Structure-function relationships in human d-amino acid oxidase

被引:82
作者
Sacchi, Silvia [1 ,2 ]
Caldinelli, Laura [1 ,2 ]
Cappelletti, Pamela [1 ]
Pollegioni, Loredano [1 ,2 ]
Molla, Gianluca [1 ,2 ]
机构
[1] Univ Insubria, Dipartimento Biotecnol & Sci Vita, I-21100 Varese, Italy
[2] Univ Insubria, Politecn Milan, Ctr Interuniv Biotecnol Proteiche, Prot Factory,ICRM,CNR Milano, I-21100 Varese, Italy
关键词
D-Serine; D-Amino acid oxidase; NMDA receptor; Schizophrenia; D-SERINE LEVELS; FREE D-ASPARTATE; KYNURENIC ACID; RAT-BRAIN; POSTNATAL CHANGES; GLYCINE SITE; SUSCEPTIBILITY GENE; CRYSTAL-STRUCTURE; ACTIVE-SITE; D-ALANINE;
D O I
10.1007/s00726-012-1345-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Since d-amino acids were identified in mammals, d-serine has been one of the most extensively studied "unnatural amino acids". This brain-enriched transmitter-like molecule plays a pivotal role in the human central nervous system by modulating the activity of NMDA receptors. Physiological levels of d-serine are required for normal brain development and function; thus, any alterations in neuromodulator concentrations might result in NMDA receptor dysfunction, which is known to be involved in several pathological conditions, including neurodegeneration(s), epilepsy, schizophrenia, and bipolar disorder. In the brain, the concentration of d-serine stored in cells is defined by the activity of two enzymes: serine racemase (responsible for both the synthesis and degradation) and d-amino acid oxidase (which catalyzes d-serine degradation). Both enzymes emerged recently as new potential therapeutic targets for NMDA receptor-related diseases. In this review we have focused on human d-amino acid oxidase and provide an extensive overview of the biochemical and structural properties of this flavoprotein and their functional significance. Furthermore, we discuss the mechanisms involved in modulating enzyme activity and stability with the aim to substantiate the pivotal role of d-amino acid oxidase in brain d-serine metabolism in physiological and pathological conditions and to highlight its great significance for novel drug design/development.
引用
收藏
页码:1833 / 1850
页数:18
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