Glyoxalase activities of Parkinson's disease relevant protein DJ-1/PARK7: Past discoveries and future perspectives.

Loss-of-function mutations in the evolutionarily conserved protein DJ-1/PARK7 cause autosomal recessive early-onset Parkinson's disease. Despite being identified more than 20 years ago, the authentic molecular function of DJ-1 remains controversial as diverse biochemical activities attributed to DJ-1 often lack a unified mechanistic explanation. In this review, we outline the hydrolase activities of DJ-1 (i.e., deglycase, protease, and esterase activities) before focusing on its glyoxalase activity, which catalyzes the glutathione-independent detoxification of reactive α-oxoaldehydes such as methylglyoxal. We summarize the historical identification of glyoxalase III activity, the discovery of bacterial and fungal DJ-1 homologs as methylglyoxalases, and the extension of this concept to human DJ-1. Structural and biochemical studies have clarified the molecular mechanism by which DJ-1 hydrolyzes glyoxal and methylglyoxal. In this mechanism, the conserved active-site cysteine residue (Cys106), together with neighboring residues, such as Glu18 and the Gly74-Gly75 oxyanion hole, cooperatively contribute to methylglyoxal degradation. These insights provide a coherent molecular framework that reconciles enzymatic activity with the structural features and evolutionary conservation of the DJ-1 family. Together, they provide a foundation for understanding the biological basis of DJ-1-mediated α-oxoaldehyde detoxification. Lastly, the limitations and unresolved questions of the DJ-1 glyoxalase hypothesis are discussed.