Human DJ-1 and its homologs are novel glyoxalases
Human DJ-1 and its homologs are novel glyoxalases
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DOI：
10.1093/hmg/dds155
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发表时间：
2012-07-15
影响因子：
3.5
通讯作者：
Park, Chankyu
中科院分区：
文献类型：
--
作者：
Lee, Ju-young;Song, Jeeyeon;Park, Chankyu
人类DJ-1是早发性帕金森病（PD）的遗传原因，尽管其生化功能尚不清楚。我们在这里报道，人类DJ-1及其小鼠和秀丽隐杆线虫的同源物是新型的乙二醛酶，在缺乏谷胱甘肽的情况下，分别将乙二醛或甲基乙二醛转化为乙醇酸或乳酸。纯化的DJ-1蛋白表现出典型的MichaelisMenten动力学，该动力学在必需催化残基（包括半胱氨酸和谷氨酸）的突变体中完全被废除。DJ-1的存在保护小鼠胚胎成纤维细胞和多巴胺能来源的SH-SY5Y细胞免受乙二醛的处理。同样，秀丽隐杆线虫缺乏cDJR-1.1（主要在肠道中表达的DJ-1同源物），可以保护线虫免受乙二醛诱导的死亡。亚致死剂量的乙二醛导致缺乏cDJR-1.2的秀丽隐杆线虫多巴胺能神经元显著变性，cDJR-1.2是另一种主要在头部区域表达的DJ-1同源物，包括神经元。我们发现DJ-1可以作为活性羰基物质的清除剂，这可能为PD的病因提供新的见解。
Human DJ-1 is a genetic cause of early-onset Parkinsons disease (PD), although its biochemical function is unknown. We report here that human DJ-1 and its homologs of the mouse and Caenorhabditis elegans are novel types of glyoxalase, converting glyoxal or methylglyoxal to glycolic or lactic acid, respectively, in the absence of glutathione. Purified DJ-1 proteins exhibit typical MichaelisMenten kinetics, which were abolished completely in the mutants of essential catalytic residues, consisting of cysteine and glutamic acid. The presence of DJ-1 protected mouse embryonic fibroblast and dopaminergically derived SH-SY5Y cells from treatments of glyoxals. Likewise, C. elegans lacking cDJR-1.1, a DJ-1 homolog expressed primarily in the intestine, protected worms from glyoxal-induced death. Sub-lethal doses of glyoxals caused significant degeneration of the dopaminergic neurons in C. elegans lacking cDJR-1.2, another DJ-1 homolog expressed primarily in the head region, including neurons. Our findings that DJ-1 serves as scavengers for reactive carbonyl species may provide a new insight into the causation of PD.