Topological role of cytochrome P450 2D6 active site residues

2006 ◽  
Vol 447 (1) ◽  
pp. 53-58 ◽  
Author(s):  
Robert A.B. van Waterschoot ◽  
Peter H.J. Keizers ◽  
Chris de Graaf ◽  
Nico P.E. Vermeulen ◽  
Richard A. Tschirret-Guth
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Cytochrome P450 2D6 ◽  
Active Site Residues ◽  
P450 2D6

scholarly journals Phe120 contributes to the regiospecificity of cytochrome P450 2D6: mutation leads to the formation of a novel dextromethorphan metabolite

2004 ◽  
Vol 380 (2) ◽  
pp. 353-360 ◽  
Author(s):  
Jack U. FLANAGAN ◽  
Jean-Didier MARÉCHAL ◽  
Richard WARD ◽  
Carol A. KEMP ◽  
Lesley A. McLAUGHLIN ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Active Site ◽  
Structural Model ◽  
Side Chain ◽  
Cytochrome P450 2D6 ◽  
Active Site Residues ◽  
Bacterial Membranes ◽  
Human Cytochrome ◽  
Methionine Residues ◽  
P450 2D6

Although the residues that determine the preference of CYP2D6 (cytochrome P450 2D6) for compounds containing a basic nitrogen are well characterized, the contribution of other active site residues to substrate binding and orientation is less well understood. Our structural model of CYP2D6 identifies the aromatic residue Phe120 as a likely major feature of the active site. To examine the role of Phe120, mutants of CYP2D6 in which this residue has been substituted by alanine, leucine, tyrosine, serine, histidine, tryptophan or methionine residues have been prepared in bacterial membranes co-expressing human cytochrome NADPH cytochrome P450 oxidoreductase. The mutants have been characterized using the prototypical bufuralol 1´ hydroxylase and dextromethorphan O- and N-demethylase activities of CYP2D6. Larger effects on Km values are observed for dextromethorphan O-demethylation than for bufuralol 1´ hydroxylation, indicating that the Phe120 side chain is more important in dextromethorphan than in bufuralol binding. A role for this side chain in determining the regiospecificity of substrate oxidation was indicated by changes in the relative rates of O- and N-demethylation of dextromethorphan and, notably, by the formation of 7-hydroxy dextromethrophan, a novel dextromethorphan metabolite, in mutants in which it had been substituted. Computational studies of dextromethorphan binding to the active site of the Phe120→Ala mutant were carried out to throw light on the way in which the removal of this side chain leads to different modes of ligand binding.

Role of cytochrome P450 2D6 (CYP2D6) in the stereospecific metabolism of E- and Z-doxepin

2000 ◽  
Vol 10 (7) ◽  
pp. 591-603 ◽  
Author(s):  
V. S. Haritos ◽  
H. Ghabrial ◽  
J. T. Ahokas ◽  
M. S. Ching
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2D6 ◽  
P450 2D6

Role of the conserved threonine 309 in mechanism of oxidation by cytochrome P450 2D6

2005 ◽  
Vol 338 (2) ◽  
pp. 1065-1074 ◽  
Author(s):  
Peter H.J. Keizers ◽  
Loek H.M. Schraven ◽  
Chris de Graaf ◽  
Mats Hidestrand ◽  
Magnus Ingelman-Sundberg ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2D6 ◽  
Mechanism Of Oxidation ◽  
P450 2D6

The role of cytochrome P450 2D6 in the metabolism of moclobemide

1996 ◽  
Vol 6 (3) ◽  
pp. 225-230 ◽  
Author(s):  
Sebastian Härtter ◽  
Jasper Dingemanse ◽  
Dieter Baier ◽  
Gismar Ziegler ◽  
Christoph Hiemke
Keyword(s):  
Cytochrome P450 ◽  
Cytochrome P450 2D6 ◽  
P450 2D6
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