Autori: Oprea, Tudor I.; Hummer, Gerhard; Garcia, Angel E.

Editorial: Proc. Natl. Acad. Sci. U. S. A., 94(6), p.2133-2138, 1997.

Rezumat:

Cytochrome P 450 enzymes are monooxygenases that contain a functional heme b group linked to a conserved cysteine with a thiolate bond. In the native state, the central iron atom is hexacoordinated with a covalently bound water mol. The exclusion of solvent mols. from the active site is essential for efficient enzymic function. Upon substrate binding, water has to be displaced from the active site to prevent electron uncoupling that results in hydrogen peroxide or water. In contrast to typical hemoproteins, the protein surface is not directly accessible from the heme of cytochromes P 450. We postulate a two-state model in which a conserved arginine, stabilizing the heme propionate in all known cytochrome P 450 crystal structures, changes from the initial, stable side-chain conformation to another rotamer (metastable). In this new state, a functional water channel (aqueduct) is formed from the active site to a water cluster located on the thiolate side of the heme, close to the protein surface. This water cluster communicates with the surface in the closed state and is partly replaced by the flipping arginine side chain in the open state, allowing water mols. to exit to the surface or to reaccess the active site. This two-state model suggests the presence of an exit pathway for water between the active site and the protein surface.

Cuvinte cheie: Active sites (enzyme), Aromatase, Cytochrome P450, Conformation (protein), Hydration (chemical), X-ray structure analysis