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dc.contributor.authorJuvonen, Risto O.
dc.contributor.authorAhinko, Mira
dc.contributor.authorJokinen, Elmeri M.
dc.contributor.authorHuuskonen, Juhani
dc.contributor.authorRaunio, Hannu
dc.contributor.authorPentikäinen, Olli T.
dc.date.accessioned2021-04-21T07:21:34Z
dc.date.available2021-04-21T07:21:34Z
dc.date.issued2021
dc.identifier.citationJuvonen, R. O., Ahinko, M., Jokinen, E. M., Huuskonen, J., Raunio, H., & Pentikäinen, O. T. (2021). Substrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes : In Vitro Enzyme Kinetics and In Silico Modeling. <i>ACS Omega</i>, <i>6</i>(17), 11286-11296. <a href="https://doi.org/10.1021/acsomega.1c00123" target="_blank">https://doi.org/10.1021/acsomega.1c00123</a>
dc.identifier.otherCONVID_67404130
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/75152
dc.description.abstractOf the three enzymes in the human cytochrome P450 family 1, CYP1A2 is an important enzyme mediating metabolism of xenobiotics including drugs in the liver, while CYP1A1 and CYP1B1 are expressed in extrahepatic tissues. Currently used CYP substrates, such as 7-ethoxycoumarin and 7-ethoxyresorufin, are oxidized by all individual CYP1 forms. The main aim of this study was to find profluorescent coumarin substrates that are more selective for the individual CYP1 forms. Eleven 3-phenylcoumarin derivatives were synthetized, their enzyme kinetic parameters were determined, and their interactions in the active sites of CYP1 enzymes were analyzed by docking and molecular dynamic simulations. All coumarin derivatives and 7-ethoxyresorufin and 7-pentoxyresorufin were oxidized by at least one CYP1 enzyme. 3-(3-Methoxyphenyl)-6-methoxycoumarin (19) was 7-O-demethylated by similar high efficiency [21–30 ML/(min·mol CYP)] by all CYP1 forms and displayed similar binding in the enzyme active sites. 3-(3-Fluoro-4-acetoxyphenyl)coumarin (14) was selectively 7-O-demethylated by CYP1A1, but with low efficiency [0.16 ML/(min mol)]. This was explained by better orientation and stronger H-bond interactions in the active site of CYP1A1 than that of CYP1A2 and CYP1B1. 3-(4-Acetoxyphenyl)-6-chlorocoumarin (20) was 7-O-demethylated most efficiently by CYP1B1 [53 ML/(min·mol CYP)], followed by CYP1A1 [16 ML/(min·mol CYP)] and CYP1A2 [0.6 ML/(min·mol CYP)]. Variations in stabilities of complexes between 20 and the individual CYP enzymes explained these differences. Compounds 14, 19, and 20 are candidates to replace traditional substrates in measuring activity of human CYP1 enzymes.en
dc.format.mimetypeapplication/pdf
dc.languageeng
dc.language.isoeng
dc.publisherAmerican Chemical Society (ACS)
dc.relation.ispartofseriesACS Omega
dc.rightsCC BY 4.0
dc.titleSubstrate Selectivity of Coumarin Derivatives by Human CYP1 Enzymes : In Vitro Enzyme Kinetics and In Silico Modeling
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-202104212451
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.oppiaineOrgaaninen kemiafi
dc.contributor.oppiaineSolu- ja molekyylibiologiafi
dc.contributor.oppiaineNanoscience Centerfi
dc.contributor.oppiaineOrganic Chemistryen
dc.contributor.oppiaineCell and Molecular Biologyen
dc.contributor.oppiaineNanoscience Centeren
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.format.pagerange11286-11296
dc.relation.issn2470-1343
dc.relation.numberinseries17
dc.relation.volume6
dc.type.versionpublishedVersion
dc.rights.copyright© 2021 The Authors. Published by American Chemical Society
dc.rights.accesslevelopenAccessfi
dc.subject.ysosytokromit
dc.subject.ysobiolääketiede
dc.subject.ysolääkkeet
dc.subject.ysoentsyymit
dc.subject.ysolääkeaineet
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p24286
jyx.subject.urihttp://www.yso.fi/onto/yso/p13097
jyx.subject.urihttp://www.yso.fi/onto/yso/p1077
jyx.subject.urihttp://www.yso.fi/onto/yso/p4769
jyx.subject.urihttp://www.yso.fi/onto/yso/p1707
dc.rights.urlhttps://creativecommons.org/licenses/by/4.0/
dc.relation.doi10.1021/acsomega.1c00123
jyx.fundinginformationThe research was funded by Jenny and Antti Wihuri Foundation, Emil Aaltonen Foundation (M.A.), and The Instrumentarium Science Foundation (E.M.J.). The Finnish IT Center for Science (CSC) is acknowledged for generous computational resources (O.T.P.; Projects jyy2516 and jyy2585).
dc.type.okmA1


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