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Article

Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates

1
Institute for Medical Research and Occupational Health, HR 10000 Zagreb, Croatia
2
Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI 1000 Ljubljana, Slovenia
*
Authors to whom correspondence should be addressed.
Academic Editor: Bernhard Loll
Molecules 2020, 25(1), 211; https://doi.org/10.3390/molecules25010211
Received: 4 December 2019 / Revised: 30 December 2019 / Accepted: 2 January 2020 / Published: 4 January 2020
(This article belongs to the Special Issue Enzymes Reacting with Organophosphorus Compounds)
Mammalian paraoxonase-1 hydrolyses a very broad spectrum of esters such as certain drugs and xenobiotics. The aim of this study was to determine whether carbamates influence the activity of recombinant PON1 (rePON1). Carbamates were selected having a variety of applications: bambuterol and physostigmine are drugs, carbofuran is used as a pesticide, while Ro 02-0683 is diagnostic reagent. All the selected carbamates reduced the arylesterase activity of rePON1 towards the substrate S-phenyl thioacetate (PTA). Inhibition dissociation constants (Ki), evaluated by both discontinuous and continuous inhibition measurements (progress curves), were similar and in the mM range. The rePON1 displayed almost the same values of Ki constants for Ro 02-0683 and physostigmine while, for carbofuran and bambuterol, the values were approximately ten times lower and two times higher, respectively. The affinity of rePON1 towards the tested carbamates was about 3–40 times lower than that of PTA. Molecular modelling of rePON1-carbamate complexes suggested non-covalent interactions with residues of the rePON1 active site that could lead to competitive inhibition of its arylesterase activity. In conclusion, carbamates can reduce the level of PON1 activity, which should be kept in mind, especially in medical conditions characterized by reduced PON1 levels. View Full-Text
Keywords: paraoxonase-1; arylesterase activity; phenyl acetate; S-phenyl thioacetate; p-nitrophenyl acetate; carbamates; reversible inhibition paraoxonase-1; arylesterase activity; phenyl acetate; S-phenyl thioacetate; p-nitrophenyl acetate; carbamates; reversible inhibition
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MDPI and ACS Style

Bosak, A.; Bavec, A.; Konte, T.; Šinko, G.; Kovarik, Z.; Goličnik, M. Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates. Molecules 2020, 25, 211. https://doi.org/10.3390/molecules25010211

AMA Style

Bosak A, Bavec A, Konte T, Šinko G, Kovarik Z, Goličnik M. Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates. Molecules. 2020; 25(1):211. https://doi.org/10.3390/molecules25010211

Chicago/Turabian Style

Bosak, Anita, Aljoša Bavec, Tilen Konte, Goran Šinko, Zrinka Kovarik, and Marko Goličnik. 2020. "Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates" Molecules 25, no. 1: 211. https://doi.org/10.3390/molecules25010211

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