Structural basis of kynurenine 3-monooxygenase inhibition.
Structural basis of kynurenine 3-monooxygenase inhibition.
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作者：
犬尿氨酸3-单加氧酶（KMO）（真核色氨酸分解代谢途径（即犬尿氨酸途径）中的酶）的抑制导致酵母、果蝇和小鼠模型以及阿尔茨海默病的小鼠模型中的亨廷顿病相关表型的改善。KMO是一种FAD依赖性单加氧酶，位于线粒体外膜中，将L-犬尿氨酸转化为3-羟基犬尿氨酸。犬尿氨酸途径代谢物水平的扰动与一系列脑疾病以及癌症和几种外周炎性病症的发病机制有关。尽管KMO作为神经退行性疾病的靶点的重要性，但可用的先导化合物抑制KMO的分子基础迄今为止仍然是未知的。在这里，我们报告的第一个晶体结构的KMO，在自由形式和复杂的紧密结合抑制剂UPF 648。UPF 648与FAD辅因子紧密结合，扰乱局部活性位点结构，阻止底物犬尿氨酸的有效结合。功能测定和靶向诱变显示，活性位点结构和UPF 648结合在人KMO中基本相同，验证了酵母KMO：UPF 648结构作为基于结构的药物设计的模板。这将为寻找新的KMO抑制剂提供信息，这些抑制剂能够在针对神经退行性疾病（如亨廷顿病、阿尔茨海默病和帕金森病）的靶向治疗中穿过血脑屏障。
Inhibition of kynurenine 3-monooxygenase (KMO), an enzyme in the eukaryotic tryptophan catabolic pathway (i.e. kynurenine pathway), leads to amelioration of Huntington’s disease-relevant phenotypes in yeast, fruit fly, and mouse models, as well as a mouse model of Alzheimer’s disease. KMO is a FAD-dependent monooxygenase, and is located in the outer mitochondrial membrane where it converts L-kynurenine to 3-hydroxykynurenine. Perturbations in the levels of kynurenine pathway metabolites have been linked to the pathogenesis of a spectrum of brain disorders, as well as cancer, and several peripheral inflammatory conditions. Despite the importance of KMO as a target for neurodegenerative disease, the molecular basis of KMO inhibition by available lead compounds has remained hitherto unknown. Here we report the first crystal structure of KMO, in the free form and in complex with the tight-binding inhibitor UPF 648. UPF 648 binds close to the FAD cofactor and perturbs the local active site structure, preventing productive binding of the substrate kynurenine. Functional assays and targeted mutagenesis revealed that the active site architecture and UPF 648 binding are essentially identical in human KMO, validating the yeast KMO:UPF 648 structure as a template for structure-based drug design. This will inform the search for new KMO inhibitors that are able to cross the blood-brain barrier in targeted therapies against neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s diseases.
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影响因子：
3.1
作者：
Clark, CJ;Mackay, GM;Phillips, RS
通讯作者：
Phillips, RS
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
4.8
作者：
Giorgini, Flaviano;Moller, Thomas;Muchowski, Paul J.
通讯作者：
Muchowski, Paul J.
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC