Novel Redox-Dependent Esterase Activity (EC for DJ-1: Implications for Parkinson's Disease

Int J Mol Sci. 2016 Aug 22;17(8):1346. doi: 10.3390/ijms17081346.


Mutations the in human DJ-1 (hDJ-1) gene are associated with early-onset autosomal recessive forms of Parkinson's disease (PD). hDJ-1/parkinsonism associated deglycase (PARK7) is a cytoprotective multi-functional protein that contains a conserved cysteine-protease domain. Given that cysteine-proteases can act on both amide and ester substrates, we surmised that hDJ-1 possessed cysteine-mediated esterase activity. To test this hypothesis, hDJ-1 was overexpressed, purified and tested for activity towards 4-nitrophenyl acetate (pNPA) as µmol of pNPA hydrolyzed/min/mg·protein (U/mg protein). hDJ-1 showed maximum reaction velocity esterase activity (Vmax = 235.10 ± 12.00 U/mg protein), with a sigmoidal fit (S0.5 = 0.55 ± 0.040 mM) and apparent positive cooperativity (Hill coefficient of 2.05 ± 0.28). A PD-associated mutant of DJ-1 (M26I) lacked activity. Unlike its protease activity which is inactivated by reactive oxygen species (ROS), esterase activity of hDJ-1 is enhanced upon exposure to low concentrations of hydrogen peroxide (<10 µM) and plateaus at elevated concentrations (>100 µM) suggesting that its activity is resistant to oxidative stress. Esterase activity of DJ-1 requires oxidation of catalytic cysteines, as chemically protecting cysteines blocked its activity whereas an oxido-mimetic mutant of DJ-1 (C106D) exhibited robust esterase activity. Molecular docking studies suggest that C106 and L126 within its catalytic site interact with esterase substrates. Overall, our data show that hDJ-1 contains intrinsic redox-sensitive esterase activity that is abolished in a PD-associated mutant form of the hDJ-1 protein.

Keywords: 4-nitrophenyl acetate; DJ1/PARK7; Parkinson’s disease; ROS; human carboxyl esterase; oxidative stress; redox sensor.

MeSH terms

  • Esterases / chemistry*
  • Esterases / genetics
  • Esterases / metabolism*
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Molecular Docking Simulation
  • Mutation
  • Nitrophenols / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / drug effects
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Protein Deglycase DJ-1 / chemistry
  • Protein Deglycase DJ-1 / genetics
  • Protein Deglycase DJ-1 / metabolism
  • Reactive Oxygen Species / metabolism


  • Nitrophenols
  • Reactive Oxygen Species
  • 4-nitrophenyl acetate
  • Hydrogen Peroxide
  • Esterases
  • PARK7 protein, human
  • Protein Deglycase DJ-1