C-H bond activation in heme proteins: the role of thiolate ligation in cytochrome P450.

The ability of cytochrome P450 to functionalize unactivated hydrocarbons at physiological temperature and pressure has attracted considerable interest from the chemical community. One of the more intriguing aspects of cytochrome P450 is the enzyme's use of a thiolate-ligated heme to perform demanding two-electron oxidations. This coordination is unusual, given that thiolate ligation can significantly decrease a heme reduction potential. In an effort to understand Nature's use of a donating thiolate in cytochrome P450, we have undertaken a systematic study of the high-valent forms of thiolate ligated heme proteins. Our investigations have revealed that the ferryl forms of these enzymes are basic. The basic ferryls afforded by thiolate ligation bias cytochrome P450 toward H-atom abstraction, creating an oxidant that cleaves CH bonds while avoiding unwanted oxidations of the protein superstructure. Recent synthetic work supports this hypothesis.