Department of Chemistry, Tunghai University, No. 1727, Sec. 4, Taiwan Boulevard, Xitun District, Taichung 40704, Taiwan.
Int J Mol Sci. 2024 Oct 15;25(20):11075. doi: 10.3390/ijms252011075.
DJ-1 is a vital enzyme involved in the maintenance of mitochondrial health, and its mutation has been associated with an increased risk of Parkinson's disease (PD). Effective regulation of DJ-1 activity is essential for the well-being of mitochondria, and DJ-1 is thus a potential target for PD drug development. In this study, two peptides (EEMETIIPVDVMRRA and SRDVVICPDA) were utilized with the aim of enhancing the activity of DJ-1. The mechanisms underlying the activity enhancement by these two peptides were investigated using hydrogen/deuterium exchange mass spectrometry (HDXMS). The HDXMS results revealed distinct mechanisms. Peptide 1 obstructs the access of solvent to the dimer interface and stabilizes the α/β hydrolase structure, facilitating substrate binding to a stabilized active site. Conversely, peptide 2 induces a destabilization of the α/β hydrolase core, enhancing substrate accessibility and subsequently increasing DJ-1 activity. The binding of these two peptides optimizes the activity site within the dimeric structure. These findings offer valuable insights into the mechanisms underlying the activity enhancement of DJ-1 by the two peptides, potentially aiding the development of new drugs that can enhance the activity of DJ-1 and, consequently, advance PD treatment.
DJ-1 是一种参与维持线粒体健康的重要酶，其突变与帕金森病（PD）的风险增加有关。有效调节 DJ-1 的活性对于线粒体的健康至关重要，因此 DJ-1 是 PD 药物开发的潜在靶点。在这项研究中，使用了两种肽（EEMETIIPVDVMRRA 和 SRDVVICPDA）来提高 DJ-1 的活性。使用氢/氘交换质谱（HDXMS）研究了这两种肽增强活性的机制。HDXMS 结果揭示了不同的机制。肽 1 阻碍溶剂进入二聚体界面并稳定 α/β 水解酶结构，促进底物结合到稳定的活性位点。相反，肽 2 导致 α/β 水解酶核心不稳定，增加底物的可及性，从而提高 DJ-1 的活性。这两种肽的结合优化了二聚体结构内的活性位点。这些发现为两种肽增强 DJ-1 活性的机制提供了有价值的见解，可能有助于开发能够增强 DJ-1 活性的新药，从而推进 PD 的治疗。
