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dc.contributor.author
Ivanov, Igor
dc.contributor.author
Golovanov, Alexey B.
dc.contributor.author
Ferretti, Cristián Alejandro
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dc.contributor.author
Canyelles-Niño, Miquel
dc.contributor.author
Heydeck, Dagmar
dc.contributor.author
Stehling, Sabine
dc.contributor.author
Lluch, José M.
dc.contributor.author
González Lafont, Ángels
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dc.contributor.author
Kühn, Hartmut
dc.date.available
2020-07-23T14:41:10Z
dc.date.issued
2019-10
dc.identifier.citation
Ivanov, Igor; Golovanov, Alexey B.; Ferretti, Cristián Alejandro; Canyelles-Niño, Miquel; Heydeck, Dagmar; et al.; Mutations of triad determinants changes the substrate alignment at the catalytic center of human ALOX5.; American Chemical Society; ACS Chemical Biology; 14; 10-2019; 2768-2782
dc.identifier.issn
1554-8929
dc.identifier.uri
http://hdl.handle.net/11336/110012
dc.description.abstract
For the specificity of ALOX15 orthologs of different mammals the geometry of the amino acids Phe353, Ile418, Met419 and Ile593 (?triad determinants?) is important and mutagenesis of these residues altered the reaction specificity of these enzymes. Here we expressed wildtype human ALOX5 and its F359W/A424I/N425M/A603I mutant in Sf9 insect cells and characterized the catalytic differences of the two enzyme variants. We found that wildtype ALOX5 converted arachidonic acid mainly to 5(S)-HpETE. In contrast, 15(S)- and 8(S)-H(p)ETE were formed by the mutant enzyme. In addition to arachidonic acid, wildtype ALOX5 accepted EPA as substrate but C18 fatty acids were not oxygenated. The quadruple mutant also accepted linoleic acid, alpha- and gamma-linolenic acid as substrate. Structural analysis of the oxygenation products and kinetic studies with stereospecifically labeled 11(S)- and 11(R)-deutero linoleic acid suggested alternative ways of substrate orientation at the active site. In silico docking studies, molecular dynamics simulations and QM/MM calculations confirmed this hypothesis. These data indicate that ?triad determinant? mutagenesis alters the catalytic properties of ALOX5 abolishing its leukotriene synthase activity but improving its biosynthetic capacity for pro-resolving lipoxins.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
American Chemical Society
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dc.rights
info:eu-repo/semantics/restrictedAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
EICOSANOIDS
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LIPOXYGENASE
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FATTY ACIDS
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MUTAGENESIS
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MOLECULAR DYNAMICS
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REACTION MECHANISM
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Otras Ciencias Químicas
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dc.subject.classification
Ciencias Químicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Mutations of triad determinants changes the substrate alignment at the catalytic center of human ALOX5.
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2020-07-20T16:21:33Z
dc.journal.volume
14
dc.journal.pagination
2768-2782
dc.journal.pais
Estados Unidos
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dc.journal.ciudad
Washington
dc.description.fil
Fil: Ivanov, Igor. Russian Technological University;
dc.description.fil
Fil: Golovanov, Alexey B.. Russian Technological University;
dc.description.fil
Fil: Ferretti, Cristián Alejandro. Universidad Nacional del Litoral. Instituto de Química Aplicada del Litoral. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe. Instituto de Química Aplicada del Litoral.; Argentina
dc.description.fil
Fil: Canyelles-Niño, Miquel. Universitat Autònoma de Barcelona; España
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Fil: Heydeck, Dagmar. Humboldt University Berlin;
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Fil: Stehling, Sabine. Humboldt University Berlin;
dc.description.fil
Fil: Lluch, José M.. Universitat Autònoma de Barcelona; España
dc.description.fil
Fil: González Lafont, Ángels. Universitat Autònoma de Barcelona; España
dc.description.fil
Fil: Kühn, Hartmut. Humboldt University Berlin;
dc.journal.title
ACS Chemical Biology
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://pubs.acs.org/doi/10.1021/acschembio.9b00674
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1021/acschembio.9b00674
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