Structures of Human Cytochrome P450 Enzymes: Variations on a Theme
The human cytochrome P450 enzymes are membrane-bound monooxygenases that perform diverse roles. Xenobiotic-metabolizing P450 enzymes are generalists responsible for the first step in the elimination of hydrophobic drugs and toxins, but can also activate protoxins, procarcinogens, and prodrugs. With the propensity of each to act on many different substrates, one small molecule drug or xenobiotic can often alter the metabolism of a second, causing adverse interactions. Other human P450 enzymes play more specific roles in the production and interconversions of key endobiotics including steroids, vitamins, fatty acids, and eicosanoids. These latter P450 enzymes are often drug targets. While poor solubility and stability prevented any membrane P450 X-ray structures until 2000, since then at least one structure has been determined for 22 enzymes of the 57 human genes. Within the conserved P450 fold, variations of secondary structure placement and side chain accommodations are apparent, both between and within a given P450 enzyme. In some cases, these structures provide a logical framework for observed function and mutational effects, but in other cases these structures raise additional questions. Regardless, enough structural information is available to begin guiding drug design, whether to target specific P450 enzymes or to avoid undesirable P450 inhibition or metabolism.