RT Journal Article
SR Electronic
T1 Thioesterification of 2-Arylpropionic Acids by Recombinant Acyl-Coenzyme A Synthetases (ACS1 and ACS2)
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 398
OP 402
VO 28
IS 4
A1 Cendrine Sevoz
A1 Etienne Benoit
A1 Thierry Buronfosse
YR 2000
UL http://dmd.aspetjournals.org/content/28/4/398.abstract
AB 2-Arylpropionic acids are a class of frequently used nonsteroidal anti-inflammatory drugs exhibiting a potent inhibition of cyclooxygenase isoforms supported by the (+)S-enantiomer alone. Nevertheless, some of these compounds in the (−)R configuration may undergo extensive inversion of configuration to their antipode. The key molecular basis for this mechanism invokes the stereoselective formation of the coenzyme A (CoA) thioester of the 2-arylpropionic acid by long-chain acyl-CoA synthetases (ACSs). In this report, rat recombinant ACS1 and ACS2 enzymes, constitutively highly expressed in adult rat liver and brain, respectively, have been overproduced in Escherichia colistrains and purified to homogeneity to investigate the involvement of these enzymes in the thioesterification of fenoprofen and ibuprofen. Recombinant ACS1 efficiently catalyzed both nonsteroidal anti-inflammatory drugs with Michaelis-Menten parameters ofKM = 1686 ± 93 μM,Vmax = 353 ± 45 nmol/min/mg protein for (−)R-ibuprofen andKM = 103 ± 12 μM,Vmax = 267 ± 10 nmol/min/mg protein for (−)R-fenoprofen, and exhibited a marked stereoselectivity in favor of the (−)R-enantiomer. Recombinant ACS2, a closely related sequence with ACS1, exhibited a lower enzymatic efficacy from 7- to 130-fold for (−)R-ibuprofen and (−)R-fenoprofen, respectively. On the basis of these findings and considering the level of tissue expression of the different long-chain ACSs, ACS1 appears to be the major enzyme involved in the first step of the chiral inversion of 2-arylpropionic acids. Nevertheless, the participation of other ACS isoforms of minor quantitative importance could not be excluded in the thioesterification of xenobiotics. The American Society for Pharmacology and Experimental Therapeutics