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Drug Metabolism and Disposition Fast Forward
First published on April 25, 2007; DOI: 10.1124/dmd.107.015149

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Received for publication February 14, 2007.
Revised April 18, 2007.
Accepted for publication April 23, 2007.

A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6

Kathrin Klein 1, Stephan Tatzel 2, Sebastian Raimundo 3, Tanja Saussele 1, Elisabeth Hustert 4, Jurgen Pleiss 2, Michel F. Eichelbaum 5, Ulrich M. Zanger 6*

1 Dr.Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen 2 Institute of Technical Biochemistry, University of Stuttgart 3 Institute for Cell Biology, Department of Molecular Biology,University of Tuebingen 4 present adress: Scil Technologies GmbH 5 Margarete Fischer-Bosch Institut 6 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology

* Address correspondence to: E-mail: uli.zanger{at}ikp-stuttgart.de

Abstract

A new variant allele CYP2D6*62 (g.4044C>T; R441C) of the drug-metabolizing cytochrome P450, CYP2D6, was identified in a person with reduced sparteine oxidation phenotype which was unexpected based on a genetic CYP2D6*1A/*41 background. The recombinantly expressed variant protein had no activity towards propafenone due to missing heme incorporation. Sequence alignment revealed that the positively charged R441 residue is part of the heme-binding signature but not strictly conserved among all P450s. A compilation of described P450 monooxygenase variants revealed that other enzymes can functionally tolerate even non-conservative amino acid changes at the corresponding position (i.e. the invariant cysteine -2). This suggests that heme binding in mammalian P450s depends not only on the integrity of the heme-binding signature but also on other family- and subfamily-specific sequence determinants.


Key words: CYP2D, cytochrome P450 structure, human CYP enzymes


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W.-Y. Zhang, Y.-B. Tu, R. L. Haining, and A.-M. Yu
Expression and Functional Analysis of CYP2D6.24, CYP2D6.26, CYP2D6.27, and CYP2D7 Isozymes
Drug Metab. Dispos., January 1, 2009; 37(1): 1 - 4.
[Abstract] [Full Text] [PDF]


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