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Expression in yeast, new substrates, and construction of a first 3D model of human orphan cytochrome P450 2U1: Interpretation of substrate hydroxylation regioselectivity from docking studies.
Ducassou, Lionel; Jonasson, Gabriella; Dhers, Laura; Pietrancosta, Nicolas; Ramassamy, Booma; Xu-Li, Yun; Loriot, Marie-Anne; Beaune, Philippe; Bertho, Gildas; Lombard, Murielle; Mansuy, Daniel; André, François; Boucher, Jean-Luc.
Affiliation
  • Ducassou L; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Jonasson G; UMR 9198 CNRS, University Paris Sud, iBiTec-S/SB2SM, CEA Saclay, 91191 Gif sur Yvette, France.
  • Dhers L; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Pietrancosta N; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Ramassamy B; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Xu-Li Y; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Loriot MA; UMR S 775 INSERM, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Beaune P; UMR S 775 INSERM, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Bertho G; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Lombard M; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • Mansuy D; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.
  • André F; UMR 9198 CNRS, University Paris Sud, iBiTec-S/SB2SM, CEA Saclay, 91191 Gif sur Yvette, France. Electronic address: francois.andre@cea.fr.
  • Boucher JL; UMR 8601 CNRS, University Paris Descartes, Paris Sorbonne Cité, 75270 Paris, France.. Electronic address: jean-luc.boucher@parisdescartes.fr.
Biochim Biophys Acta ; 1850(7): 1426-37, 2015 Jul.
Article in En | MEDLINE | ID: mdl-25857771
ABSTRACT

BACKGROUND:

Cytochrome P450 2U1 (CYP2U1) has been identified from the human genome and is highly conserved in the living kingdom. In humans, it has been found to be predominantly expressed in the thymus and in the brain. CYP2U1 is considered as an "orphan" enzyme as few data are available on its physiological function(s) and active site topology. Its only substrates reported so far were unsaturated fatty acids such as arachidonic acid, and, much more recently, N-arachidonoylserotonin.

METHODS:

We expressed CYP2U1 in yeast Saccharomyces cerevisiae, built a 3D homology model of CYP2U1, screened a library of compounds known to be substrates of CYP2 family with metabolite detection by high performance liquid chromatography-mass spectrometry, and performed docking experiments to explain the observed regioselectivity of the reactions.

RESULTS:

We show that drug-related compounds, debrisoquine and terfenadine derivatives, subtrates of CYP2D6 and CYP2J2, are hydroxylated by recombinant CYP2U1 with regioselectivities different from those reported for CYP2D6 and 2J2. Docking experiments of those compounds and of arachidonic acid allow us to explain the regioselectivity of the hydroxylations on the basis of their interactions with key residues of CYP2U1 active site. MAJOR

CONCLUSION:

Our results show for the first time that human orphan CYP2U1 can oxidize several exogenous molecules including drugs, and describe a first CYP2U1 3D model. GENERAL

SIGNIFICANCE:

These results could have consequences for the metabolism of drugs particularly in the brain. The described 3D model should be useful to identify other substrates of CYP2U1 and help in understanding its physiologic roles.
Subject(s)
Key words

Full text: 1 Database: MEDLINE Main subject: Recombinant Proteins / Models, Molecular / Protein Structure, Tertiary / Cytochrome P-450 Enzyme System Language: En Journal: Biochim Biophys Acta Year: 2015 Type: Article Affiliation country: France

Full text: 1 Database: MEDLINE Main subject: Recombinant Proteins / Models, Molecular / Protein Structure, Tertiary / Cytochrome P-450 Enzyme System Language: En Journal: Biochim Biophys Acta Year: 2015 Type: Article Affiliation country: France