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Title: Studies on the bacterial potassium efflux system KefC, and its ancillary protein KefK
Author: Healy, Jess
ISNI:       0000 0004 2709 780X
Awarding Body: University of Aberdeen
Current Institution: University of Aberdeen
Date of Award: 2010
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KefC is a prokaryotic potassium efflux system, which is vital for the maintenance of cell homeostasis and the protection of cells against toxic electrophiles. As such, this system presents a novel target for antimicrobial agents. The channel is maintained shut by the tripeptide glutathione (Ɣglutamylcysteinyl glycine, GSH) and is activated by glutathione Sconjugates formed by the reaction of GSH with electrophiles such as Nethylmaleimide and methylglyoxal. It provides protection via modulation of the intracellular pH, thus making the nucleophilic groups on DNA and proteins less reactive towards the toxic compound. X-ray crystal structures of KefC have been obtained in both the open and closed conformations, which has allowed a model for channel regulation at the molecular level to be proposed. This structure has been used to rationally design activators/inhibitors of the channel and explore the SAR of the system. Systematic modification of the GSH core structure has been undertaken in an effort to develop molecules with both increased affinity and selectivity and to identify the core components necessary for binding. A novel GSHbased fluorescent probe has also been developed to allow development of a rapid and robust assay to test potential inhibitors/activators of this system. The greater aim associated with this work is to develop drug-like molecules, which through binding to KefC disrupt cell homeostasis and as such display bactericidal properties. O O H O GS H HO Enz-B: OH O GS O OH GS H-BEnz GS O OH H OH O OH S-lactoyl glutathione Hemithioacetal D-lactate GSH GlxI Glx II Detoxification K+ H+ Damage to DNA and proteins Drop in pHi GSH GS O OH H inhibition activation
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available