DJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride

Aizhan Akhmadi, Adilkhan Yeskendir, Nelly Dey, Arman Mussakhmetov, Zariat Shatkenova, Arman Kulyyassov, Anna Andreeva and Darkhan Utepbergenov ()
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Aizhan Akhmadi: Nazarbayev University
Adilkhan Yeskendir: Nazarbayev University
Nelly Dey: Nazarbayev University
Arman Mussakhmetov: National Center for Biotechnology
Zariat Shatkenova: Nazarbayev University
Arman Kulyyassov: National Center for Biotechnology
Anna Andreeva: Nazarbayev University
Darkhan Utepbergenov: Nazarbayev University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-46391-9

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