UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes-Sorbonne Paris Cité, 75270, Paris, France.
School of Pharmacy, Lebanese American University, Byblos, 2038 1401, Lebanon.
Biochem Biophys Res Commun. 2018 Sep 5;503(2):703-709. doi: 10.1016/j.bbrc.2018.06.064. Epub 2018 Jun 23.
We reported recently that the Parkinsonism-associated protein DJ-1 and its bacterial homologs Hsp31, YhbO and YajL function as deglycases that repair proteins and nucleotides from endogeneous glycation by glyoxal and methylglyoxal, two reactive by-products of glucose metabolism responsible for up to 60% of glycation damage. Here, we show that DJ-1, deglycase 1 and deglycase 2 repair glyoxal- and methylglyoxal-glycated substrates, whereas deglycase 3 principally repairs glyoxal-glycated substrates. Moreover, deglycase 1 and 2 are overexpressed in stationary phase, whereas deglycase 3 is steadily expressed throughout bacterial growth. Finally, deglycase mutants overexpress glyoxalases, aldoketoreductases, glutathione-S-transferase and efflux pumps to alleviate carbonyl stress. In the discussion, we present an overview of the multiple functions of DJ-1 proteins. Our thourough work on deglycases provides compelling evidence that their previously reported glyoxalase III activity merely reflects their deglycase activity. Moreover, for their deglycase activity the Maillard deglycases likely recruit: i) their chaperone activity to interact with glycated proteins, ii) glyoxalase 1 activity to catalyze the rearrangement of Maillard products (aminocarbinols and hemithioacetals) into amides and thioesters, respectively, iii) their protease activity to cleave amide bonds of glycated arginine, lysine and guanine, and iv) glyoxalase 2 activity to cleave thioester bonds of glycated cysteine. Finally, because glycation affects many cellular processes, the discovery of the Maillard deglycases, awaited since 1912, likely constitutes a major advance for medical research, including ageing, cancer, atherosclerosis, neurodegenerative, post-diabetic, renal and autoimmune diseases.
我们最近报道称，帕金森病相关蛋白 DJ-1 及其细菌同源物 Hsp31、YhbO 和 YajL 作为去糖基酶发挥作用，可修复由内源性糖基化产生的蛋白质和核苷酸，这些蛋白质和核苷酸是由葡萄糖代谢产生的两种反应性副产物——乙醛和甲基乙二醛造成的，这两种副产物可导致高达 60%的糖基化损伤。在这里，我们发现 DJ-1、脱糖苷酶 1 和脱糖苷酶 2 可修复乙醛和甲基乙二醛糖基化的底物，而脱糖苷酶 3 主要修复乙醛糖基化的底物。此外，脱糖苷酶 1 和 2 在静止期表达上调，而脱糖苷酶 3 在整个细菌生长过程中稳定表达。最后，脱糖苷酶突变体过表达了醛酮还原酶、谷胱甘肽-S-转移酶和外排泵，以减轻羰基应激。在讨论部分，我们对 DJ-1 蛋白的多种功能进行了概述。我们对脱糖苷酶的深入研究提供了令人信服的证据，证明它们之前报道的醛糖酶 III 活性仅仅反映了它们的脱糖苷酶活性。此外，对于它们的脱糖苷酶活性，美拉德脱糖苷酶可能会招募：i）它们的伴侣活性与糖基化蛋白相互作用，ii）醛糖酶 1 活性分别催化美拉德产物（氨基醇和半缩醛）重排为酰胺和硫酯，iii）它们的蛋白酶活性切割糖基化精氨酸、赖氨酸和鸟嘌呤的酰胺键，iv）醛糖酶 2 活性切割糖基化半胱氨酸的硫酯键。最后，由于糖化会影响许多细胞过程，自 1912 年以来一直被期待的美拉德脱糖苷酶的发现，很可能是医学研究的一个重大进展，包括衰老、癌症、动脉粥样硬化、神经退行性、糖尿病后、肾脏和自身免疫性疾病。
