Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase
The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A<sub>4</sub> epoxide which is converted to a chemotactic...
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7539 |
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| author | Tarvi Teder Stefanie König Rajkumar Singh Bengt Samuelsson Oliver Werz Ulrike Garscha Jesper Z. Haeggström |
| author_facet | Tarvi Teder Stefanie König Rajkumar Singh Bengt Samuelsson Oliver Werz Ulrike Garscha Jesper Z. Haeggström |
| author_sort | Tarvi Teder |
| collection | DOAJ |
| description | The 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A<sub>4</sub> epoxide which is converted to a chemotactic leukotriene B<sub>4</sub> (LTB<sub>4</sub>) by leukotriene A<sub>4</sub> hydrolase (LTA<sub>4</sub>H). In addition, LTA<sub>4</sub>H possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTA<sub>4</sub>H, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTA<sub>4</sub>H at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTA<sub>4</sub>H with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB<sub>4</sub> and can potentially be used as modulators of inflammatory response by the 5-LOX pathway. |
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| last_indexed | 2024-03-11T04:55:28Z |
| publishDate | 2023-04-01 |
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| spelling | doaj.art-c79294583b1b4a64850cd27f0f44a1902023-11-17T19:42:00ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248753910.3390/ijms24087539Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> HydrolaseTarvi Teder0Stefanie König1Rajkumar Singh2Bengt Samuelsson3Oliver Werz4Ulrike Garscha5Jesper Z. Haeggström6Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Greifswald University, 17489 Greifswald, GermanyDivision of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, SwedenDivision of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, SwedenDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, 7743 Jena, GermanyDepartment of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Greifswald University, 17489 Greifswald, GermanyDivision of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, SwedenThe 5-lipoxygenase (5-LOX) pathway gives rise to bioactive inflammatory lipid mediators, such as leukotrienes (LTs). 5-LOX carries out the oxygenation of arachidonic acid to the 5-hydroperoxy derivative and then to the leukotriene A<sub>4</sub> epoxide which is converted to a chemotactic leukotriene B<sub>4</sub> (LTB<sub>4</sub>) by leukotriene A<sub>4</sub> hydrolase (LTA<sub>4</sub>H). In addition, LTA<sub>4</sub>H possesses aminopeptidase activity to cleave the N-terminal proline of a pro-inflammatory tripeptide, prolyl-glycyl-proline (PGP). Based on the structural characteristics of LTA<sub>4</sub>H, it is possible to selectively inhibit the epoxide hydrolase activity while sparing the inactivating, peptidolytic, cleavage of PGP. In the current study, chalcogen-containing compounds, 4-(4-benzylphenyl) thiazol-2-amine (ARM1) and its selenazole (TTSe) and oxazole (TTO) derivatives were characterized regarding their inhibitory and binding properties. All three compounds selectively inhibit the epoxide hydrolase activity of LTA<sub>4</sub>H at low micromolar concentrations, while sparing the aminopeptidase activity. These inhibitors also block the 5-LOX activity in leukocytes and have distinct inhibition constants with recombinant 5-LOX. Furthermore, high-resolution structures of LTA<sub>4</sub>H with inhibitors were determined and potential binding sites to 5-LOX were proposed. In conclusion, we present chalcogen-containing inhibitors which differentially target essential steps in the biosynthetic route for LTB<sub>4</sub> and can potentially be used as modulators of inflammatory response by the 5-LOX pathway.https://www.mdpi.com/1422-0067/24/8/75395-lipoxygenaseaminopeptidaseinflammationleukotriene A<sub>4</sub> hydrolase |
| spellingShingle | Tarvi Teder Stefanie König Rajkumar Singh Bengt Samuelsson Oliver Werz Ulrike Garscha Jesper Z. Haeggström Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase International Journal of Molecular Sciences 5-lipoxygenase aminopeptidase inflammation leukotriene A<sub>4</sub> hydrolase |
| title | Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase |
| title_full | Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase |
| title_fullStr | Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase |
| title_full_unstemmed | Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase |
| title_short | Modulation of the 5-Lipoxygenase Pathway by Chalcogen-Containing Inhibitors of Leukotriene A<sub>4</sub> Hydrolase |
| title_sort | modulation of the 5 lipoxygenase pathway by chalcogen containing inhibitors of leukotriene a sub 4 sub hydrolase |
| topic | 5-lipoxygenase aminopeptidase inflammation leukotriene A<sub>4</sub> hydrolase |
| url | https://www.mdpi.com/1422-0067/24/8/7539 |
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