Substrate activation for O ₂ reactions by oxidized metal centers in biology

Abstract

The uncatalyzed reactions of O 2 (S = 1) with organic substrates (S = 0) are thermodynamically favorable but kinetically slow because they are spin-forbidden and the one-electron reduction potential of O 2 is unfavorable. In nature, many of these important O 2 reactions are catalyzed by metalloenzymes. In the case of mononuclear non-heme iron enzymes, either Fe II or Fe III can play the catalytic role in these spin-forbidden reactions. Whereas the ferrous enzymes activate O 2 directly for reaction, the ferric enzymes activate the substrate for O 2 attack. The enzyme–substrate complex of the ferric intradiol dioxygenases exhibits a low-energy catecholate to Fe III charge transfer transition that provides a mechanism by which both the Fe center and the catecholic substrate are activated for the reaction with O 2 . In this Perspective, we evaluate how the coupling between this experimentally observed charge transfer and the change in geometry and ligand field of the oxidized metal center along the reaction coordinate can overcome the spin-forbidden nature of the O 2 reaction.

Crystal structures of alkylperoxo and anhydride intermediates in an intradiol ring-cleaving dioxygenase

“…Y408 complex (15,22). This convergence suggests that the mechanistic insight into the ring-cleavage mechanism for 4FC is relevant to that for PCA.…”

“…These observations are consistent with the proposed concerted attack mechanism 3 (15). Second, although the initial concerted O 2 attack results in a 6C iron species 4, a rapid rearrangement to a 5C iron species 5 is computationally predicted to be required for stability and reestablishment of the S = 5/2 spin state of the iron (15,22). The observed alkylperoxo species is in the predicted shifted position (Fig.…”

“…4A). Third, a subsequent shift in the position of the bridging peroxo moiety is predicted to increase the reactivity of the species and establish a geometry 6 that facilitates protonation of the proximal peroxo oxygen (15,22). This proton is proposed to drive O-O bond cleavage and insertion.…”

“…1 and designated 1-8 (1,13,15,17,(20)(21)(22)(23). First, PCA binds to the metal of the resting enzyme 1 in a multistep process leading to a complex 2 where both hydroxyls are ionized and the ring of PCA is axially oriented.…”

“…Much of our mechanistic knowledge of IDOs comes from kinetic, spectroscopic, and crystallographic studies of 3,4-PCD, catechol 1,2-dioxygenase (11)(12)(13)(14)(15)(16)(17), and bio-inspired model compounds (18,19). The 3,4-PCD coordinates the Fe 3+ in a 2-His, 2-Tyr ligand set that is conserved in IDOs (11).…”