Cytochrome P450 2D6 is a heme-containing enzyme that is responsible for the metabolism of at least 20% of known drugs. Substrates of 2D6 typically contain a basic nitrogen and a planar aromatic ring. The crystal structure of human 2D6 has been solved and refined to 3.0 Å resolution. The structure shows the characteristic P450 fold as seen in other members of the family, with the lengths and orientations of the individual secondary structural elements being very similar to those seen in 2C9. There are, however, several important differences, the most notable involving the F helix, the F-G loop, the B helix,  sheet 4, and part of  sheet 1, all of which are situated on the distal face of the protein. The 2D6 structure has a well defined active site cavity above the heme group, containing many important residues that have been implicated in substrate recognition and binding, including Asp-301, Glu-216, Phe-483, and Phe-120. The crystal structure helps to explain how Asp-301, Glu-216, and Phe-483 can act as substrate binding residues and suggests that the role of Phe-120 is to control the orientation of the aromatic ring found in most substrates with respect to the heme. The structure has been compared with published homology models and has been used to explain much of the reported site-directed mutagenesis data and help understand the metabolism of several compounds.
The cytochromes P4504 constitute a superfamily of heme-containing enzymes that catalyze the metabolism of a wide variety of endogenous and xenobiotic compounds. This is accomplished through the activation of molecular oxygen by the heme group, a process that involves the delivery of two electrons to the P450 system followed by cleavage of the dioxygen bond, yielding water and an activated iron-oxygen species (Compound 1), which reacts with substrates through a variety of mechanisms (1). In eukaryotic species, the electron source is a single flavoprotein, the FAD/FMN-containing cytochrome P450 reductase, which binds to the largely basic proximal face of the cytochrome through a number of salt bridges. Of the known human isoforms, cytochrome P450 2D6 is responsible for the metabolism of at least 20% of known drugs (2), with only 3A4 being responsible for a higher (50%) percentage.The cDNA encoding human P450 2D6 has been characterized (3) and subsequently localized to chromosome 22 in the q13.1 region (4). A relatively large number of genetic polymorphisms have been described for 2D6, some of which can either result in rapid or very poor metabolism. One well characterized allelic variant is responsible for a condition known as debrisoquine/sparteine type polymorphism (5, 6). This arises as a result of various genetic mutations and affects a significant percentage of the Caucasian population (7). It results in the defective metabolism of a number of important drug molecules, including debrisoquine, from which the condition got its name. The inability of patients to turn over compounds such as debrisoquine eventually leads to toxic levels of the drug in t...
