DJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Akhmadi A. Yeskendir A. Dey N. Mussakhmetov A. Shatkenova Z. Kulyyassov A. Andreeva A. Utepbergenov D.
December 2024Nature Research
Nature Communications
2024#15Issue 1
Mutations in the human PARK7 gene that encodes protein DJ-1 lead to familial Parkinsonism due to loss of dopaminergic neurons. However, the molecular function of DJ-1 underpinning its cytoprotective effects are unclear. Recently, DJ-1 has been shown to prevent acylation of amino groups of proteins and metabolites by 1,3-bisphosphoglycerate. This acylation is indirect and thought to proceed via the formation of an unstable intermediate, presumably a cyclic 3-phosphoglyceric anhydride (cPGA). Several lines of evidence indicate that DJ-1 destroys cPGA, however this enzymatic activity has not been directly demonstrated. Here, we report simple and effective procedures for synthesis and quantitation of cPGA and present a comprehensive characterization of this highly reactive acylating electrophile. We demonstrate that DJ-1 is an efficient cPGA hydrolase with kcat/Km = 5.9 × 106 M−1s−1. Experiments with DJ-1-null cells reveal that DJ-1 protects against accumulation of 3-phosphoglyceroyl-lysine residues in proteins. Our results establish a definitive cytoprotective function for DJ-1 that uses catalytic hydrolysis of cPGA to mitigate the damage from this glycolytic byproduct.
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Ph.D. Program in Life Sciences, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Department of Chemistry, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Master Program, School of Medicine, Nazarbayev University, Astana, 010000, Kazakhstan
National Center for Biotechnology, Astana, 010000, Kazakhstan
Ph.D. Program in Biology, L.N. Gumilyov Eurasian National University, Astana, 010000, Kazakhstan
Department of Biology, School of Sciences and Humanities, Nazarbayev University, Astana, 010000, Kazakhstan
Ph.D. Program in Life Sciences
Department of Chemistry
Master Program
National Center for Biotechnology
Ph.D. Program in Biology
Department of Biology
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