The reduction and the release of product three

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the reduction and the release of product. Three species are potential candidates for" active oxygen," the oxygen-containing species that attacks the substrate, in cytochrome P-450. They are: (1) a ferric peroxo, la, or hydroperoxo complex, lb, formed from one- electron reduction of the oxy complex (Reaction 5.65); (2) an iron(1V) oxo complex, 2, formed by homolytic 0-0 bond cleavage of a ferric hydroperoxo complex (Reaction 5.66); and (3) a complex at the oxidation level of an iron(V) oxo complex, 3, formed by heterolytic 0-0 bond cleavage of a ferric hydroperoxo complex (Reaction 5.67). The hydroxyl radical, HO', although highly reactive and capable of attacking P-450 substrates, is considered to be an unlikely candidate for "active oxygen" because of the indiscriminate character of its reactivity. e- H+ Fe Il P+0 2 ---i> FeP0 2 ~ [FeIl1P(Ol-W --7 Fe1IlP(02H-) 1a 1b FeIlIP(02H) ~ FeIVP(O)+HO' 1b 2 Fe Il1 P(02 W ) ~ [Fe V (P 2 -)(O)+<---->Fe 1v (P-)(O)+]+HO- 1b 3 (P 2 - = porphyrin ligand; P- = one-electron oxidized porphyrin ligand) (5.65) (5.66) (5.67) An iron(V) oxo complex (or a related species at the same oxidation level), 3, formed via Reaction (5.67), is the favored candidate for "active oxygen" in cytochrome P-450. 81 This conclusion was initially drawn from studies of reac- tions of the enzyme with alkylhydroperoxides and single-oxygen-atom donors. Single-oxygen-atom donors are reagents such as iodosylbenzene, 01Ph, and per- iodate, 10 4 ,capable of donating a neutral oxygen atom to an acceptor, form- ing a stable product in the process (here, iodobenzene, 1Ph, and iodate, 10 3 -). It was discovered that ferric cytochrome P-450 could catalyze oxygenation re- actions using organic peroxides or single-oxygen-atom donors in place of diox- ygen and reducing agents. Usually the same substrates would give the identical oxygenated product. This reaction pathway was referred to as the "peroxide shunt" (see Figure 5.10). The implication of this discovery was that the same form of "active oxygen" was generated in each reaction, and the fact that sin- gle-oxygen-atom donors could drive this reaction implied that this species con- tained only one oxygen atom, i.e., was generated subsequent to 0-0 bond
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288 5 I DIOXYGEN REACTIONS cleavage. The mechanism suggested for this reaction was Reactions (5.68) and (5.69). Fe(III)P + + ox ---i> 3 + X 3 + substrate ---i> Fe(III)P + + substrate(O) (5.68) (5.69) b. Metalloporphyrin Model Systems Studies of the reactivities of synthetic metalloporphyrin complexes in oxygen-transfer reactions and characterization of intermediate species observed during the course of such reactions have been invaluable in evaluating potential intermediates and reaction pathways for cyto- chrome P-450. Logically, it would be most desirable if one could mimic the enzymatic oxygenation reactions of substrates using iron porphyrins, dioxygen, and reducing agents. However, studies of such iron-porphyrin-catalyzed reac- tions have failed to produce meaningful results that could be related back to the P-450 mechanism. This is perhaps not surprising, since the enzyme system is designed to funnel electrons into the iron-dioxygen-substrate complex, and thus to
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