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Interaction of organotin compounds with three major glutathione S-transferases in zebrafish

Mihaljević, Ivan; Bašica, Branka; Maraković, Nikola; Kovačević, Radmila; Smital, Tvrtko (2020) Interaction of organotin compounds with three major glutathione S-transferases in zebrafish. Toxicology in Vitro, 62 . ISSN 0887-2333

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Glutathione S-transferases (GSTs) play an important role in cellular detoxification as enzymatic mediators of glutathione (GSH) conjugation with a wide range of deleterious compounds, enabling their easier extrusion out of the organism. GSTs are shown to interact with organotin compounds (OTCs), known environmental pollutants, either as substrates, serving as electrophilic targets to the nucleophilic attack of GSH, or as noncompetitive inhibitors by binding to GST active sites and disrupting their enzymatic functions. There is a wide range of deleterious biological effects caused by OTCs in low concentration range. Their environmental concentrations, further potentiated by bioaccumulation in aquatic organisms, correspond with inhibitory constants reported for Gsts in zebrafish, which implies their environmental significance. Therefore, our main goal in this study was to analyze interactions of three major zebrafish Gsts – Gstp1, Gstr1, and Gstt1a – with a series of ten environmentally relevant organotin compounds. Using previously developed Gst inhibition assay with recombinant Gst proteins and fluorescent monochlorobimane as a model substrate, we determined Gst inhibitory constants for all tested OCTs. Furthermore, in order to elucidate nature of Gst interactions with OTCs, we determined type of interactions between tested Gsts and the strongest OTC inhibitors. Our results showed that OTCs can interact with zebrafish Gsts as competitive, noncompetitive, or mixed-type inhibitors. Determined types of interactions were additionally confirmed in silico by molecular docking studies of tested OTCs with newly developed Gst models. In silico models were further used to reveal structures of tested Gsts in more detail and identify crucial amino acid residues which interact with OTCs within Gst active sites. Our results revealed more extensive involvement of Gstr1 and Gstp1 in detoxification of numerous tested OTCs, with low inhibitory constants in nanomolar to low micromolar range and different types of inhibition, whereas Gstt1a noncompetitively interacted with only two tested OTCs with significantly higher inhibitory constants.

Item Type: Article
Additional Information: This research was financed by the SCOPES joint research project supported by Swiss National Science Foundation (SNSF) (Grant No. SCOPES - IZ73ZO_152274/1), and partially supported under the project STIM - REI, Contract Number: KK., a project funded by the European Union through the European Regional Development Fund - the Operational Programme Competitiveness and Cohesion 20142020 (KK. The computational resources and Biovia Discovery Studio Client v17.2 software (Accelrys, San Diego, CA, USA), used for homology modeling and molecular docking studies, were provided through Croatian Science Foundation projects (grant numbers HrZZ-IP-2013-11-4307 and HrZZ-IP-2018-01-7683).
Uncontrolled Keywords: glutathione S-transferases ; zebrafish ; organotin compounds ; type of interaction ; homology modeling ; molecular docking
Subjects: NATURAL SCIENCES > Biology
Divisions: Division for Marine and Enviromental Research
Project titleProject leaderProject codeProject type
Dizajn, sinteza i evaluacija novih protuotrova kod trovanja živčanim bojnim otrovima i pesticidima-CHOLINESTERASEZrinka KovarikIP-2013-11-4307HRZZ
Analiza interakcija butirilkolinesteraze s novim inhibitorima i reaktivatorima-AnalyseBChEZrinka KovarikIP-2018-01-7683HRZZ
Depositing User: Tvrtko Smital
Date Deposited: 07 May 2020 06:32
DOI: 10.1016/j.tiv.2019.104713

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