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Title: The molecular basis of substrate translocation by monocarboxylate transporters and their isoform specific inhibition
Author: Nancolas , Bethany Amilia
ISNI:       0000 0004 5920 9183
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2014
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The transport of lactate and other monocarboxylates across the plasma membrane is mediated by the proton linked Monocarboxylate Iransporters (MCTs), members of the Solute Carrier family (SLC16) and the wider Major Facilitator Superfamily (MFS) of secondary active transporters. MCTs require an ancillary protein, basigin in the case of MCTl, for trafficking to and activity at the plasma membrane. Recently the importance of MCTs in tumour cell metabolism and their potential as drug targets for cancer therapy have been recognised. The work in this thesis has used molecular modelling and dynamic simulation techniques to understand the mechanisms responsible for substrate translocation by MCTl. An important role for K38, D302, R306 and F360 was confirmed and conformational changes associated with translocation proposed that involve protonation/deprotonation of other key residues. In addition, preliminary studies on the purification of the MCT1-anciliary protein complex from mammalian erythrocytes are reported with an ultimate goal of structural determination. The labelling of an extracellular cysteine residue of basigin with an organomercurial-biotin conjugate was shown to be a promising initial step for purification. The inhibition of MCTs by isoform-specific inhibitors has also been investigated. Site directed mutagenesis and molecular modelling have been employed to indicate a possible binding site for AR-C155858 in MCTl with key roles proposed for residues D302 and R306. In addition, Ki values of~ 30-50 nM were determined in both Xenopus laevis oocytes and mammalian cell lines for some novel MCT4 specific inhibitors recently developed by AstraZeneca .
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available