The pterin- and α-ketoglutarate (αKG)-dependent mononuclear nonheme iron enzymes are ubiquitous in nature and play key roles in neurotransmitter and antibiotic biosynthesis by performing various different substrate oxidation and oxygenation reactions. These classes of enzymes activate dioxygen to form highly electrophilic FeIV=O intermediates that are facile in either electrophilic aromatic chemistry (for the pterin-dependent hydroxylases) or hydrogen atom abstraction (HAA, for the αKG-dependent enzymes). In tryptophan hydroxylase, we have trapped the pre-FeIV=O intermediate and characterized it using Mössbauer, resonance Raman and nuclear resonant vibrational spectroscopies and used these data combined with kinetics to understand the reaction coordinate. In the αKG-dependent hydroxylases, following HAA by the FeIV=O intermediate, the resulting FeIII-OH is capable of rebound hydroxylation/halogenation or desaturation/ring closure/ring expansion reactions. In deacetoxycephalosporin C synthase (DAOCS), we have demonstrated the requirement of the general mechanistic strategy (i.e. ensuring cofactor and substrate binding before O2 for productive catalysis) in nonheme iron O2 activation and observed a post-ferryl-oxo species that helps reveal the mechanism of ring expansion. Together, these results have elucidated how O2 is activated to form FeIV=O intermediates and how an FeIII-OH intermediate is able to perform ring expansion chemistry.

Oxygen intermediates before and after ferryl-oxos in mononuclear nonheme iron enzymes

2019 Fall National Meeting

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