Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2 : A combined molecular dynamics and QM/MM study
Suñer Rubio, Adrián (Universitat Autònoma de Barcelona. Departament de Química)
Cebrián Prats, Anna (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:	2019
Resumen:	Cyclooxygenases (COXs) are the enzymes responsible for the biosynthesis of prostaglandins, eicosanoids that play a major role in many physiological processes. Particularly, prostaglandins are known to trigger inflammation, and COX-2, the enzyme isoform associated with this inflammatory response, catalyzes the cyclooxidation of arachidonic acid, leading to prostaglandin G2. For this reason, COX-2 has been a very important pharmacological target for several decades now. The catalytic mechanism of COX-2, a so-called all-radical mechanism, consists of six chemical steps. One of the most intriguing aspects of this mechanism is how COX-2 manages to control the regio- and stereospecificity of the products formed at each step. Mutagenesis experiments have previously been performed in an attempt to find those hot-spot residues that make such control possible. In this context, it is worth mentioning that in experiments with the Gly526Ser COX-2 mutant, prostaglandins were not detected. In this paper, we have combined molecular dynamics simulations and quantum mechanics/molecular mechanics calculations to analyze how the COX-2 catalytic mechanism is modified in the Gly526Ser mutant. Therefore, this study provides new insights into the COX-2 catalytic function.
Ayudas:	Ministerio de Ciencia e Innovación CTQ2017-83745-P
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, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Arachidonic acids ; Catalytic functions ; Catalytic mechanisms ; Inflammatory response ; Molecular dynamics simulations ; Mutagenesis experiment ; Physiological process ; Quantum mechanics/molecular mechanics
Publicado en:	RSC advances, Vol. 10, issue 2 (2019) , p. 986-997, ISSN 2046-2069

DOI: 10.1039/c9ra08860a
PMID: 35494430

12 p, 1.4 MB

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