Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2

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, cat...

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Autores: Suñer Rubio, Adrián|||0000-0002-6738-0082, Cebrián Prats, Anna|||0000-0001-6974-0670, González-Lafont, Àngels|||0000-0003-0729-2483, Lluch, José M.|||0000-0002-7536-1869
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:223209
Acceso en línea:https://ddd.uab.cat/record/223209
https://dx.doi.org/urn:doi:10.1039/c9ra08860a
Access Level:acceso abierto
Palabra clave:Arachidonic acids
Catalytic functions
Catalytic mechanisms
Inflammatory response
Molecular dynamics simulations
Mutagenesis experiment
Physiological process
Quantum mechanics/molecular mechanics
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spelling Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2A combined molecular dynamics and QM/MM studySuñer Rubio, Adrián|||0000-0002-6738-0082Cebrián Prats, Anna|||0000-0001-6974-0670González-Lafont, Àngels|||0000-0003-0729-2483Lluch, José M.|||0000-0002-7536-1869Arachidonic acidsCatalytic functionsCatalytic mechanismsInflammatory responseMolecular dynamics simulationsMutagenesis experimentPhysiological processQuantum mechanics/molecular mechanicsCyclooxygenases (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. 22019-01-0120192019-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/223209https://dx.doi.org/urn:doi:10.1039/c9ra08860areponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengAgencia Estatal de Investigación https://doi.org/10.13039/501100011033 CTQ2017-83745-Popen accesshttp://purl.org/coar/access_right/c_abf2Aquesta url de drets no existeix a la base de dades.https://creativecommons.org/licenses/by-nc/3.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2232092026-06-06T12:50:31Z
dc.title.none.fl_str_mv Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
A combined molecular dynamics and QM/MM study
title Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
spellingShingle Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
Suñer Rubio, Adrián|||0000-0002-6738-0082
Arachidonic acids
Catalytic functions
Catalytic mechanisms
Inflammatory response
Molecular dynamics simulations
Mutagenesis experiment
Physiological process
Quantum mechanics/molecular mechanics
title_short Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
title_full Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
title_fullStr Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
title_full_unstemmed Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
title_sort Unraveling how the Gly526Ser mutation arrests prostaglandin formation from arachidonic acid catalyzed by cyclooxygenase-2
dc.creator.none.fl_str_mv Suñer Rubio, Adrián|||0000-0002-6738-0082
Cebrián Prats, Anna|||0000-0001-6974-0670
González-Lafont, Àngels|||0000-0003-0729-2483
Lluch, José M.|||0000-0002-7536-1869
author Suñer Rubio, Adrián|||0000-0002-6738-0082
author_facet Suñer Rubio, Adrián|||0000-0002-6738-0082
Cebrián Prats, Anna|||0000-0001-6974-0670
González-Lafont, Àngels|||0000-0003-0729-2483
Lluch, José M.|||0000-0002-7536-1869
author_role author
author2 Cebrián Prats, Anna|||0000-0001-6974-0670
González-Lafont, Àngels|||0000-0003-0729-2483
Lluch, José M.|||0000-0002-7536-1869
author2_role author
author
author
dc.subject.none.fl_str_mv Arachidonic acids
Catalytic functions
Catalytic mechanisms
Inflammatory response
Molecular dynamics simulations
Mutagenesis experiment
Physiological process
Quantum mechanics/molecular mechanics
topic Arachidonic acids
Catalytic functions
Catalytic mechanisms
Inflammatory response
Molecular dynamics simulations
Mutagenesis experiment
Physiological process
Quantum mechanics/molecular mechanics
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2
2019-01-01
2019
2019-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/223209
https://dx.doi.org/urn:doi:10.1039/c9ra08860a
url https://ddd.uab.cat/record/223209
https://dx.doi.org/urn:doi:10.1039/c9ra08860a
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 CTQ2017-83745-P
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Aquesta url de drets no existeix a la base de dades.
https://creativecommons.org/licenses/by-nc/3.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Aquesta url de drets no existeix a la base de dades.
https://creativecommons.org/licenses/by-nc/3.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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