TY - JOUR T1 - A Natural Variant of the Heme-Binding Signature (R441C) Resulting in Complete Loss of Function of CYP2D6 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1247 LP - 1250 DO - 10.1124/dmd.107.015149 VL - 35 IS - 8 AU - Kathrin Klein AU - Stephan Tatzel AU - Sebastian Raimundo AU - Tanja Saussele AU - Elisabeth Hustert AU - Jürgen Pleiss AU - Michel Eichelbaum AU - Ulrich M. Zanger Y1 - 2007/08/01 UR - http://dmd.aspetjournals.org/content/35/8/1247.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -