CHARACTERIZATION OF A MOLECULAR FUNCTION OF DJ-1 AS CPGA HYDROLASE
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Date
2024
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Nazarbayev University School of Sciences and Humanities
Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder marked by a steady decrease
in motor function due to the death of dopaminergic neurons in the substantia nigra, resulting
in the reduced levels of dopamine in the striatum. Most cases of PD are sporadic, though 10-
15% of individuals have hereditary Parkinsonism linked to mutations affecting various
proteins. Studying the molecular function of proteins linked to hereditary PD helps in
understanding the mechanisms underlying the development and progression of this disease
even in individuals with sporadic PD. Therefore, is of utmost biomedical significance. This
thesis paper focuses on DJ-1 - a small protein mutated in rare cases of early-onset autosomal
recessive Parkinson's disease. While the neuroprotective function of DJ-1 in humans is clearly
established, there is no universally accepted mechanism clearly explaining how DJ-1 prevents
the premature death of dopaminergic neurons. This uncertainty manifests itself in a very large
number of functions that have been suggested for DJ-1 in different systems none of which
definitively clarified its role in the genesis and advancement of Parkinson's disease. Our
results describe in detail a novel function of DJ-1 as a hydrolase of cyclic 3-phosphoglyceric
anhydride (cPGA). Formation of cPGA in glycolysis and cPGA hydrolase activity have been
recently suggested based on indirect evidence however neither could be demonstrated in a
direct experiment because of instability of cPGA. We synthesized cPGA from 3-
phosphoglycerate using a standard dehydrating agent (EDC) in acidic conditions and, for the
first time, demonstrated the existence of cPGA in solution by NMR. We established simple
procedures for quantitative assessment of cPGA spectrophotometrically after converting it
into a thioester. These methods allowed a comprehensive characterization of cPGA as an
unstable electrophile with a high propensity to acylate biological nucleophiles. Further, we
demonstrate that human DJ-1 and its E. coli homolog YajL are highly efficient cPGA
hydrolases and provide evidence that the endogenous cPGA hydrolase activity of DJ-1 is both
necessary and sufficient for the protection of proteins from acylation by cPGA. This work
establishes cPGA as a novel reactive metabolite that can irreversibly acylate proteins and
presents strong evidence that DJ-1 possesses a unique function that inactivates cPGA by
hydrolysis. This new and unique function of DJ-1 provides the best explanation of
neuroprotection by DJ-1 so far and opens a new and exciting chapter in research of reactive
metabolites and their role in neurodegeneration.
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Keywords
Type of access: Embargo, Parkinson’s disease
Citation
Akhmadi, A. (2024). Characterization Of A Molecular Function Of Dj-1 As Cpga Hydrolase. Nazarbayev University School of Sciences and Humanities