Deciphering the Molecular Details of the Lipoxin Formation Mechanism in the 5(S),15(S)-DiHpETE Biosynthetic Pathway Catalyzed by Reticulocyte 15-Lipoxygenase-1
Cruz Saez, Alejandro (Universitat Autònoma de Barcelona. Departament de Química)
González Lafont, Àngels (Universitat Autònoma de Barcelona. Departament de Química)
Lluch López, Josep Maria (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")

Fecha:	2020
Descripción:	13 pàg.
Resumen:	Chronic inflammation is now widely recognized to play important roles in many commonly occurring diseases, including COVID-19. The resolution response to this chronic inflammation is an active process governed by specialized pro-resolving mediators (SPMs) like the lipid mediators known as lipoxins. The biosynthesis of lipoxins is catalyzed by several lipoxygenases (LOXs) from arachidonic acid. However, the molecular details of the mechanisms involved are not well known yet. In this paper, we have combined molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations to analyze how reticulocyte 15-LOX-1 catalyzes the production of lipoxins from 5(S),15(S)-diHpETE. Our results indicate that the dehydration mechanism from 5(S),15(S)-diHpETE, via the formation of an epoxide, presents huge energy barriers even though it was one of the two a priori synthetic proposals. This result is compatible with the fact that no epoxide has been directly detected as an intermediate in the catalytic formation of lipoxins from 5(S),15(S)-diHpETE. Conversely, the oxygenation of 5(S),15(S)-diHpETE at C14 is feasible because there is an open channel connecting the protein surface with this carbon atom, and the energy barrier for oxygen addition through this channel is small. The analysis of the following steps of this mechanism, leading to the corresponding hydroperoxide at the 15-LOX-1 active site, indicates that the oxygenation mechanism will lead to the formation of lipoxinB4 after the final action of a reductase. In contrast, our calculations are in agreement with experiments that lipoxinA4 cannot derive from 5(S),15(S)-diHpETE by either of the two proposed mechanisms and that 5(S),15(S)-diHETE is not an intermediate of lipoxin biosynthesis catalyzed by 15-LOX-1.
Ayudas:	Agencia Estatal de Investigación CTQ2017-83745-P
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Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Lipoxins ; Biosynthetic pathways ; 15-Lipoxygenase ; Hydrogen abstraction reactions ; Dehydration mechanism ; Oxygen access channels ; QM/MM calculations ; Molecular dynamics simulations
Publicado en:	Journal of physical chemistry B, Vol. 124, Num. 50 (December 2020) , p. 11406-11418, ISSN 1520-5207

DOI: 10.1021/acs.jpcb.0c09147
PMID: 33274949

Postprint 43 p, 1.8 MB

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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)
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