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PERSPECTIVES: BIOINORGANIC CHEMISTRY
Many key metabolic transformations require the controlled oxidation of organic species. These transformations often rely on the activation of molecular oxygen, O2, by metal ions in the active sites of oxygenase enzymes. At a recent symposium on "Oxygen Activation by Metalloenzymes and Their Models" (1), highlighted in this perspective, two themes threaded through a number of the talks: a common oxygen activation scheme and the importance of O2 in posttranslational modification of proteins.
Oxygen activation can occur at mononuclear heme (porphyrin) sites, nonheme monoiron and diiron sites, mononuclear and dinuclear copper sites, and even at a heterodinuclear heme-copper site. Despite this diversity of active sites, a common mechanistic hypothesis for oxygen activation is emerging. In this unified scheme, oxygen first binds to a reduced metal center; a metal-peroxo intermediate is then formed, followed by 00 bond cleavage to form a high-valent metal-oxo oxidant that carries out substrate oxidation (see the first figure). The extent to which the catalytic cycle of an enzyme (and its corresponding model compounds) follows this mechanism varies from enzyme to enzyme.
The heme enzyme cytochrome P450 is one of the most widely studied systems in bioinorganic chemistry. A high-valent iron-oxo species has generally been thought to be the oxidant responsible for P450-catalyzed oxygenation, but the possibility that an iron-peroxo species may also be involved in some reactions has been raised. For example, Wonwoo Nam (Eh,wa Womens University, Seoul, Korea) presented evidence that synthetic iron complexes of highly halogenated, electron-deficient porphyrins catalyze oxygenation reactions through either iron-peroxo or iron-oxo species (2). To shed further light on this question, Yoshihito Watanabe (Institute for Molecular Science, Okazaki, Japan) used site-directed mutagenesis to redesign the oxygen carrier myoglobin into a P450-like monooxygenase that can catalyze olefin epoxidation (3). Kinetic studies showed that the formation of a high-valent iron-oxo intermediate was the rate-determining step, thus excluding the Fe(III)-OOH (peroxo) intermediate as the oxidant under these conditions. Further evidence comes from studies by Brian Hoffman (Northwestern University, Evanston, IL) and co-workers, who have used a novel radiolytic approach to introduce an electron into the reduced P450-dioxygen complex to generate the Fe(III)-OOH (peroxo) intermediate of cytochrome P450 at cryogenic temperatures in the presence of its substrate, d-camphor. Brief annealing to around 200 K converted...