Gilead Sciences and IOCB Research Center Prague, Institute of Organic Chemistry and Biochemistry, Academy of Science of the Czech Republic, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
Curr Drug Targets. 2011 Jun;12(7):1037-55. doi: 10.2174/138945011795677755.
Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders; however, their effect is often compromised by undesirable side effects. Therefore, alternative ways of modulating NMDA receptor function need to be sought after. The opening of the NMDA receptor ion channel requires occupation of two distinct binding sites, the glutamate site and the glycine site. It has been shown that D-serine, rather than glycine, can trigger the physiological NMDA receptor function. D-serine is a product of the activity of a specific enzyme, serine racemase (SR), which was identified a decade ago. SR has therefore emerged as a new potential target for the NMDA-receptor-based diseases. There is evidence linking increased levels of D-Ser to amyotrophic lateral sclerosis and Alzheimer's disease and decreased concentrations of D-serine to schizophrenia. SR is a pyridoxal-5'-phosphate dependent enzyme found in the cytosol of glial and neuronal cells. It is activated by ATP, divalent cations like Mg(2+) or Ca(2+), and reducing agents. This paper reviews the present literature on the activity and inhibition of mammalian SRs. It summarizes approaches that have been applied to design SR inhibitors and lists the known active compounds. Based on biochemical and docking analyses, i) we delineate for the first time the ATP binding site of human SR, and ii) we suggest possible mechanisms of action for the active compounds. In the end, we discuss the SR features that make the discovery of its inhibitors a challenging, yet very important, task of medicinal chemistry.
谷氨酸能 NMDA 受体信号通路的蛋白已被研究作为多种神经病理学疾病（包括神经退行性疾病、癫痫、神经病理性疼痛、药物成瘾和精神分裂症）干预的靶点。高活性 NMDA 阻断剂已被设计用于治疗其中一些疾病；然而，它们的效果往往因不良副作用而受到影响。因此，需要寻找替代方法来调节 NMDA 受体功能。NMDA 受体离子通道的开放需要占据两个不同的结合位点，即谷氨酸结合位点和甘氨酸结合位点。已经表明，D-丝氨酸而不是甘氨酸可以触发生理 NMDA 受体功能。D-丝氨酸是一种特定酶，即丝氨酸消旋酶（SR）的产物，该酶在十年前被鉴定出来。因此，SR 已成为基于 NMDA 受体疾病的新的潜在靶点。有证据表明，D-丝氨酸水平升高与肌萎缩侧索硬化症和阿尔茨海默病有关，而 D-丝氨酸浓度降低与精神分裂症有关。SR 是一种依赖于吡哆醛-5'-磷酸的酶，存在于神经胶质细胞和神经元细胞的细胞质中。它被 ATP、二价阳离子（如 Mg(2+)或 Ca(2+)）和还原剂激活。本文综述了目前关于哺乳动物 SR 活性和抑制的文献。它总结了用于设计 SR 抑制剂的方法，并列出了已知的活性化合物。基于生化和对接分析，i）我们首次描绘了人 SR 的 ATP 结合位点，和 ii）我们提出了活性化合物的可能作用机制。最后，我们讨论了 SR 的特征，这些特征使得发现其抑制剂成为药物化学中一项具有挑战性但非常重要的任务。
