Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology.
Kynurenine 3-Monooxygenase: An Influential Mediator of Neuropathology.
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DOI：
10.3389/fpsyt.2015.00116
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发表时间：
2015
影响因子：
4.7
通讯作者：
O'Connor JC
中科院分区：
文献类型：
--
作者：
Parrott JM;O'Connor JC
越来越多的证据表明，犬尿氨酸代谢可能在多种神经和神经精神疾病的发生发展中发挥重要的致病作用。犬尿氨酸途径由两个功能不同的分支组成，它们同时产生神经活性代谢物和氧化反应性代谢物。在大脑中，其中一个分支的限速酶-犬尿氨酸3-单加氧酶(KMO)主要在小胶质细胞中表达，并已成为代谢调节的关键点。KMO底物和表达水平被促炎细胞因子上调，并被功能性基因突变改变。KMO代谢增加会导致代谢产物的形成，从而激活谷氨酸受体并增加氧化应激，而最近的证据表明，KMO活性降低会对神经发育造成影响。总而言之，证据表明，KMO处于一个关键的代谢连接点，可以影响无数神经疾病的发展或轨迹。了解KMO活性变化能够损害神经元功能和生存能力的机制(S)将增强我们对相关疾病病理学的知识，并为新的治疗机会提供洞察力。这篇综述将讨论KMO对脑犬尿氨酸代谢的影响，以及KMO活性改变可能导致神经发育、神经退行性疾病和神经精神疾病的分子机制的研究现状。
Mounting evidence demonstrates that kynurenine metabolism may play an important pathogenic role in the development of multiple neurological and neuropsychiatric disorders. The kynurenine pathway consists of two functionally distinct branches that generate both neuroactive and oxidatively reactive metabolites. In the brain, the rate-limiting enzyme for one of these branches, kynurenine 3-monooxygenase (KMO), is predominantly expressed in microglia and has emerged as a pivotal point of metabolic regulation. KMO substrate and expression levels are upregulated by pro-inflammatory cytokines and altered by functional genetic mutations. Increased KMO metabolism results in the formation of metabolites that activate glutamate receptors and elevate oxidative stress, while recent evidence has revealed neurodevelopmental consequences of reduced KMO activity. Together, the evidence suggests that KMO is positioned at a critical metabolic junction to influence the development or trajectory of a myriad of neurological diseases. Understanding the mechanism(s) by which alterations in KMO activity are able to impair neuronal function, and viability will enhance our knowledge of related disease pathology and provide insight into novel therapeutic opportunities. This review will discuss the influence of KMO on brain kynurenine metabolism and the current understanding of molecular mechanisms by which altered KMO activity may contribute to neurodevelopment, neurodegenerative, and neuropsychiatric diseases.