Parkinson's disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite

Abstract

Cells are continuously exposed to potentially dangerous compounds. Progressive accumulation of damage is suspected to contribute to neurodegenerative diseases and aging, but the molecular identity of the damage remains largely unknown. Here we report that PARK7, an enzyme mutated in hereditary Parkinson’s disease, prevents damage of proteins and metabolites caused by a metabolite of glycolysis. We found that the glycolytic metabolite 1,3-bisphosphoglycerate (1,3-BPG) spontaneously forms a novel reactive intermediate that avidly reacts with amino groups. PARK7 acts by destroying this intermediate, thereby preventing the formation of proteins and metabolites with glycerate and phosphoglycerate modifications on amino groups. As a consequence, inactivation of PARK7 (or its orthologs) in human cell lines, mouse brain, and Drosophila melanogaster leads to the accumulation of these damaged compounds, most of which have not been described before. Our work demonstrates that PARK7 function represents a highly conserved strategy to prevent damage in cells that metabolize carbohydrates. This represents a fundamental link between metabolism and a type of cellular damage that might contribute to the development of Parkinson’s disease.

DJ‐1 is not a deglycase and makes a modest contribution to cellular defense against methylglyoxal damage in neurons

“…Very recently, DJ‐1 and its close homologs were shown to strongly protect proteins and metabolites against glycerate and phosphoglycerate modifications (Heremans et al, 2022). In that study, DJ‐1 was proposed to use Cys106 to open a reactive cyclic 1,3 phosphoglycerate metabolite that may be spontaneously formed from 1,3 bisphosphoglycerate (i.e., DJ‐1 is a cyclic 1,3 phosphoglycerate phosphodiesterase).…”

“…Other activities proposed for DJ-1 include protease (Mitsugi et al, 2013;Olzmann et al, 2004), esterase (Vazquez-Mayorga et al, 2016), chaperone (Lee et al, 2003;Shendelman et al, 2004), transnitrosylase (Choi, Nakamura, et al, 2014), and an RNA binding protein (Hod et al, 1999;van der Brug et al, 2008). Very recently, DJ-1 was shown to prevent protein damage by derivatives of 1,3, bisphosphoglycerate (Heremans et al, 2022). Despite years of intensive study motivated by its biomedical importance, the molecular activities of DJ-1 that are responsible for its role in cell survival remain incompletely understood.…”

DJ-1 glyoxalase activity makes a modest contribution to cellular defense against methylglyoxal damage in neurons

“…Very recently, DJ-1 and its close homologs were shown to strongly protect proteins and metabolites against glycerate and phosphoglycerate modifications (37). In that study, DJ-1 was proposed to use Cys106 to open a reactive cyclic 1,3 phosphoglycerate metabolite that may be spontaneously formed from 1,3 bisphosphoglycerate (i.e.…”

“…Other activities proposed for DJ-1, include protease (29,30), esterase (31), chaperone (32,33), transnitrosylase (34) and an RNA binding protein (35,36). Very recently, DJ-1 was shown to prevent protein damage by derivatives of 1,3, bisphosphoglycerate (37). Despite years of intensive study motivated by its biomedical importance, the molecular activities of DJ-1 that are responsible for its role in cell survival remain incompletely understood.…”

Cellular Exposure to Chloroacetanilide Herbicides Induces Distinct Protein Destabilization Profiles

“…PARK7 is a chaperone-like peptidase that can repair proteins damaged by a series of aldehyde products, including methylglyoxal and glyoxal. PARK7 specifically protects GAPDH from cysteine and lysine adducts, including glycerate damage caused by metabolic products generated by GAPDH itself 114,115 . PARK7 is also significantly destabilized after propachlor treatment and thus could be inactive.…”