D-serine, a potent endogenous ligand of N-methyl-D-aspartate type glutamate receptors. It also has been suggested that D-DOPA, the stereoisomer of L-DOPA, is oxidized by DAO and then converted to dopamine via an alternative biosynthetic pathway. Here, we provide direct crystallographic evidence that D-DOPA is readily fitted into the active site of human DAO, where it is oxidized by the enzyme. Moreover, our kinetic data show that the maximal velocity for oxidation of D-DOPA is much greater than for D-serine, which strongly supports the proposed alternative pathway for dopamine biosynthesis in the treatment of Parkinson's disease. In addition, determination of the structures of human DAO in various states revealed that the conformation of the hydrophobic VAAGL stretch (residues 47-51) to be uniquely stable in the human enzyme, which provides a structural basis for the unique kinetic features of human DAO.
authors.affiliation: The Institute for Enzyme Research, The University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawazoe
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tsuge
authors.forename: Takahito
authors.initials: T
authors.lastname: Imagawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Aki
authors.forename: Seiki
authors.initials: S
authors.lastname: Kuramitsu
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukui
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D003460:Crystallization; D004295:Dihydroxyphenylalanine / Q000737:chemistry / Q000378:metabolism*; D004298:Dopamine / Q000096:biosynthesis*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D011994:Recombinant Proteins; D004295:Dihydroxyphenylalanine; D000594:Amino Acid Oxidoreductases; D004298:Dopamine