Apparent deglycase activity of DJ-1 results from the conversion of free
methylglyoxal present in fast equilibrium with hemithioacetals and
hemiaminals
Anna Andreeva, Zhanibek Bekhozhin, Nuriza Omertassova, Timur Baizhumanov, Gaziza Yeltay,
Mels Akhmetali, Daulet Toibazar, and Darkhan Utepbergenov
Departments of Chemistry and Biology, School of Science and Humanities,
Nazarbayev University, Nur-Sultan, Kazakhstan
Email: [email protected]
Abstract
Mutations in the human protein DJ-1 cause an early onset of Parkinson’s disease suggesting that this protein
protects dopaminergic neurons. Molecular mechanisms of neuroprotection are unclear however DJ-1 was
implicated as a glutathione-independent glyoxalase that detoxifies methylglyoxal (MGO) converting it into
lactate. Several studies also suggest that DJ-1 may serve as a deglycase that catalyzes hydrolysis of
hemithioacetals and hemiaminals formed by reaction of MGO with thiol and amino groups of proteins. In
this report we demonstrate that equilibrium constant of reaction of MGO with glutathione is ~500 M -1 and
a half-life of the resulting hemithioacetal is only ~12 seconds. These thermodynamic parameters dictate
that a significant fraction of free MGO will be present in solution in fast equilibrium with hemithioacetals.
Removal of free MGO by glyoxalase activity of DJ-1 forces immediate spontaneous decomposition of
hemithioacetals due to the shift in equilibrium position. This spontaneous decomposition of hemithioacetals
is mistaken for deglycase activity of DJ-1. Further, we demonstrate that higher initial concentrations of
hemithioacetals correspond to lower rates of conversion of MGO by DJ-1 ruling out the possibility that
hemithioacetals are substrates for DJ-1. Combined, our data suggest that DJ-1 is not a protein deglycase.