Spectroscopic, Electrochemical, and Kinetic Trends in Fe(III)–Thiolate Autoredox Reactions Near Physiological pH

10 August 2022, Version 3
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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 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 physiological pH. Autoredox reactions are initiated by forming Fe(III)–thiolate intermediates in situ using cysteamine and cysteamine analogues penicillamine, mercaptopropionate, cysteine, N-acetylcysteine, and N-acetylcysteine methyl ester. We observe trends in UV–vis absorption maxima, autoredox rate constants, and cathodic peak potentials 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.

Keywords

iron(III)
thiolate
autoredox
cysteamine dioxygenase
thiol dioxygenase
ADO
electrochemistry

Supplementary materials

Title
Description
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Supporting Information
Description
UV-vis spectra of 1(aq) + cysteine methyl ester, NMR spectra of cysteine to cystine conversion, Mass spectra demonstrating disulfide formation, FT-IR spectrum of 2, NMR spectra of 2.
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