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Department of Experimental and Clinical Pharmacology and
Toxicology, University of Erlangen/Nürnberg, D-91054 Erlangen,
Germany
The 2-arylpropionic acid derivatives, including ibuprofen, are the most
widely used anti-inflammatory analgesic cyclooxygenase inhibitors. The
(
)-R-enantiomer, which is inactive in terms of cyclooxygenase inhibition, is epimerized in vivo via the
2-arylpropionyl-coenzyme A (CoA) epimerase to the
cyclooxygenase-inhibiting (+)-S-enantiomer. The
molecular biology of the epimerization pathway is largely unknown. To
clarify this mechanism, the sequence of the 2-arylpropionyl-CoA epimerase was identified, and the enzyme cloned and expressed. A cDNA
clone encoding the 2-arylpropionyl-CoA epimerase was isolated from a
rat liver cDNA library. The nucleotide and the deduced amino acid
sequence of this enzyme was determined. Significant amino acid sequence
similarity was found between the rat epimerase and carnitine
dehydratases from Caenorhabditis elegans (41%) and Escherichia coli (27%). A bacterial expression system
(E. coli strain M15[pREP4]) was used to express the
epimerase protein, representing up to 20-30% of the total cellular
E. coli protein. The expression of the epimerase was
confirmed with Western blots using specific anti-epimerase antibodies
and by measuring the rate of inversion of
(R)-ibuprofenoyl-CoA. Northern blot analysis revealed a
prominent 1.9-kb mRNA transcript in different rat tissues. In addition
to its obvious importance in drug metabolism, the homology of the
epimerase with carnitine dehydratases from several species suggests
that this protein, which up to now has only been characterized as
having a role in drug transformation, has a function in lipid
metabolism.
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