Structural basis of D-DOPA oxidation by D-amino acid oxidase: Alternative pathway for dopamine biosynthesis
Structural basis of D-DOPA oxidation by D-amino acid oxidase: Alternative pathway for dopamine biosynthesis
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DOI：
10.1016/j.bbrc.2007.01.181
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发表时间：
2007-04-06
影响因子：
3.1
通讯作者：
Fukui, Kiyoshi
中科院分区：
文献类型：
--
作者：
Kawazoe, Tomoya;Tsuge, Hideaki;Fukui, Kiyoshi
D-氨基酸氧化酶(DAO)降解神经胶质递质D-丝氨酸，D-丝氨酸是N-甲基-D-天冬氨酸型谷氨酸受体的内源性配体。也有人认为，L-多巴的立体异构体D-多巴可以被DAO氧化，然后通过另一种生物合成途径转化为多巴胺。在这里，我们提供了直接的结晶学证据，证明D-DOPA很容易被人DAO的活性部位所适合，在那里它被酶氧化。此外，我们的动力学数据显示，D-DOPA的最大氧化速度远远大于D-丝氨酸的氧化速度，这有力地支持了提出的治疗帕金森病的多巴胺生物合成的替代途径。此外，对人DAO在不同状态下的结构测定表明，疏水的VAAGL伸展部分(残基47-51)的构象在人酶中是唯一稳定的，这为人DAO独特的动力学特征提供了结构基础。(C)2007 Elsevier Inc.保留所有权利。
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. (c) 2007 Elsevier Inc. All rights reserved.