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

0090-9556/07/3508-1247-1250$20.00
DMD 35:1247-1250, 2007

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SHORT COMMUNICATION

A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6Formula

Kathrin Klein, Stephan Tatzel, Sebastian Raimundo, Tanja Saussele, Elisabeth Hustert, Jürgen Pleiss, Michel Eichelbaum, and Ulrich M. Zanger

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany (K.K., S.R., T.S., M.E., U.M.Z.); University Tuebingen, Tuebingen, Germany (K.K., S.R., T.S.,M.E., U.M.Z.); Institute of Technical Biochemistry, University of Stuttgart, Stuttgart, Germany (S.T., J.P.); and Epidauros Biotechnology AG, Bernried, Germany (E.H.)

A new variant allele CYP2D6*62 (g.4044C>T; R441C) of the drug-metabolizing cytochrome P450 (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 toward propafenone as a result of 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 the P450s. A compilation of described P450 monooxygenase variants revealed that other enzymes can functionally tolerate even nonconservative 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.

Address correspondence to: Ulrich M. Zanger, Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Auerbachstr. 112, D-70376 Stuttgart, Germany. E-mail: uli.zanger{at}ikp-stuttgart.de




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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.
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