Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes
Glutathione transferases (GSTs; EC 2.5.1.18) form a group of multifunctional enzymes that are involved in phase II of the cellular detoxification mechanism and are associated with increased susceptibility to cancer development and resistance to anticancer drugs. The present study aims to evaluate th...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3606 |
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| author | Charoutioun S. Bodourian Nirmal Poudel Anastassios C. Papageorgiou Mariana Antoniadi Nikolaos D. Georgakis Hiroshi Abe Nikolaos E. Labrou |
| author_facet | Charoutioun S. Bodourian Nirmal Poudel Anastassios C. Papageorgiou Mariana Antoniadi Nikolaos D. Georgakis Hiroshi Abe Nikolaos E. Labrou |
| author_sort | Charoutioun S. Bodourian |
| collection | DOAJ |
| description | Glutathione transferases (GSTs; EC 2.5.1.18) form a group of multifunctional enzymes that are involved in phase II of the cellular detoxification mechanism and are associated with increased susceptibility to cancer development and resistance to anticancer drugs. The present study aims to evaluate the ligandability of the human GSTM1-1 isoenzyme (hGSTM1-1) using a broad range of structurally diverse pesticides as probes. The results revealed that hGSTM1-1, compared to other classes of GSTs, displays limited ligandability and ligand-binding promiscuity, as revealed by kinetic inhibition studies. Among all tested pesticides, the carbamate insecticide pirimicarb was identified as the strongest inhibitor towards hGSTM1-1. Kinetic inhibition analysis showed that pirimicarb behaved as a mixed-type inhibitor toward glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). To shine a light on the restricted hGSTM1-1 ligand-binding promiscuity, the ligand-free crystal structure of hGSTM1-1 was determined by X-ray crystallography at 1.59 Å-resolution. Comparative analysis of ligand-free structure with the available ligand-bound structures allowed for the study of the enzyme’s plasticity and the induced-fit mechanism operated by hGSTM1-1. The results revealed important structural features of the H-site that contribute to xenobiotic-ligand binding and specificity. It was concluded that hGSTM1-1 interacts preferentially with one-ring aromatic compounds that bind at a discrete site which partially overlaps with the xenobiotic substrate binding site (H-site). The results of the study form a basis for the rational design of new drugs targeting hGSTM1-1. |
| first_indexed | 2024-03-09T11:47:11Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:47:11Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-17bbf0e5c4464b3c83f9c0b30707e9df2023-11-30T23:19:22ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237360610.3390/ijms23073606Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical ProbesCharoutioun S. Bodourian0Nirmal Poudel1Anastassios C. Papageorgiou2Mariana Antoniadi3Nikolaos D. Georgakis4Hiroshi Abe5Nikolaos E. Labrou6Laboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 118 55 Athina, GreeceTurku Bioscience Centre, University of Turku and Åbo Akademi University, 20521 Turku, FinlandTurku Bioscience Centre, University of Turku and Åbo Akademi University, 20521 Turku, FinlandLaboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 118 55 Athina, GreeceLaboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 118 55 Athina, GreeceDepartment of Chemistry, Graduate School of Science, Nagoya University, Furo-cho, Chikusa-Ku, Nagoya 464-8602, JapanLaboratory of Enzyme Technology, Department of Biotechnology, School of Applied Biology and Biotechnology, Agricultural University of Athens, 75 Iera Odos Street, 118 55 Athina, GreeceGlutathione transferases (GSTs; EC 2.5.1.18) form a group of multifunctional enzymes that are involved in phase II of the cellular detoxification mechanism and are associated with increased susceptibility to cancer development and resistance to anticancer drugs. The present study aims to evaluate the ligandability of the human GSTM1-1 isoenzyme (hGSTM1-1) using a broad range of structurally diverse pesticides as probes. The results revealed that hGSTM1-1, compared to other classes of GSTs, displays limited ligandability and ligand-binding promiscuity, as revealed by kinetic inhibition studies. Among all tested pesticides, the carbamate insecticide pirimicarb was identified as the strongest inhibitor towards hGSTM1-1. Kinetic inhibition analysis showed that pirimicarb behaved as a mixed-type inhibitor toward glutathione (GSH) and 1-chloro-2,4-dinitrobenzene (CDNB). To shine a light on the restricted hGSTM1-1 ligand-binding promiscuity, the ligand-free crystal structure of hGSTM1-1 was determined by X-ray crystallography at 1.59 Å-resolution. Comparative analysis of ligand-free structure with the available ligand-bound structures allowed for the study of the enzyme’s plasticity and the induced-fit mechanism operated by hGSTM1-1. The results revealed important structural features of the H-site that contribute to xenobiotic-ligand binding and specificity. It was concluded that hGSTM1-1 interacts preferentially with one-ring aromatic compounds that bind at a discrete site which partially overlaps with the xenobiotic substrate binding site (H-site). The results of the study form a basis for the rational design of new drugs targeting hGSTM1-1.https://www.mdpi.com/1422-0067/23/7/3606CDNB1-chloro-2,4-dinitrobenzeneGSHglutathioneGSTglutathione transferase |
| spellingShingle | Charoutioun S. Bodourian Nirmal Poudel Anastassios C. Papageorgiou Mariana Antoniadi Nikolaos D. Georgakis Hiroshi Abe Nikolaos E. Labrou Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes International Journal of Molecular Sciences CDNB 1-chloro-2,4-dinitrobenzene GSH glutathione GST glutathione transferase |
| title | Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes |
| title_full | Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes |
| title_fullStr | Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes |
| title_full_unstemmed | Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes |
| title_short | Ligandability Assessment of Human Glutathione Transferase M1-1 Using Pesticides as Chemical Probes |
| title_sort | ligandability assessment of human glutathione transferase m1 1 using pesticides as chemical probes |
| topic | CDNB 1-chloro-2,4-dinitrobenzene GSH glutathione GST glutathione transferase |
| url | https://www.mdpi.com/1422-0067/23/7/3606 |
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