Thiol dioxygenases are mononuclear nonheme iron enzymes that are essential for regulating levels of thiol compounds in mammalian cells. The best characterized example is cysteine dioxygenase (CDO), which catalyzes the dioxygen-dependent conversion of L-cysteine to cysteine sulfinic acid. This reaction is the initial step in the catabolism of cysteine to byproducts such as sulfate and taurine. The closely-related enzyme cysteamine dioxygenase (ADO) participates in the degradation of coenzyme A. The active sites of CDO and ADO each contain a high-spin Fe(II) center coordinated to three histidine residues in a facial geometry: the 3His facial triad. We have prepared a series of synthetic thiol dioxygenase models featuring a tris(imidazolyl)phosphine (TIP) supporting ligand to mimic the 3His triad and a bidentate thiolate ligand to replicate the bound substrate. The synthesis and X-ray crystal structures of these CDO/ADO models are presented in this report, and their reactivity with O<sub>2</sub> is discussed. In addition, we will describe our attempts to isolate species that resemble proposed, but elusive, intermediates of the CDO mechanism, including those with iron-bound superoxo, peroxo, and oxo ligands. An assortment of spectroscopic (UV-vis absorption, EPR, resonance Raman) and density functional theory (DFT) methods have been employed to probe the geometric and electronic structures of the synthetic intermediates. Finally, the implications of our results for the catalytic mechanism of thiol dioxygenases will be considered.

Modeling catalytic intermediates of the thiol dioxygenases

251st National Meeting (2016)

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