New insights into the structural characteristics and functional relevance of the human cytochrome P450 2D6 enzyme

Abstract

To date, the crystal structures of at least 12 human CYPs (1A2, 2A6, 2A13, 2C8, 2C9, 2D6, 2E1, 2R1, 3A4, 7A1, 8A1, and 46A1) have been determined. CYP2D6 accounts for only a small percentage of all hepatic CYPs (< 2%), but it metabolises ~25% of clinically used drugs with significant polymorphisms. CYP2D6 also metabolizes procarcinogens and neurotoxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, and indolealkylamines. Moreover, the enzyme utilizes hydroxytryptamines and neurosteroids as endogenous substrates. Typical CYP2D6 substrates are usually lipophilic bases with an aromatic ring and a nitrogen atom, which can be protonated at physiological pH. Substrate binding is generally followed by oxidation (5–7 å) from the proposed nitrogen-Asp301 interaction. A number of homology models have been constructed to explore the structural features of CYP2D6, while antibody studies also provide useful structural information. Site-directed mutagenesis studies have demonstrated that Glu216, Asp301, Phe120, Phe481, and Phe483 play important roles in determining the binding of ligands to CYP2D6. The structure of human CYP2D6 has been recently determined and shows the characteristic CYP fold observed for other members of the CYP superfamily. The lengths and orientations of the individual secondary structural elements in the CYP2D6 structure are similar to those seen in other human CYP2 members, such as CYP2C9 and 2C8. The 2D6 structure has a well-defined active-site cavity located above the heme group with a volume of ~540 å³, which is larger than equivalent cavities in CYP2A6 (260 å³), 1A2 (375 å³), and 2E1 (190 å³), but smaller than those in CYP3A4 (1385 å³) and 2C8 (1438 å³). Further studies are required to delineate the molecular mechanisms involved in CYP2D6 ligand interactions and their implications for drug development and clinical practice.

Keywords::

• CYP2D6
• Homology modeling
• Pharmacophore
• Site-directed mutagenesis
• active site

Acknowledgments

The authors appreciate the grant support of the RMIT Health Innovations Research Institute (RMIT University, Bundoora, Victoria, Australia) and National Institute of Complementary Medicine (New South Wales, Australia). L-P was a holder of the Australian Postgraduate (PhD) Awards (APA) funded by the Commonwealth Government of Australia. The authors also appreciate the support of Prof. Hualiang Jiang, PhD (Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China).

Declaration of interest: The authors report no financial conflicts of interest. The authors alone are responsible for the content and writing of this paper.