The enzyme α-methylacyl coenzyme A racemase (AMACR) is overexpressed in a variety of cancers, including prostate cancer. siRNA knockdown of the AMACR gene has identified it as being a potential therapeutic target. The racemase is involved in B-oxidation of branched-chain fatty acids and in bile acid biosynthesis of cholesterol derivatives, in both cases providing the required (S)-stereoisomer for the branched-chain acyl-CoA oxidase. This is achieved by equilibration of the naturally produced (R) and (S) stereoisomers of pristanoyl-CoA and (R)-THC-CoA. We have synthesised a range of potential inhibitors of the enzyme that are based on the natural substrates of the enzyme. These designed inhibitors incorporate a range of functional groups that aim to probe the mechanism of action of the enzyme, as well as the ability of AMACR to tolerate alterations to the a-methyl moiety. We have also synthesised a number of truncated analogues of CoA in order to discover how well such modifications of this moiety are accepted by the enzyme. In addition to this, modelling studies on the enzyme have revealed the existence of an alternative binding pocket close to the active site. A range of compounds designed to exploit this novel pocket have also been synthesised, in order to provide inhibitors that are specific for AMACR. A number of these compounds have been assayed against the racemase from Mycobacterium tuberculosis (MCR). These compounds include the first designed inhibitor of AMACR that does not include a CoA moiety. The initial results obtained suggest that these substrates act as reversible inhibitors of the enzyme.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:569155 |
| Date | January 2011 |
| Creators | Smith, Matthew |
| Publisher | University of Liverpool |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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