Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase
LTA<sub>4</sub>H is a bifunctional zinc metalloenzyme that converts leukotriene A<sub>4</sub> (LTA<sub>4</sub>) into leukotriene B<sub>4</sub> (LTB<sub>4</sub>), one of the most potent chemotactic agents involved in acute and chronic inflam...
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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/1422-0067/23/6/3140 |
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| author | Miquel Canyelles-Niño Àngels González-Lafont José M. Lluch |
| author_facet | Miquel Canyelles-Niño Àngels González-Lafont José M. Lluch |
| author_sort | Miquel Canyelles-Niño |
| collection | DOAJ |
| description | LTA<sub>4</sub>H is a bifunctional zinc metalloenzyme that converts leukotriene A<sub>4</sub> (LTA<sub>4</sub>) into leukotriene B<sub>4</sub> (LTB<sub>4</sub>), one of the most potent chemotactic agents involved in acute and chronic inflammatory diseases. In this reaction, LTA<sub>4</sub>H acts as an epoxide hydrolase with a unique and fascinating mechanism, which includes the stereoselective attachment of one water molecule to the carbon backbone of LTA<sub>4</sub> several methylene units away from the epoxide moiety. By combining Molecular Dynamics simulations and Quantum Mechanics/Molecular Mechanics calculations, we obtained a very detailed molecular picture of the different consecutive steps of that mechanism. By means of a rather unusual 1,7-nucleophilic substitution through a clear S<sub>N</sub>1 mechanism, the epoxide opens and the triene moiety of the substrate twists in such a way that the bond C<sub>6</sub>-C<sub>7</sub> adopts its <i>cis</i> (<i>Z</i>) configuration, thus exposing the <i>R</i> face of C<sub>12</sub> to the addition of a water molecule hydrogen-bonded to ASP375. Thus, the two stereochemical features that are required for the bioactivity of LTB<sub>4</sub> appear to be closely related. The noncovalent π-π stacking interactions between the triene moiety and two tyrosines (TYR267 and, especially, TYR378) that wrap the triene system along the whole reaction explain the preference for the <i>cis</i> configuration inside LTA<sub>4</sub>H. |
| first_indexed | 2024-03-09T19:42:47Z |
| format | Article |
| id | doaj.art-d8275da40d20474d9b7b475ac1119b30 |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T19:42:47Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d8275da40d20474d9b7b475ac1119b302023-11-24T01:33:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01236314010.3390/ijms23063140Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> HydrolaseMiquel Canyelles-Niño0Àngels González-Lafont1José M. Lluch2Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, SpainDepartament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, SpainLTA<sub>4</sub>H is a bifunctional zinc metalloenzyme that converts leukotriene A<sub>4</sub> (LTA<sub>4</sub>) into leukotriene B<sub>4</sub> (LTB<sub>4</sub>), one of the most potent chemotactic agents involved in acute and chronic inflammatory diseases. In this reaction, LTA<sub>4</sub>H acts as an epoxide hydrolase with a unique and fascinating mechanism, which includes the stereoselective attachment of one water molecule to the carbon backbone of LTA<sub>4</sub> several methylene units away from the epoxide moiety. By combining Molecular Dynamics simulations and Quantum Mechanics/Molecular Mechanics calculations, we obtained a very detailed molecular picture of the different consecutive steps of that mechanism. By means of a rather unusual 1,7-nucleophilic substitution through a clear S<sub>N</sub>1 mechanism, the epoxide opens and the triene moiety of the substrate twists in such a way that the bond C<sub>6</sub>-C<sub>7</sub> adopts its <i>cis</i> (<i>Z</i>) configuration, thus exposing the <i>R</i> face of C<sub>12</sub> to the addition of a water molecule hydrogen-bonded to ASP375. Thus, the two stereochemical features that are required for the bioactivity of LTB<sub>4</sub> appear to be closely related. The noncovalent π-π stacking interactions between the triene moiety and two tyrosines (TYR267 and, especially, TYR378) that wrap the triene system along the whole reaction explain the preference for the <i>cis</i> configuration inside LTA<sub>4</sub>H.https://www.mdpi.com/1422-0067/23/6/3140leukotriensleukotriene A<sub>4</sub> hydrolaseenzyme catalysisQM/MM calculationsmolecular dynamics simulationsproinflammatory lipid mediators |
| spellingShingle | Miquel Canyelles-Niño Àngels González-Lafont José M. Lluch Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase International Journal of Molecular Sciences leukotriens leukotriene A<sub>4</sub> hydrolase enzyme catalysis QM/MM calculations molecular dynamics simulations proinflammatory lipid mediators |
| title | Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase |
| title_full | Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase |
| title_fullStr | Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase |
| title_full_unstemmed | Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase |
| title_short | Theoretical Characterization of the Step-by-Step Mechanism of Conversion of Leukotriene A<sub>4</sub> to Leukotriene B<sub>4</sub> Catalysed by the Enzyme Leukotriene A<sub>4</sub> Hydrolase |
| title_sort | theoretical characterization of the step by step mechanism of conversion of leukotriene a sub 4 sub to leukotriene b sub 4 sub catalysed by the enzyme leukotriene a sub 4 sub hydrolase |
| topic | leukotriens leukotriene A<sub>4</sub> hydrolase enzyme catalysis QM/MM calculations molecular dynamics simulations proinflammatory lipid mediators |
| url | https://www.mdpi.com/1422-0067/23/6/3140 |
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