A natural variant of the heme-binding signature (R441C) resulting in complete loss of function of CYP2D6.
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.
Klein
Kathrin
K
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Auerbachstr. 112, D-70376 Stuttgart, Germany.
Tatzel
Stephan
S
Raimundo
Sebastian
S
Saussele
Tanja
T
Hustert
Elisabeth
E
Pleiss
Jürgen
J
Eichelbaum
Michel
M
Zanger
Ulrich M
UM
D000595:Amino Acid Sequence; D001120:Arginine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D016384:Consensus Sequence / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D006418:Heme / Q000737:chemistry / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D008958:Models, Molecular; D020641:Polymorphism, Single Nucleotide; D011405:Propafenone / Q000378:metabolism; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013034:Sparteine / Q000378:metabolism
D011994:Recombinant Proteins; D013034:Sparteine; D006418:Heme; D011405:Propafenone; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D019389:Cytochrome P-450 CYP2D6