Hutchings, T. J.

Jiao, P.

Lloyd, M. D.

Steel, G. R.

Thompson, A. S.

Threadgill, M. D.

Wood, P. J.

Woodman, T. J.

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        Citation for published version:Woodman, TJ, Wood, PJ, Thompson, AS, Hutchings, TJ, Jiao, P, Steel, GR, Threadgill, MD & Lloyd, MD 2012,'Chiral inversion of NSAID-CoA esters by human -methylacyl-CoA racemase' Biochemical SocietyConference,2012, Cambridge, UK United Kingdom, 1/01/12, .Publication date:2012Link to publicationUniversity of BathGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright ownersand it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Download date: 07. Dec. 2019 Chiral inversion of NSAID-CoA esters by human α-methylacyl-CoA racemase 1A T. J. Woodman, P. J. Wood, A. S. Thompson, T. Hutchings, P. Jiao, G. R. Steel, M. D. Threadgill, M. D. Lloyd Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom; M.D.Lloyd@bath.ac.uk  Ibuprofen and other 2-arylpropanoic acids (2-APAs) are non-steroidal anti-inflammatory drugs (NSAIDs) and the 2S- enantiomers act by inhibition of cyclo-oxygenase 1 and 2 (COX-1 and -2). 2-APA drugs are given as racemic mixtures and chiral inversion is essential for pharmacological activity. This pathway for 2R-ibuprofen consists of conversion to the 2R-acyl-CoA ester, chiral inversion to the 2S-epimer, and hydrolysis to 2S-ibuprofen. The chiral inversion reaction is catalysed by α-methylacyl-CoA racemase (AMACR; P504S). AMACR is increased ~10-fold in prostate and other cancers, and is a novel cancer drug target. Other 2-APAs undergo chiral inversion in vivo, but it is unclear if AMACR is involved. The present study investigates whether AMACR catalyses chiral inversion of other 2-APA-CoA esters. Substrates were incubated with human AMACR 1A in 2H2O-containing buffer and all exchanged the 2-proton, an obligatory step for chiral inversion. Derivatization of products from chiral substrates showed a ca. 1:1 epimeric mixture of products, consistent with the proposed deprotonation/reprotonation mechanism. Steady state kinetic analysis showed that most substrates were converted with similar efficiency (kcat/Km = 100-150 M-1 s-1). Fenoprofenoyl-CoA was converted much more efficiently (kcat/Km = ~1426 M-1 s-1), due to its low Km value (~2.3 μM cf. 26-74 μM). The results suggest that all 2-APA drugs undergo the same chiral inversion pathway. 2-APAs may be useful for treatment of cancers with increased AMACR levels.   222 words  MTG2011/0001040 

Chiral inversion of NSAID-CoA esters by human ∝-methylacyl-CoA racemase

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Chiral inversion of NSAID-CoA esters by human ∝-methylacyl-CoA racemase

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