Putative Irreversible Inhibitors of the Human Sodium-Dependent Bile Acid Transporter (hASBT; SLC10A2) Support the Role of Transmembrane Domain 7 in Substrate Binding/Translocation

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dc.contributor.authorGonzalez, Pablo M.
dc.contributor.authorHussainzada, Naissan
dc.contributor.authorSwaan, Peter W.
dc.contributor.authorMacKerell, Alexander D., Jr.
dc.contributor.authorPolli, James E.
dc.date.accessioned2025-01-20T23:57:57Z
dc.date.available2025-01-20T23:57:57Z
dc.date.issued2012
dc.description.abstractTo explore the involvement of transmembrane domain (TM) 7 of the human apical sodium-dependent bile acid transporter (hASBT) on bile acid (BA) binding/translocation, using two electrophilic BA derivatives as molecular probes.
dc.description.abstractTwo electrophilic derivatives of chenodeoxycholic acid (CDCA) were designed, synthesized and evaluated for their ability to inactivate hASBT, and the human organic cation/carnitine transporter (hOCTN2) as a control (i.e. a non-BA transporting model). The ability of electrophilic derivatives to interact with hASBT was evaluated by 2-aminoethyl-methanethiosulfonate (MTSEA)-biotin labeling of thiol groups in TM7 cysteine mutants.
dc.description.abstractUnlike native BAs, the electrophilic CDCA derivatives specifically inactivated hASBT, but not hOCTN2, and inhibited hASBT in a time- and concentration-dependent fashion. Preincubation of hASBT Cys-mutants in the exofacial half of TM7 with reactive electrophilic probes blocked transporter biotinylation by MTSEA-biotin, similar to 2-(trimethylammonium)ethyl-methanethiosulfonate (MTSET) blocking. This blocking pattern differed from that produced by native BAs, which exposed exofacial TM7 residues, thereby increasing staining.
dc.description.abstractKinetic and biochemical data indicate these novel electrophilic BAs are potent and specific irreversible inhibitors of hASBT and offer new evidence about the role of TM7 in binding/translocation of bile acids.
dc.fuente.origenWOS
dc.identifier.doi10.1007/s11095-012-0706-8
dc.identifier.eissn1573-904X
dc.identifier.issn0724-8741
dc.identifier.urihttps://doi.org/10.1007/s11095-012-0706-8
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/95223
dc.identifier.wosidWOS:000305222000011
dc.issue.numero7
dc.language.isoen
dc.pagina.final1831
dc.pagina.inicio1821
dc.revistaPharmaceutical research
dc.rightsacceso restringido
dc.subjectbile acid
dc.subjecthASBT
dc.subjectirreversible inhibitor
dc.subjectMTS-reagent
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titlePutative Irreversible Inhibitors of the Human Sodium-Dependent Bile Acid Transporter (hASBT; SLC10A2) Support the Role of Transmembrane Domain 7 in Substrate Binding/Translocation
dc.typeartículo
dc.volumen29
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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