Muronetz Vladimir I, Barinova Kseniya V, Stroylova Yulia Y, Semenyuk Pavel I, Schmalhausen Elena V
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119234, Russia.
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 119234, Russia; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow 119234, Russia.
Int J Biol Macromol. 2017 Jul;100:55-66. doi: 10.1016/j.ijbiomac.2016.05.066. Epub 2016 May 20.
The review analyses data on specific features of aggregation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and possible role of this enzyme in the development of neurodegenerative diseases. Different post-translational modifications of the enzyme are considered: oxidation, nitrosylation, and S-glutathionylation of the active site sulfhydryl groups, as well as phosphorylation, glycation and homocysteinylation of other amino acid residues. Modification of the sulfhydryl groups of the enzyme inhibits the enzymatic activity of GAPDH, resulting in slowdown of glycolysis, and may lead to the dissociation of the cofactor NAD from the active site of the enzyme. The resulting apo-GAPDH (without NAD) is less stable and prone to dissociation, denaturation, and subsequent aggregation. These processes could play a crucial role in the translocation of GAPDH subunits from the cytoplasm into the nucleus, which is linked to the induction of apoptosis. Phosphorylation and glycation of GAPDH are presumably involved in the regulation of protein-protein interactions and intracellular localization of the enzyme. Besides, glycation by dicarbonyl compounds and aldehydes may directly inhibit glycolysis. Homocysteinylation of GAPDH may stabilize aggregates of the enzyme by additional disulfide bonding. All types of post-translational modifications affect aggregation of GAPDH. A special attention is given to the role of chaperones in the amyloidogenic transformation of proteins and to confirmation of the hypothesis on blocking of the chaperones by misfolded protein forms. The denatured GAPDH forms were shown to interact directly with amyloidogenic proteins (alpha-synuclein and amyloid-beta peptide) and to play a crucial role in blocking of chaperone system.
本综述分析了甘油醛-3-磷酸脱氢酶（GAPDH）聚集的特定特征数据，以及该酶在神经退行性疾病发展中可能发挥的作用。文中考虑了该酶的不同翻译后修饰：活性位点巯基的氧化、亚硝基化和S-谷胱甘肽化，以及其他氨基酸残基的磷酸化、糖基化和同型半胱氨酸化。酶的巯基修饰会抑制GAPDH的酶活性，导致糖酵解减缓，并可能导致辅因子NAD从酶的活性位点解离。由此产生的脱辅基GAPDH（无NAD）稳定性较低，易于解离、变性及随后的聚集。这些过程可能在GAPDH亚基从细胞质转运到细胞核中发挥关键作用，而这与细胞凋亡的诱导有关。GAPDH的磷酸化和糖基化可能参与蛋白质-蛋白质相互作用的调节及该酶的细胞内定位。此外，二羰基化合物和醛类的糖基化可能直接抑制糖酵解。GAPDH的同型半胱氨酸化可能通过额外的二硫键来稳定酶的聚集体。所有类型的翻译后修饰都会影响GAPDH的聚集。文中特别关注了伴侣蛋白在蛋白质淀粉样变性转化中的作用，以及对错误折叠蛋白形式阻断伴侣蛋白这一假说的证实。已证明变性的GAPDH形式可直接与淀粉样蛋白（α-突触核蛋白和β-淀粉样肽）相互作用，并在阻断伴侣蛋白系统中发挥关键作用。
