Parkinson's disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro.
Parkinson's disease-related DJ-1 functions in thiol quality control against aldehyde attack in vitro.
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DOI：
10.1038/s41598-017-13146-0
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发表时间：
2017-10-09
影响因子：
4.6
通讯作者：
Tanaka K
中科院分区：
文献类型：
--
作者：
Matsuda N;Kimura M;Queliconi BB;Kojima W;Mishima M;Takagi K;Koyano F;Yamano K;Mizushima T;Ito Y;Tanaka K
DJ-1（也称为PARK 7）已被鉴定为遗传性隐性帕金森病（PD）的致病基因。因此，充分阐明DJ-1的功能将有助于破译PD发病机制的分子机制。然而，由于各种，有时不一致，DJ-1的作用已被报道，DJ-1的分子功能仍然存在争议。近年来，大量的研究表明DJ-1家族蛋白参与了乙醛的解毒过程。我们发现DJ-1确实将甲基乙二醛（乙醛）加合的谷胱甘肽（GSH）转化为完整的GSH和乳酸盐。基于DJ-1在线粒体内稳态中起作用的证据，我们关注DJ-1保护辅酶A（CoA）及其合成途径中的前体免受醛攻击的可能性。在这里，我们表明，完整的CoA和β-丙氨酸，CoA合成的中间体，从甲基甘氨酸加合物回收重组DJ-1纯化的E。杆菌在这个过程中，甲基乙二醛被转化为L-乳酸，而不是由传统的glycoprotein酶产生的D-乳酸。PD相关的DJ-1致病性突变（L10 P、M26 I、A104 T、D149 A和L166 P）损害或消除解毒活性，表明具有病理学意义。我们推断，理解DJ-1的生物学功能的关键在于其甲基甘氨酸加合物水解酶活性，该活性保护低分子硫醇，包括CoA，免受醛的影响。
DJ-1 (also known as PARK7) has been identified as a causal gene for hereditary recessive Parkinson’s disease (PD). Consequently, the full elucidation of DJ-1 function will help decipher the molecular mechanisms underlying PD pathogenesis. However, because various, and sometimes inconsistent, roles for DJ-1 have been reported, the molecular function of DJ-1 remains controversial. Recently, a number of papers have suggested that DJ-1 family proteins are involved in aldehyde detoxification. We found that DJ-1 indeed converts methylglyoxal (pyruvaldehyde)-adducted glutathione (GSH) to intact GSH and lactate. Based on evidence that DJ-1 functions in mitochondrial homeostasis, we focused on the possibility that DJ-1 protects co-enzyme A (CoA) and its precursor in the CoA synthetic pathway from aldehyde attack. Here, we show that intact CoA and β-alanine, an intermediate in CoA synthesis, are recovered from methylglyoxal-adducts by recombinant DJ-1 purified from E. coli. In this process, methylglyoxal is converted to L-lactate rather than the D-lactate produced by a conventional glyoxalase. PD-related pathogenic mutations of DJ-1 (L10P, M26I, A104T, D149A, and L166P) impair or abolish detoxification activity, suggesting a pathological significance. We infer that a key to understanding the biological function of DJ-1 resides in its methylglyoxal-adduct hydrolase activity, which protects low-molecular thiols, including CoA, from aldehydes.
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影响因子：
6
作者：
Galvin, JE;Giasson, B;Trojanowski, JQ
通讯作者：
Trojanowski, JQ
DOI：
10.1073/pnas.0911175107
发表时间：
2010-05-25
影响因子：
11.1
作者：
Hao, Ling-Yang;Giasson, Benoit I.;Bonini, Nancy M.
通讯作者：
Bonini, Nancy M.
影响因子：
4.8
作者：
Honbou, K;Suzuki, NN;Inagaki, F
通讯作者：
Inagaki, F
影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
3.7
作者：
Maita C;Maita H;Iguchi-Ariga SM;Ariga H
通讯作者：
Ariga H