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dc.contributor.authorJuvonen, Risto O.
dc.contributor.authorRauhamäki, Sanna
dc.contributor.authorKortet, Sami
dc.contributor.authorNiinivehmas, Sanna
dc.contributor.authorTroberg, Johanna
dc.contributor.authorPetsalo, Aleksanteri
dc.contributor.authorHuuskonen, Juhani
dc.contributor.authorRaunio, Hannu
dc.contributor.authorFinel, Moshe
dc.contributor.authorPentikäinen, Olli
dc.date.accessioned2018-03-06T07:13:21Z
dc.date.available2019-02-10T22:35:43Z
dc.date.issued2018
dc.identifier.citationJuvonen, R. O., Rauhamäki, S., Kortet, S., Niinivehmas, S., Troberg, J., Petsalo, A., Huuskonen, J., Raunio, H., Finel, M., & Pentikäinen, O. (2018). Molecular docking-based design and development of a highly selective probe substrate for UDP-glucuronosyltransferase 1A10. <i>Molecular Pharmaceutics</i>, <i>15</i>(3), 923-933. <a href="https://doi.org/10.1021/acs.molpharmaceut.7b00871" target="_blank">https://doi.org/10.1021/acs.molpharmaceut.7b00871</a>
dc.identifier.otherCONVID_27897589
dc.identifier.otherTUTKAID_76789
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/57252
dc.description.abstractIntestinal and hepatic glucuronidation by the UDP-glucuronosyltransferases (UGTs) greatly affect the bioavailability of phenolic compounds. UGT1A10 catalyzes glucuronidation reactions in the intestine, but not in the liver. Here, our aim was to develop selective, fluorescent substrates to easily elucidate UGT1A10 function. To this end, homology models were constructed and used to design new substrates, and subsequently, six novel C3-substituted (4-fluorophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-(dimethylamino)phenyl, 4-methylphenyl, or triazole) 7-hydroxycoumarin derivatives were synthesized from inexpensive starting materials. All tested compounds could be glucuronidated to nonfluorescent glucuronides by UGT1A10, four of them highly selectively by this enzyme. A new UGT1A10 mutant, 1A10-H210M, was prepared on the basis of the newly constructed model. Glucuronidation kinetics of the new compounds, in both wild-type and mutant UGT1A10 enzymes, revealed variable effects of the mutation. All six new C3-substituted 7-hydroxycoumarins were glucuronidated faster by human intestine than by liver microsomes, supporting the results obtained with recombinant UGTs. The most selective 4-(dimethylamino)phenyl and triazole C3-substituted 7-hydroxycoumarins could be very useful substrates in studying the function and expression of the human UGT1A10.
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.relation.ispartofseriesMolecular Pharmaceutics
dc.subject.other7-hydroxycoumarin
dc.subject.otherUDP-glucuronosyltransferase
dc.subject.otherglucuronidation
dc.subject.otherin silico
dc.subject.otherdrug metabolism
dc.titleMolecular docking-based design and development of a highly selective probe substrate for UDP-glucuronosyltransferase 1A10
dc.typearticle
dc.identifier.urnURN:NBN:fi:jyu-201803051654
dc.contributor.laitosBio- ja ympäristötieteiden laitosfi
dc.contributor.laitosKemian laitosfi
dc.contributor.laitosDepartment of Biological and Environmental Scienceen
dc.contributor.laitosDepartment of Chemistryen
dc.contributor.oppiaineSolu- ja molekyylibiologiafi
dc.contributor.oppiaineOrgaaninen kemiafi
dc.contributor.oppiaineCell and Molecular Biologyen
dc.contributor.oppiaineOrganic Chemistryen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.date.updated2018-03-05T13:15:07Z
dc.description.reviewstatuspeerReviewed
dc.format.pagerange923-933
dc.relation.issn1543-8384
dc.relation.numberinseries3
dc.relation.volume15
dc.type.versionacceptedVersion
dc.rights.copyright© 2018 American Chemical Society. This is a final draft version of an article whose final and definitive form has been published by American Chemical Society. Published in this repository with the kind permission of the publisher.
dc.rights.accesslevelopenAccessfi
dc.subject.ysofluoresenssi
jyx.subject.urihttp://www.yso.fi/onto/yso/p3265
dc.relation.doi10.1021/acs.molpharmaceut.7b00871


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