The paper demonstrates and characterizes a new enzymatic activity of human protein DJ-1 providing a mechanistic background for its long-known neuroprotective properties.
The study has shed light on the underlying molecular function of the PARK7 gene product, DJ-1, in protecting against familial Parkinsonism. This gene mutation leads to the loss of dopaminergic neurons, a key feature of Parkinson's disease. Although DJ-1's cytoprotective effects have been known, the specific role it plays in this process has remained unclear. The study reveals that DJ-1 prevents the acylation of amino groups of proteins and metabolites by 1,3-bisphosphoglycerate (1,3-BPG) – a glycolytic byproduct. This acylation process is indirect and presumed to occur via the formation of an unstable intermediate, specifically a cyclic 3-phosphoglyceric anhydride (cPGA). To understand the enzymatic activity of DJ-1 in this context, the researchers developed simple and effective procedures for synthesis and quantitation of cPGA. They characterized cPGA as a highly reactive acylating electrophile and demonstrated that DJ-1 is an efficient cPGA hydrolase, with a kcat/Km of 5.9 × 106 M−1 s−1. To further validate the cytoprotective function of DJ-1, the researchers conducted experiments using DJ-1-null cells. The results showed that DJ-1 protects against the accumulation of 3-phosphoglyceroyl-lysine residues in proteins. This finding confirms that DJ-1's catalytic hydrolysis of cPGA plays a crucial role in mitigating the damage caused by this glycolytic byproduct. In summary, this study establishes a definitive cytoprotective function for DJ-1. By destroying cPGA, DJ-1 prevents protein acylation and protects against the accumulation of harmful 3-phosphoglyceroyl-lysine residues. These findings contribute to our understanding of the molecular mechanisms underlying Parkinson's disease and may pave the way for the development of novel therapeutic strategies.