The reaction mechanism for glycolysis side product degradation by Parkinson's disease-linked DJ-1

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.