title: A study on the chiral inversion of mandelic acid in humans.
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.
authors: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom. M.D.Lloyd@bath.ac.uk.
authors: Maksims
authors: M
authors: Yevglevskis
authors: Catherine R
authors: CR
authors: Bowskill
authors: Chloe C Y
authors: CC
authors: Chan
authors: Justin H-J
authors: JH
authors: Heng
authors: Michael D
authors: MD
authors: Threadgill
authors: Timothy J
authors: TJ
authors: Woodman
authors: Matthew D
authors: MD
authors: Lloyd
mesh_terms: D000105:Acetyl Coenzyme A / Q000737:chemistry; D001711:Biotransformation; D006801:Humans; D006868:Hydrolysis; D007052:Ibuprofen / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry; D008333:Mandelic Acids / Q000737:chemistry* / Q000378:metabolism; D010170:Palmitoyl-CoA Hydrolase / Q000737:chemistry*; D019998:Racemases and Epimerases / Q000737:chemistry*; D012996:Solutions; D013237:Stereoisomerism
chemical_list: D007527:Isoenzymes; D008333:Mandelic Acids; D012996:Solutions; D000105:Acetyl Coenzyme A; C037816:phenylacetyl-coenzyme A; D010170:Palmitoyl-CoA Hydrolase; D019998:Racemases and Epimerases; C108352:alpha-methylacyl-CoA racemase; C037938:mandelic acid; D007052:Ibuprofen