A study on the chiral inversion of mandelic acid in humans

Maksims Jevglevskis, C.R. Bowskill, C.C.Y. Chan, J.H.-J. Heng, M D Threadgill, T.J. Woodman, M.D. Lloyd

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Abstract

Mandelic acid is a chiral metabolite of the industrial pollutant styrene and is used in chemical skin peels, as a urinary antiseptic and as a component of other medicines. In humans, S-mandelic acid undergoes rapid chiral inversion to R-mandelic acid by an undefined pathway but it has been proposed to proceed via the acyl-CoA esters, S- and R-2-hydroxy-2-phenylacetyl-CoA, in an analogous pathway to that for Ibuprofen. This study investigates chiral inversion of mandelic acid using purified human recombinant enzymes known to be involved in the Ibuprofen chiral inversion pathway. Both S- and R-2-hydroxy-2-phenylacetyl- CoA were hydrolysed to mandelic acid by human acyl-CoA thioesterase-1 and -2 (ACOT1 and ACOT2), consistent with a possible role in the chiral inversion pathway. However, human α-methylacyl-CoA racemase (AMACR; P504S) was not able to catalyse exchange of the α-proton of S- and R-2-hydroxy-2- phenylacetyl-CoA, a requirement for chiral inversion. Both S- and R-2-phenylpropanoyl-CoA were epimerised by AMACR, showing that it is the presence of the hydroxy group that prevents epimerisation of R- and S-2-hydroxy-2-phenylacetyl-CoAs. The results show that it is unlikely that 2-hydroxy-2-phenylacetyl-CoA is an intermediate in the chiral inversion of mandelic acid, and that the chiral inversion of mandelic acid is via a different pathway to that of Ibuprofen and related drugs.

Original languageEnglish
Pages (from-to)6737-6744
Number of pages8
JournalOrganic and Biomolecular Chemistry
Volume12
Issue number34
Early online date10 Jul 2014
DOIs
Publication statusPublished - 14 Sep 2014

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    Jevglevskis, M., Bowskill, C. R., Chan, C. C. Y., Heng, JH-J., Threadgill, M. D., Woodman, T. J., & Lloyd, M. D. (2014). A study on the chiral inversion of mandelic acid in humans. Organic and Biomolecular Chemistry, 12(34), 6737-6744. https://doi.org/10.1039/c3ob42515k