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")

Data:	2019
Resum:	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.
Ajuts:	Agencia Estatal de Investigación CTQ2017-83745-P
Drets:	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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Arachidonic acids ; Catalytic functions ; Catalytic mechanisms ; Inflammatory response ; Molecular dynamics simulations ; Mutagenesis experiment ; Physiological process ; Quantum mechanics/molecular mechanics
Publicat a:	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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