| Title : Hydrolysis of ibuprofenoyl-CoA and other 2-APA-CoA esters by human acyl-CoA thioesterases-1 and -2 and their possible role in the chiral inversion of profens - Qu_2013_Biochem.Pharmacol_86_1621 |
| Author(s) : Qu X , Allan A , Chui G , Hutchings TJ , Jiao P , Johnson L , Leung WY , Li PK , Steel GR , Thompson AS , Threadgill MD , Woodman TJ , Lloyd MD |
| Ref : Biochemical Pharmacology , 86 :1621 , 2013 |
| Abstract : Ibuprofen and related 2-arylpropanoic acid (2-APA) drugs are often given as a racemic mixture and the R-enantiomers undergo activation in vivo by metabolic chiral inversion. The chiral inversion pathway consists of conversion of the drug to the coenzyme A ester (by an acyl-CoA synthetase) followed by chiral inversion by alpha-methylacyl-CoA racemase (AMACR; P504S). The enzymes responsible for hydrolysis of the product S-2-APA-CoA ester to the active S-2-APA drug have not been identified. In this study, conversion of a variety of 2-APA-CoA esters by human acyl-CoA thioesterase-1 and -2 (ACOT-1 and -2) was investigated. Human recombinant ACOT-1 and -2 (ACOT-1 and -2) were both able to efficiently hydrolyse a variety of 2-APA-CoA substrates. Studies with the model substrates R- and S-2-methylmyristoyl-CoA showed that both enzymes were able to efficiently hydrolyse both of the epimeric substrates with (2R)- and (2S)- methyl groups. ACOT-1 is located in the cytosol and is able to hydrolyse 2-APA-CoA esters exported from the mitochondria and peroxisomes for inhibition of cyclo-oxygenase-1 and -2 in the endoplasmic reticulum. It is a prime candidate to be the enzyme responsible for the pharmacological action of chiral inverted drugs. ACOT-2 activity may be important in 2-APA toxicity effects and for the regulation of mitochondrial free coenzyme A levels. These results support the idea that 2-APA drugs undergo chiral inversion via a common pathway. |
| ESTHER : Qu_2013_Biochem.Pharmacol_86_1621 |
| PubMedSearch : Qu_2013_Biochem.Pharmacol_86_1621 |
| PubMedID: 24041740 |
Qu X, Allan A, Chui G, Hutchings TJ, Jiao P, Johnson L, Leung WY, Li PK, Steel GR, Thompson AS, Threadgill MD, Woodman TJ, Lloyd MD (2013)
Hydrolysis of ibuprofenoyl-CoA and other 2-APA-CoA esters by human acyl-CoA thioesterases-1 and -2 and their possible role in the chiral inversion of profens
Biochemical Pharmacology
86 :1621
Qu X, Allan A, Chui G, Hutchings TJ, Jiao P, Johnson L, Leung WY, Li PK, Steel GR, Thompson AS, Threadgill MD, Woodman TJ, Lloyd MD (2013)
Biochemical Pharmacology
86 :1621