The reaction mechanism for glycolysis side product degradation by Parkinson's disease-linked DJ-1
Data files
Jun 02, 2025 version files 15.77 MB
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cPGA_source_data_Figure_1.xlsx
30.44 KB
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cPGA_source_data_Figure_4.xlsx
52.78 KB
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cPGA_source_data_Figure_5.xlsx
54.27 KB
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cPGA_source_data_Figure_6.xlsx
31.40 KB
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cPGA_source_data_Figure_S3.xlsx
47.25 KB
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Fig2.pse
4.64 MB
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Fig3.pse
7.50 MB
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Fig5A.pse
1.70 MB
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Fig6A.pse
1.70 MB
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README.md
3.53 KB
Abstract
DJ-1/PARK7 is the causative gene for hereditary recessive Parkinson's disease. Recent studies have reported that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), a highly reactive metabolite. However, the molecular mechanisms underlying cPGA hydrolase activity have yet to be fully elucidated. To gain a more comprehensive understanding of this activity in DJ-1, we performed molecular simulations that predicted how DJ-1 recognizes and hydrolyzes cPGA. The accuracy of these structural predictions was validated through systematic mutational analyses exemplified by loss of activity with the A107P mutation. Although DJ-1 possesses both cPGA hydrolase and α-oxoaldehyde hydratase activities in vitro, we confirmed that DJ-1 dysfunction caused an increase in cPGA-derived modifications but had no effect on α-oxoaldehyde-derived modifications in cells. Importantly, A107 and P158, pathogenic missense mutation sites found in Parkinson's disease patients, are critical for cPGA-hydrolysis both in vitro and in cells. The evidence-based catalytic mechanism for DJ-1 hydrolysis of cPGA that we propose here explains their pathophysiological significance.
Dataset DOI: 10.5061/dryad.3j9kd51wz
Description of the data and file structure
Absorbance data to monitor cPGA and structure model predicted in silico.
Files and variables
File: cPGA_source_data_Figure_1.xlsx
Description: Source_data (Absorbance data) for Fig. 1 indicating the cPGA hydrolase activities of DJ-1 (WT or C106S mutant), YajL (WT or C106S mutant), YhbO, ElbB, and HchA. The data represent absorbance at 235 nm, calculated as Abs = -log₁₀T (T = transmittance at 235 nm). Since absorbance is a dimensionless quantity, no unit is assigned.
File: cPGA_source_data_Figure_4.xlsx
Description: Source_data (Absorbance data) for Fig. 4 indicating the cPGA hydrolase activities of DJ-1 mutants (WT, E15A, E18A, E18Q, R28A, or R48A) and YajL mutants (WT, E14A, E17A, R27A, or R49A). The data represent absorbance at 235 nm, calculated as Abs = -log₁₀T (T = transmittance at 235 nm). Since absorbance is a dimensionless quantity, no unit is assigned.
File: cPGA_source_data_Figure_5.xlsx
Description: Source_data (Absorbance data) for Fig. 5 indicating the cPGA hydrolase activities of DJ-1 mutants (WT, G74S, G75S, C106S, A107H, A107I, or A107P) and YajL mutants (WT, G74S, G75S, C106S, or A107P). The data represent absorbance at 235 nm, calculated as Abs = -log₁₀T (T = transmittance at 235 nm). Since absorbance is a dimensionless quantity, no unit is assigned.
File: cPGA_source_data_Figure_6.xlsx
Description: Source_data (Absorbance data) for Fig. 6 indicating the cPGA hydrolase activities of DJ-1 mutants (WT, N76W, H126A, P158A, or P158delta) and YajL mutants (WT, P158A, or P158delta). The data represent absorbance at 235 nm, calculated as Abs = -log₁₀T (T = transmittance at 235 nm). Since absorbance is a dimensionless quantity, no unit is assigned.
File: cPGA_source_data_Figure_S3.xlsx
Description: Source_data (Absorbance data) for Fig. S3 indicating the methylglyoxalase and cPGA hydrolase activities of DJ-1. The data represent absorbance at 288 nm and 235 nm, calculated as Abs = -log₁₀T (T = transmittance at 288 nm or 235 nm). Since absorbance is a dimensionless quantity, no unit is assigned.
File: Fig2.pse
Description: Structure model showing how cPGA interacts with DJ-1 or YajL, as predicted in silico (Fig. 2), provided as a PyMOL session file. Since this PyMOL session file is dimensionless, no unit is assigned.
File: Fig3.pse
Description: Structure model showing how dimeric structures of ElbB, HchA, and YhbO weaken cPGA binding, as predicted in silico (Fig. 3), provided as a PyMOL session file. Since this PyMOL session file is dimensionless, no unit is assigned.
File: Fig5A.pse
Description: Structure model showing how cPGA is recognized by G74, G75, C106, and A107 of DJ-1, as predicted in silico (Fig. 5), provided as a PyMOL session file. Since this PyMOL session file is dimensionless, no unit is assigned.
File: Fig6A.pse
Description: Structure model showing how cPGA is recognized by E18, R28, and P158 of DJ-1, as predicted in silico (Fig. 6), provided as a PyMOL session file. Since this PyMOL session file is dimensionless, no unit is assigned.
Access information
Other publicly accessible locations of the data:
- Not applicable
Data was derived from the following sources:
- Not applicable