Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates
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 physostig...
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MDPI AG
2020-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/1/211 |
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| author | Anita Bosak Aljoša Bavec Tilen Konte Goran Šinko Zrinka Kovarik Marko Goličnik |
| author_facet | Anita Bosak Aljoša Bavec Tilen Konte Goran Šinko Zrinka Kovarik Marko Goličnik |
| author_sort | Anita Bosak |
| collection | DOAJ |
| description | 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 <i>S</i>-phenyl thioacetate (PTA). Inhibition dissociation constants (<i>K</i><sub>i</sub>), 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 <i>K</i><sub>i</sub> 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. |
| first_indexed | 2024-12-19T06:52:28Z |
| format | Article |
| id | doaj.art-8716715bc3754e49ba7768b56e7d6ee6 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-19T06:52:28Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-8716715bc3754e49ba7768b56e7d6ee62022-12-21T20:31:41ZengMDPI AGMolecules1420-30492020-01-0125121110.3390/molecules25010211molecules25010211Interactions of Paraoxonase-1 with Pharmacologically Relevant CarbamatesAnita Bosak0Aljoša Bavec1Tilen Konte2Goran Šinko3Zrinka Kovarik4Marko Goličnik5Institute for Medical Research and Occupational Health, HR 10000 Zagreb, CroatiaInstitute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI 1000 Ljubljana, SloveniaInstitute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI 1000 Ljubljana, SloveniaInstitute for Medical Research and Occupational Health, HR 10000 Zagreb, CroatiaInstitute for Medical Research and Occupational Health, HR 10000 Zagreb, CroatiaInstitute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI 1000 Ljubljana, SloveniaMammalian 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 <i>S</i>-phenyl thioacetate (PTA). Inhibition dissociation constants (<i>K</i><sub>i</sub>), 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 <i>K</i><sub>i</sub> 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.https://www.mdpi.com/1420-3049/25/1/211paraoxonase-1arylesterase activityphenyl acetate<i>s</i>-phenyl thioacetate<i>p</i>-nitrophenyl acetatecarbamatesreversible inhibition |
| spellingShingle | Anita Bosak Aljoša Bavec Tilen Konte Goran Šinko Zrinka Kovarik Marko Goličnik Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates Molecules paraoxonase-1 arylesterase activity phenyl acetate <i>s</i>-phenyl thioacetate <i>p</i>-nitrophenyl acetate carbamates reversible inhibition |
| title | Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates |
| title_full | Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates |
| title_fullStr | Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates |
| title_full_unstemmed | Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates |
| title_short | Interactions of Paraoxonase-1 with Pharmacologically Relevant Carbamates |
| title_sort | interactions of paraoxonase 1 with pharmacologically relevant carbamates |
| topic | paraoxonase-1 arylesterase activity phenyl acetate <i>s</i>-phenyl thioacetate <i>p</i>-nitrophenyl acetate carbamates reversible inhibition |
| url | https://www.mdpi.com/1420-3049/25/1/211 |
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