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

Novel Redox-Dependent Esterase Activity (EC 3.1.1.2) for DJ-1: Implications for Parkinson’s Disease

1
Instituto de Ciencias Biomédicas, Universidad Autónoma de Ciudad Juárez, Anillo envolvente Pronaf y Estocolmo s/n, Ciudad Juarez, Chihuahua 32310, Mexico
2
Department of Pharmacology, University of Nevada, Reno School of Medicine, Mailstop 318, Manville Building 19A(Office)/18(Lab), Reno, NV 89557, USA
3
El Colegio de Chihuahua, Calle Partido Díaz 4723 esquina con Anillo Envolvente del Pronaf, colonia Progresista, Ciudad Juárez, Chihuahua 32310, Mexico
*
Authors to whom correspondence should be addressed.
Academic Editor: Irmgard Tegeder
Received: 29 June 2016 / Revised: 3 August 2016 / Accepted: 9 August 2016 / Published: 22 August 2016
(This article belongs to the Special Issue Neuronal Protein Homeostasis in Health and Disease)
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Abstract

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. View Full-Text
Keywords: 4-nitrophenyl acetate; human carboxyl esterase; redox sensor; oxidative stress; DJ1/PARK7; ROS; Parkinson’s disease 4-nitrophenyl acetate; human carboxyl esterase; redox sensor; oxidative stress; DJ1/PARK7; ROS; Parkinson’s disease
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Vázquez-Mayorga, E.; Díaz-Sánchez, Á.G.; Dagda, R.K.; Domínguez-Solís, C.A.; Dagda, R.Y.; Coronado-Ramírez, C.K.; Martínez-Martínez, A. Novel Redox-Dependent Esterase Activity (EC 3.1.1.2) for DJ-1: Implications for Parkinson’s Disease. Int. J. Mol. Sci. 2016, 17, 1346.

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