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Studies on the Inhibition of Mandelate Racemase by Arylboronic Acids

dc.contributor.authorHayden, Joshua A.
dc.contributor.copyright-releaseNot Applicableen_US
dc.contributor.degreeMaster of Scienceen_US
dc.contributor.departmentDepartment of Biochemistry & Molecular Biologyen_US
dc.contributor.ethics-approvalNot Applicableen_US
dc.contributor.external-examinern/aen_US
dc.contributor.graduate-coordinatorDr. James M. Krameren_US
dc.contributor.manuscriptsNot Applicableen_US
dc.contributor.thesis-readerDr. David L. Jakemanen_US
dc.contributor.thesis-readerDr. K. Vanya Ewarten_US
dc.contributor.thesis-readerDr. Paul X-Q. Liuen_US
dc.contributor.thesis-supervisorDr. Stephen L. Bearneen_US
dc.date.accessioned2023-08-10T12:04:35Z
dc.date.available2023-08-10T12:04:35Z
dc.date.defence2023-07-28
dc.date.issued2023-08-08
dc.description.abstractMandelate racemase (MR) is an enzyme that catalyzes the Mg2+-dependent interconversion of (R)- and (S)-mandelate, and has served as a model enzyme for exploring the limit of the available free energy of transition state (TS) stabilization (ΔGtx) that an inhibitor can capture. This work explored this limit by studying the inhibition of MR by various arylboronic acids, and found that phenylboronic acid (PBA)-based inhibitors were the most potent competitive inhibitors of MR. From a survey of various polysubstituted PBAs, 3,4-dichloro-PBA was found to be the most potent inhibitor of MR identified to date, and recognized by MR as an analogue of the TS. MR preferentially binds 3,4-dichloro-PBA in its sp3-hybridized form (Ki = 5.7 ± 0.5 nM), capturing ~45% of ΔGtx. This work highlights the value of the boronic acid group and halogen substitution in the design of potent enzyme inhibitors.en_US
dc.identifier.urihttp://hdl.handle.net/10222/82768
dc.language.isoenen_US
dc.subjectEnzymologyen_US
dc.subjectEnzyme Inhibitionen_US
dc.subjectInhibitor Designen_US
dc.subjectProtein-Ligand Interactionsen_US
dc.subjectMandelate Racemaseen_US
dc.subjectBoronic Acidsen_US
dc.titleStudies on the Inhibition of Mandelate Racemase by Arylboronic Acidsen_US
dc.typeThesisen_US

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