Theoretical Study of the Arachidonic Acid Conversion into Leukotriene A4 Catalyzed by Human 5-Lipoxygenase : Hydroperoxidation and Epoxidation Mechanisms and Arachidonic Acid Active Site Access
Cruz Saez, Alejandro (Universitat Autònoma de Barcelona. Departament de Química)
González Lafont, Àngels (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Fecha:	2024
Resumen:	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.
Ayudas:	Agencia Estatal de Investigación PID2020-113764GB-I00
Nota:	Altres ajuts: acords transformatius de la UAB
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Carbon ; Chemical structure ; Hydrogen abstraction ; Oxygen ; Peptides and proteins
Publicado en:	ACS catalysis, Vol. 14, Issue 2 (January 2024) , p. 637-656, ISSN 2155-5435

DOI: 10.1021/acscatal.3c04954

20 p, 15.9 MB

El registro aparece en las colecciones:
Documentos de investigación > Documentos de los grupos de investigación de la UAB > Centros y grupos de investigación (producción científica) > Ciencias de la salud y biociencias > Instituto de Biotecnología y de Biomedicina (IBB)
Artículos > Artículos de investigación
Artículos > Artículos publicados