Näytä suppeat kuvailutiedot

Molecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13

Karkkainen Olli; Juvonen Risto O; Jokinen Elmeri M; Raunio Hannu; Huuskonen Juhani; Pentikäinen Olli T

dc.contributor.authorKarkkainen Olli
dc.contributor.authorJuvonen Risto O
dc.contributor.authorJokinen Elmeri M
dc.contributor.authorRaunio Hannu
dc.contributor.authorHuuskonen Juhani
dc.contributor.authorPentikäinen Olli T
dc.date.accessioned2022-10-28T12:38:20Z
dc.date.available2022-10-28T12:38:20Z
dc.identifier.urihttps://www.utupub.fi/handle/10024/160975
dc.description.abstractCYP2A13 enzyme is expressed in human extrahepatic tissues, while CYP2A6 is a hepatic enzyme. Reactions catalysed by CYP2A13 activate tobacco-specific nitrosamines and some other toxic xenobiotics in lungs. To compare oxidation characteristics and substrate-enzyme active site interactions in CYP2A13 vs CYP2A6, we evaluated CYP2A13 mediated oxidation characteristics of 23 coumarin derivatives and modelled their interactions at the enzyme active site. CYP2A13 did not oxidise six coumarin derivatives to corresponding fluorescent 7-hydroxycoumarins. The K-m-values of the other coumarins varied 0.85-97 mu M, V-max-values of the oxidation reaction varied 0.25-60 min(-1), and intrinsic clearance varied 26-6190 kL/min*mol CYP2A13). K-m of 6-chloro-3-(3-hydroxyphenyl)-coumarin was 0.85 (0.55-1.15 95% confidence limit) mu M and V-max 0.25 (0.23-0.26) min(-1), whereas K-m of 6-hydroxy-3-(3-hydroxyphenyl)-coumarin was 10.9 (9.9-11.8) mu M and V-max 60 (58-63) min(-1). Docking analyses demonstrated that 6-chloro or 6-methoxy and 3-(3-hydroxyphenyl) or 3-(4-trifluoromethylphenyl) substituents of coumarin increased affinity to CYP2A13, whereas 3-triazole or 3-(3-acetate phenyl) or 3-(4-acetate phenyl) substituents decreased it. The active site of CYP2A13 accepts more diversified types of coumarin substrates than the hepatic CYP2A6 enzyme. New sensitive and convenient profluorescent CYP2A13 substrates were identified, such as 6-chloro-3-(3-hydroxyphenyl)-coumarin having high affinity and 6-hydroxy-3-(3-hydroxyphenyl)-coumarin with high intrinsic clearance.
dc.language.isoen
dc.publisherTAYLOR & FRANCIS LTD
dc.titleMolecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13
dc.identifier.urlhttps://doi.org/10.1080/00498254.2021.1898700
dc.identifier.urnURN:NBN:fi-fe2021120859684
dc.relation.volume51
dc.contributor.organizationfi=biolääketieteen laitos, yhteiset|en=Institute of Biomedicine|
dc.contributor.organization-code2607100
dc.converis.publication-id67971924
dc.converis.urlhttps://research.utu.fi/converis/portal/Publication/67971924
dc.format.pagerange1207
dc.format.pagerange1216
dc.identifier.jour-issn0049-8254
dc.okm.affiliatedauthorPentikäinen, Olli
dc.okm.affiliatedauthorJokinen, Elmeri
dc.okm.discipline3111 Biolääketieteetfi_FI
dc.okm.discipline3111 Biomedicineen_GB
dc.okm.internationalcopublicationnot an international co-publication
dc.okm.internationalityInternational publication
dc.okm.typeJournal article
dc.publisher.countryUnited Kingdomen_GB
dc.publisher.countryBritanniafi_FI
dc.publisher.country-codeGB
dc.relation.doi10.1080/00498254.2021.1898700
dc.relation.ispartofjournalXenobiotica
dc.relation.issue11
dc.year.issued2021


Aineistoon kuuluvat tiedostot

Thumbnail

Aineisto kuuluu seuraaviin kokoelmiin

Näytä suppeat kuvailutiedot