Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen.

@article{Reichel1997MolecularCA,
  title={Molecular cloning and expression of a 2-arylpropionyl-coenzyme A epimerase: a key enzyme in the inversion metabolism of ibuprofen.},
  author={Christoph Reichel and R Brugger and Holger Bang and Gerd Geisslinger and K. Brune},
  journal={Molecular pharmacology},
  year={1997},
  volume={51 4},
  pages={
          576-82
        }
}
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… Expand
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References

SHOWING 1-10 OF 45 REFERENCES
2-Arylpropionyl-CoA epimerase: partial peptide sequences and tissue localization.
TLDR
The polyclonal anti-epimerase antibodies were used to analyze the tissue distribution of the in guinea pigs and rats by Western blot analysis and the correlation of inversion enzyme activity in various tissues under comparable incubation conditions and cross-reactivity inWestern blot analysis was investigated. Expand
Purification and characterization of novel "2-arylpropionyl-CoA epimerases" from rat liver cytosol and mitochondria.
TLDR
Results suggest that the cytosolic and mitochondrial epimerases may be structurally related and that the proton exchange may be mediated by a 2-base mechanism and that a carboxylic residue in the active site may serve as a general base for proton abstraction. Expand
The role of coenzyme A in the biotransformation of 2-arylpropionic acids.
  • S. Hall, X. Quan
  • Chemistry, Medicine
  • Chemico-biological interactions
  • 1994
TLDR
Data from isolated rat hepatocytes indicate that other xenobiotics can modulate the formation and hydrolysis of ibuprofenyl-CoA by influencing inversion pathways, non-inversion pathways or both and accentuate inter-individual variability in response to 2-aryl-propionic acids. Expand
Microbial metabolism of 2-arylpropionic acids: chiral inversion of ibuprofen and 2-phenylpropionic acid.
TLDR
The results of these investigations indicate that microorganisms, in addition to mammals, are able to mediate the chiral inversion of 2-arylpropionic acid, which may have implications for the preparation of optically pure 2- Darylpropionic acids. Expand
Chiral inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs--II. Racemization and hydrolysis of (R)- and (S)-ibuprofen-CoA thioesters.
TLDR
The racemization and hydrolysis processes have been examined in this study using chemically synthesized CoA thioesters of the ibuprofen enantiomers and in vitro models employing rat liver homogenate and the mitochondrial and microsomal fractions as the source of the 'racemase' enzymes. Expand
Metabolic inversion of (R)-ibuprofen. Epimerization and hydrolysis of ibuprofenyl-coenzyme A.
  • T. Tracy, S. Hall
  • Chemistry, Medicine
  • Drug metabolism and disposition: the biological fate of chemicals
  • 1992
TLDR
It is demonstrated that the inversion of (R)-ibuprofen occurs, at least in part, via the epimerization of the metabolic intermediate, ib uprofenyl-CoA, in both rat and human liver tissues. Expand
Metabolic chiral inversion of 2-arylpropionates in rat H4IIE and human Hep G2 hepatoma cells. Relationship to in vivo metabolism.
TLDR
Although inversion occurred slowly in the tumor cells and thus long incubation periods were required, the hepatoma cells were nevertheless able to mimic qualitatively the species and substance specificity of inversion of 2-AP as observed in vivo. Expand
Isolation and characterization of rat liver microsomal R-ibuprofenoyl-CoA synthetase.
TLDR
Data given give strong evidence for the identity of R-ibuprofenoyl-CoA and long-chain acyl- CoA synthetase in a Mg(2+)- and ATP-dependent process. Expand
The metabolic chiral inversion and dispositional enantioselectivity of the 2-arylpropionic acids and their biological consequences.
TLDR
The biological consequences of the metabolic chiral inversion and enantioselective disposition of the 2-arylpropionates have been summarized in terms of their implications for the development and use of safer and more effective drugs of this class. Expand
Stereoselective arylpropionyl-CoA thioester formation in vitro.
TLDR
The hypothesis that R- to S-enantiomeric inversion of arylpropionic acids proceeds via the stereoselective formation of CoA thioester followed by enzymatic racemization and hydrolysis of the thioesters to regenerate free acid is supported. Expand
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