Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase by multimode mechanisms.

Hdl Handle:
http://hdl.handle.net/10034/606615
Title:
Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase by multimode mechanisms.
Authors:
Ogunbayo, Oluseye A.; Michelangeli, Francesco
Abstract:
Flavonoids are group of plant-derived hydroxylated polycyclic molecules found in fruit and vegetables. They are known to bio-accumulate within humans and are considered to have beneficial health effects, including cancer chemoprotection. One mechanism proposed to explain this is that they are able to induce apoptosis in cancer cells by inhibiting a variety of kinases and also the Ca²⁺ ATPase. An investigation was undertaken with respect to the mechanism of inhibition for three flavonoids: quercetin, galangin and 3,6 dihydroxyflavone (3,6-DHF). Each inhibited the Ca²⁺ ATPase with K(i) values of 8.7, 10.3 and 5.4 μM, respectively, showing cooperative inhibition with n ~ 2. Given their similar structures, the flavonoids showed several differences in their mechanisms of inhibition. All three flavonoids stabilized the ATPase in the E₁ conformation and reduced [³²P]-ATP binding. However, both galangin and 3,6-DHF increased the affinity of Ca²⁺ for the ATPase by decreasing the Ca²⁺-dissociation rate constant, whereas quercetin had little effect. Ca²⁺-induced changes in tryptophan fluorescence levels were reduced in the presence of 3,6-DHF and galangin (but not with quercetin), indicating that Ca²⁺-associated changes within the transmembrane helices are altered. Both galangin and quercetin reduced the rates of ATP-dependent phosphorylation and dephosphorylation, whereas 3,6-DHF did not. Modelling studies suggest that flavonoids could potentially bind to two sites: one directly where nucleotides bind within ATP binding site and the other at a site close by. We hypothesize that interactions of these two neighbouring sites may account for both the cooperative inhibition and the multimode mechanisms of action seen with related flavonoids.
Affiliation:
University of Birmingham
Citation:
Ogunbayo, O. A., & Michelangeli, F. (2014). Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca2+ ATPase by multimode mechanisms. FEBS Journal, 281(3), 766-777. doi:10.1111/febs.12621
Publisher:
Wiley
Journal:
FEBS Journal
Publication Date:
27-Jan-2014
URI:
http://hdl.handle.net/10034/606615
DOI:
doi: 10.1111/febs.12621
Additional Links:
http://onlinelibrary.wiley.com/doi/10.1111/febs.12621/full
Type:
Article
Language:
en
Description:
This is the peer reviewed version of the following article: Ogunbayo, O. A., & Michelangeli, F. (2014). Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca2+ ATPase by multimode mechanisms. FEBS Journal, 281(3), 766-777, which has been published in final form at doi: 10.1111/febs.12621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.
ISSN:
1742-4658
Appears in Collections:
Biological Sciences

Full metadata record

DC FieldValue Language
dc.contributor.authorOgunbayo, Oluseye A.en
dc.contributor.authorMichelangeli, Francescoen
dc.date.accessioned2016-04-22T13:40:44Zen
dc.date.available2016-04-22T13:40:44Zen
dc.date.issued2014-01-27en
dc.identifier.citationOgunbayo, O. A., & Michelangeli, F. (2014). Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca2+ ATPase by multimode mechanisms. FEBS Journal, 281(3), 766-777. doi:10.1111/febs.12621en
dc.identifier.issn1742-4658en
dc.identifier.doidoi: 10.1111/febs.12621en
dc.identifier.urihttp://hdl.handle.net/10034/606615en
dc.descriptionThis is the peer reviewed version of the following article: Ogunbayo, O. A., & Michelangeli, F. (2014). Related flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca2+ ATPase by multimode mechanisms. FEBS Journal, 281(3), 766-777, which has been published in final form at doi: 10.1111/febs.12621. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.en
dc.description.abstractFlavonoids are group of plant-derived hydroxylated polycyclic molecules found in fruit and vegetables. They are known to bio-accumulate within humans and are considered to have beneficial health effects, including cancer chemoprotection. One mechanism proposed to explain this is that they are able to induce apoptosis in cancer cells by inhibiting a variety of kinases and also the Ca²⁺ ATPase. An investigation was undertaken with respect to the mechanism of inhibition for three flavonoids: quercetin, galangin and 3,6 dihydroxyflavone (3,6-DHF). Each inhibited the Ca²⁺ ATPase with K(i) values of 8.7, 10.3 and 5.4 μM, respectively, showing cooperative inhibition with n ~ 2. Given their similar structures, the flavonoids showed several differences in their mechanisms of inhibition. All three flavonoids stabilized the ATPase in the E₁ conformation and reduced [³²P]-ATP binding. However, both galangin and 3,6-DHF increased the affinity of Ca²⁺ for the ATPase by decreasing the Ca²⁺-dissociation rate constant, whereas quercetin had little effect. Ca²⁺-induced changes in tryptophan fluorescence levels were reduced in the presence of 3,6-DHF and galangin (but not with quercetin), indicating that Ca²⁺-associated changes within the transmembrane helices are altered. Both galangin and quercetin reduced the rates of ATP-dependent phosphorylation and dephosphorylation, whereas 3,6-DHF did not. Modelling studies suggest that flavonoids could potentially bind to two sites: one directly where nucleotides bind within ATP binding site and the other at a site close by. We hypothesize that interactions of these two neighbouring sites may account for both the cooperative inhibition and the multimode mechanisms of action seen with related flavonoids.en
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttp://onlinelibrary.wiley.com/doi/10.1111/febs.12621/fullen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectBiochemistryen
dc.subjectEnzymologyen
dc.titleRelated flavonoids cause cooperative inhibition of the sarcoplasmic reticulum Ca²⁺ ATPase by multimode mechanisms.en
dc.typeArticleen
dc.contributor.departmentUniversity of Birminghamen
dc.identifier.journalFEBS Journalen
dc.date.accepted2013-11-11en
or.grant.openaccessYesen
rioxxterms.funderunfundeden
rioxxterms.identifier.projectunfunded researchen
rioxxterms.versionAMen
rioxxterms.licenseref.startdate2015-01-27en
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