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A study on the AMACR catalysed elimination reaction and its application to inhibitor testing

Yevglevskis, Maksims, Lee, Guat L., Sun, Jenny, Zhou, Shiyi, Sun, Xiaolong, Kociok-Köhn, Gabriele, James, Tony D., Woodman, Timothy J. and Lloyd, Matthew D. 2016. A study on the AMACR catalysed elimination reaction and its application to inhibitor testing. Organic and Biomolecular Chemistry 14 (2) , pp. 612-622. 10.1039/C5OB01541C

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α-Methylacyl-CoA racemase (AMACR; P504S) catalyses a key step in the degradation of branched-chain fatty acids and is important for the pharmacological activation of Ibuprofen and related drugs. Levels of AMACR are increased in prostate and other cancers, and it is a drug target. Development of AMACR as a drug target is hampered by lack of a convenient assay. AMACR irreversibly catalyses the elimination of HF from 3-fluoro-2-methylacyl-CoA substrates, and this reaction was investigated for use as an assay. Several known inhibitors and alternative substrates reduced conversion of 3-fluoro-2-methyldecanoyl-CoA by AMACR, as determined by 1H NMR. The greatest reduction of activity was observed with known potent inhibitors. A series of novel acyl-CoA esters with aromatic side chains were synthesised for testing as chromophoric substrates. These acyl-CoA esters were converted to unsaturated products by AMACR, but their use was limited by non-enzymatic elimination. Fluoride sensors were also investigated as a method of quantifying released fluoride and thus AMACR activity. These sensors generally suffered from high background signal and lacked reproducibility under the assay conditions. In summary, the elimination reaction can be used to characterise inhibitors, but it was not possible to develop a convenient colorimetric or fluorescent assay using 3-fluoro-2-methylacyl-CoA substrates.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Royal Society of Chemistry
ISSN: 1477-0520
Date of First Compliant Deposit: 6 July 2020
Date of Acceptance: 27 October 2015
Last Modified: 15 Jul 2021 01:11

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