Molecular modelling of cytochrome P4502D6 (CYP2D6) based on an alignment with CYP102: structural studies on specific CYP2D6 substrate metabolism.
1. A molecular model of CYP2D6 has been constructed from the bacterial form CYP102 via a homology alignment between the CYP2D subfamily and CYP102 protein sequences. 2. A number of typical CYP2D6 substrates are shown to fit the putative active site of the enzyme, as can the specific inhibitor quinidine. 3. Some of the allelic variants in CYP2D6, which give rise to genetic polymorphisms in 2D6-mediated metabolism, can be rationalized in terms of their position within the active site region. 4. The results of site-directed mutagenesis experiments are consistent with the CYP2D6 model generated from the CYP102 crystal structure. 5. The possibility of an alternative orientation within the active site may explain the CYP2D6-mediated metabolism of relatively large-sized substrates.
Lewis
D F
DF
Molecular Toxicology Group, School of Biological Sciences, University of Surrey, UK.
Eddershaw
P J
PJ
Goldfarb
P S
PS
Tarbit
M H
MH
D000483:Alleles; D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009251:NADPH-Ferrihemoprotein Reductase; D017294:Ondansetron / Q000378:metabolism; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid; D012702:Serotonin Antagonists / Q000378:metabolism
D001426:Bacterial Proteins; D007527:Isoenzymes; D012702:Serotonin Antagonists; D017294:Ondansetron; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D009251:NADPH-Ferrihemoprotein Reductase; C052423:flavocytochrome P450 BM3 monoxygenases