Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors

Mammalian ALOX15 are allosteric enzymes but the mechanism of allosteric regulation remains a matter of discussion. Octyl (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamate inhibits the linoleate oxygenase activity of ALOX15 at nanomolar concentrations, but oxygenation of arachidonic acid is h...

Descripción completa

Detalles Bibliográficos
Autores: Gavrilyuk, Viktor, Cruz Sáez, Alejandro|||0000-0003-0928-0718, Aksenov, Vladislav, Nurgaliev, Danila, Zhuravlev, Alexander, Golovanov, Alexey, Lluch López, Josep Maria, Kuhn, Hartmut, Ivanov, Igor, González Lafont, Àngels
Tipo de recurso: artículo
Fecha de publicación:2025
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:dnet:upcommonspor::1051dcb8755ecb74b6082f86955c6293
Acceso en línea:https://hdl.handle.net/2117/460911
https://dx.doi.org/10.1039/D5RA03640B
Access Level:acceso abierto
Palabra clave:Mammalian
ALOX15
Allosteric properties
Àrees temàtiques de la UPC::Enginyeria química
id ES_fc4e54bc5167eae165f1582105648fca
oai_identifier_str oai:dnet:upcommonspor::1051dcb8755ecb74b6082f86955c6293
network_acronym_str ES
network_name_str España
repository_id_str
spelling Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitorsGavrilyuk, ViktorCruz Sáez, Alejandro|||0000-0003-0928-0718Aksenov, VladislavNurgaliev, DanilaZhuravlev, AlexanderGolovanov, AlexeyLluch López, Josep MariaKuhn, HartmutIvanov, IgorGonzález Lafont, ÀngelsMammalianALOX15Allosteric propertiesÀrees temàtiques de la UPC::Enginyeria químicaMammalian ALOX15 are allosteric enzymes but the mechanism of allosteric regulation remains a matter of discussion. Octyl (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamate inhibits the linoleate oxygenase activity of ALOX15 at nanomolar concentrations, but oxygenation of arachidonic acid is hardly affected. The mechanism of substrate selective inhibition suggests inter-monomer communication within the allosteric ALOX15 dimer complex, in which the inhibitor binding to monomer A induces conformational alterations in the structure of the active site of monomer B. Interactions of the NH-group of the indole moiety with the Fe(III)–OH- cofactor or of the SO2 group of the sulfocarbamate moiety with the side chain NH2 group of Gln596 may be important for proper inhibitor placement in the ALOX15 allosteric complex. Substitution of a H-bond donor to a H-bond acceptor (NH–O-exchange) impacts but does not eliminate the ability of the compound to inhibit preferentially the LA-oxygenase activity of ALOX15. In contrast, swapping the positions of CH3O- and NH groups at the 2-aryl moiety led to a loss of substrate selective inhibition. In silico docking studies and molecular dynamics-simulations using a dimeric allosteric ALOX15 model have shown that binding of the substrate molecule to ALOX15 monomer B may alter the structure of the monomer A-inhibitor complex forcing the inhibitor to adopt a different binding mode. Taken together, this data suggests the possibility of two-way communication between ALOX15 monomers during enzymatic catalysis.Russian Ministry of Science and High Education (FSFZ-2023-0004) supported the experimental part of this work. We thank the Spanish “Ministerio de Ciencia, Innovación y Universidades” (Grant PID2020-113764GB-I00 and Grant PID2023-147140NB-I00). We also acknowledge CSUC for computational facilities as well as a Shared Science and training Center for Collective Use of RTU MIREA supported by the Ministry of Science and Higher Education by Agreement No. 075-15-2025-548.Peer ReviewedRoyal Society of Chemistry (RSC)20252025-09-0820262026-04-22journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/460911https://dx.doi.org/10.1039/D5RA03640Breponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)InglésengAgencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2020-113764GB-I00 USO DE LA INGENIERIA BIOMOLECULAR Y DE LA FOTOFARMACOLOGIA TEORICAS PARA DISEÑAR Y OBTENER NUEVOS FARMACOS PARA ENFERMEDADES HUMANAS, INCLUYENDO LA COVID-19Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2023-147140NB-I00 ABORDAJE DEL CANCER COMO UNA ENFERMEDAD BASADA EN LA INFLAMACION: DESARROLLO TEORICO DE FORMAS INNOVADORAS PARA DISEÑAR NUEVOS TRATAMIENTOS FARMACOLOGICOS Y FOTOFARMACOLOGICOSopen accesshttp://purl.org/coar/access_right/c_abf2Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessoai:dnet:upcommonspor::1051dcb8755ecb74b6082f86955c62932026-05-27T15:37:01Z
dc.title.none.fl_str_mv Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
title Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
spellingShingle Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
Gavrilyuk, Viktor
Mammalian
ALOX15
Allosteric properties
Àrees temàtiques de la UPC::Enginyeria química
title_short Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
title_full Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
title_fullStr Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
title_full_unstemmed Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
title_sort Exploring allosteric properties of mammalian ALOX15: octyl (N-(4-(benzofuran-2-yl)-2-methoxyphenyl)sulfamoyl)- and octyl (N-(4-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates as ALOX inhibitors
dc.creator.none.fl_str_mv Gavrilyuk, Viktor
Cruz Sáez, Alejandro|||0000-0003-0928-0718
Aksenov, Vladislav
Nurgaliev, Danila
Zhuravlev, Alexander
Golovanov, Alexey
Lluch López, Josep Maria
Kuhn, Hartmut
Ivanov, Igor
González Lafont, Àngels
author Gavrilyuk, Viktor
author_facet Gavrilyuk, Viktor
Cruz Sáez, Alejandro|||0000-0003-0928-0718
Aksenov, Vladislav
Nurgaliev, Danila
Zhuravlev, Alexander
Golovanov, Alexey
Lluch López, Josep Maria
Kuhn, Hartmut
Ivanov, Igor
González Lafont, Àngels
author_role author
author2 Cruz Sáez, Alejandro|||0000-0003-0928-0718
Aksenov, Vladislav
Nurgaliev, Danila
Zhuravlev, Alexander
Golovanov, Alexey
Lluch López, Josep Maria
Kuhn, Hartmut
Ivanov, Igor
González Lafont, Àngels
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Mammalian
ALOX15
Allosteric properties
Àrees temàtiques de la UPC::Enginyeria química
topic Mammalian
ALOX15
Allosteric properties
Àrees temàtiques de la UPC::Enginyeria química
description Mammalian ALOX15 are allosteric enzymes but the mechanism of allosteric regulation remains a matter of discussion. Octyl (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamate inhibits the linoleate oxygenase activity of ALOX15 at nanomolar concentrations, but oxygenation of arachidonic acid is hardly affected. The mechanism of substrate selective inhibition suggests inter-monomer communication within the allosteric ALOX15 dimer complex, in which the inhibitor binding to monomer A induces conformational alterations in the structure of the active site of monomer B. Interactions of the NH-group of the indole moiety with the Fe(III)–OH- cofactor or of the SO2 group of the sulfocarbamate moiety with the side chain NH2 group of Gln596 may be important for proper inhibitor placement in the ALOX15 allosteric complex. Substitution of a H-bond donor to a H-bond acceptor (NH–O-exchange) impacts but does not eliminate the ability of the compound to inhibit preferentially the LA-oxygenase activity of ALOX15. In contrast, swapping the positions of CH3O- and NH groups at the 2-aryl moiety led to a loss of substrate selective inhibition. In silico docking studies and molecular dynamics-simulations using a dimeric allosteric ALOX15 model have shown that binding of the substrate molecule to ALOX15 monomer B may alter the structure of the monomer A-inhibitor complex forcing the inhibitor to adopt a different binding mode. Taken together, this data suggests the possibility of two-way communication between ALOX15 monomers during enzymatic catalysis.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025-09-08
2026
2026-04-22
dc.type.none.fl_str_mv journal 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://hdl.handle.net/2117/460911
https://dx.doi.org/10.1039/D5RA03640B
url https://hdl.handle.net/2117/460911
https://dx.doi.org/10.1039/D5RA03640B
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 http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 PID2020-113764GB-I00 USO DE LA INGENIERIA BIOMOLECULAR Y DE LA FOTOFARMACOLOGIA TEORICAS PARA DISEÑAR Y OBTENER NUEVOS FARMACOS PARA ENFERMEDADES HUMANAS, INCLUYENDO LA COVID-19
Agencia Estatal de Investigación http://doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023 PID2023-147140NB-I00 ABORDAJE DEL CANCER COMO UNA ENFERMEDAD BASADA EN LA INFLAMACION: DESARROLLO TEORICO DE FORMAS INNOVADORAS PARA DISEÑAR NUEVOS TRATAMIENTOS FARMACOLOGICOS Y FOTOFARMACOLOGICOS
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
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
Attribution-NonCommercial 4.0 International
http://creativecommons.org/licenses/by-nc/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Royal Society of Chemistry (RSC)
publisher.none.fl_str_mv Royal Society of Chemistry (RSC)
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869425410141323264
score 15,812455

Similares en LA Referencia