Theoretical Study of the Arachidonic Acid Conversion into Leukotriene A4 Catalyzed by Human 5-Lipoxygenase
Inflammation is at the base of many different diseases. Leukotrienes (LTs) are pro-inflammatory mediators derived from arachidonic acid (AA), which play significant roles in acute inflammation. Lipoxins are specialized pro-resolving mediators (SPMs), also formed from AA, that promote the resolution...
| Autores: | , , |
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| Tipo de recurso: | artículo |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Idioma: | inglés |
| OAI Identifier: | oai:ddd.uab.cat:287793 |
| Acceso en línea: | https://ddd.uab.cat/record/287793 https://dx.doi.org/urn:doi:10.1021/acscatal.3c04954 |
| Access Level: | acceso abierto |
| Palabra clave: | Carbon Chemical structure Hydrogen abstraction Oxygen Peptides and proteins |
| Sumario: | Inflammation is at the base of many different diseases. Leukotrienes (LTs) are pro-inflammatory mediators derived from arachidonic acid (AA), which play significant roles in acute inflammation. Lipoxins are specialized pro-resolving mediators (SPMs), also formed from AA, that promote the resolution of acute inflammation. However, if resolution fails, chronic inflammatory processes might develop. The enzyme human-5-lipoxygenase (5-LOX) catalyzes the biosynthesis of leukotriene named LTA but also intervenes in the formation of the lipoxin LXA. These two biological functions have made the 5-LOX isoform a current target for pharmaceutical investigations in several inflammatory-based diseases searching for inhibitors that block the leukotriene reaction pathway but not lipoxin's formation. However, the development of those selective inhibitors has been hampered by the lack of a crystal structure of human 5-LOX. In this work, we have built a complete solvated model of the human-5-LOX: AA Michaelis complex using, as initial coordinates, the human 5-LOX structure from the AlphaFold protein structure database. We aim to analyze at the molecular level the overall catalytic mechanism of 5-LOX that first converts AA into 5(S)-HpETE through a hydroperoxidation reaction and, second, transforms this hydroperoxide into LTA following an epoxidation process. Methodologically, we have performed molecular dynamics simulations and quantum mechanics/molecular mechanics calculations. The free energy profiles for AA entrance into the 5-LOX's binding cavity have been calculated by steered molecular dynamics. This detailed molecular information can explain human-5-LOX's in vitro activity (without the presence of the membrane-embedded 5-lipoxygenase-activating protein) and help to design selective inhibitors favoring inflammation resolution. |
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