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

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 α-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.

High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia

“…Both ACOT1 and ACOT2 can effectively hydrolyze a variety of 2-APA-CoA substrates. ACOT1 can hydrolyze 2-APA-CoA esters outputted from mitochondria and peroxisomes, thereby suppressing cyclo-oxygenase (COX) -1 and -2 in the endoplasmic reticulum, while ACOT2 can regulate 2-APA toxicity and mitochondrial free CoA levels [ 56 ]. St Clair et al [ 57 ] found that ACOT, as a rheostat controlling activated fatty acid, has a regulatory effect on the replication of dengue virus serotype 2 (DENV2) and the release of infectious particles.…”

Transition metal complexes with ibuprofen hydrazide

“…The organism processing of ibuprofen reduces the normal activity of AMACR, which could reduce cancer developing. Although this mechanism study is still not conclusive, it is an interesting subject of study because AMACR is used as a marker (P504S) for several types of cancers 25,26 .…”