Binding Modes of Cysteamine Homologues Control Fe(III)–Thiolate Autoredox Rates in a Thiol Dioxygenase Model Complex

Thiol dioxygenases transform thiols to sulfinates facilitating cysteine homeostasis and biosynthetic pathways. Substrate binding modes at thiol dioxygenase active sites have received increasing attention to better understand how selectivity and activation is achieved. Of particular interest is the substrate-binding mode within cysteamine dioxygenase (ADO) because of its unique selectivity for both cysteamine and N-terminal cysteine residues. ADO also exhibits unique reactivity with both substrates through an autoredox reaction of the form ADO-Fe(III)-SR → ADO-Fe(II) + ½ RSSR which is proposed to maintain Fe(II) under oxidative stress conditions. Here we use the thiol dioxygenase model complex [Fe(tacn)Cl3] (tacn = 1,4,7-triazacyclononane) to replicate the 3N facial coordination environment in ADO-Fe(III) and to enable experiments buffered near neutral pH. Autoredox reactions are initiated by forming Fe(III)–thiolate intermediates in situ using cysteamine and cysteamine homologues penicillamine, mercaptopropionic acid, cysteine, N-acetylcysteine, and N-acetylcysteine methyl ester. We observe trends in autoredox rate constants as a function of substrate binding mode. Moreover, we observe autoredox reactivity on the same timescale reported for ADO autoredox activity. To provide evidence of tridentate coordination in the relatively reactive cysteine intermediate, we isolated a stable penicillamine-containing intermediate and characterized its coordination environment and electronic structure using FT-IR, NMR, and magnetic susceptibility measurements.