Nickel‐substituted iron‐dependent cysteine dioxygenase: Implications for the dioxygenation activity of nickel model compounds

Abstract

Reported here is a density functional theory study on the ability of Ni‐substituted iron‐dependent cysteine dioxygenase (CDO) to catalyze the oxidation of cysteine to cysteine sulfinic acid. The first steps of the commonly accepted mechanism for CDO, the O2 activation mechanism, suggests the binding of O2 to the metal ion (where redox isomerism takes place converting O2 to ) followed by the attack of the distal oxygen atom on the cysteine sulfur—in line with most previous evidence. An alternative mechanism entailing the attack of the cysteine sulfur on the proximal oxygen atom of the dioxygen moiety to form a persulfenate intermediate without any redox exchange between the metal ion and the O2 ligand, is supported by an X‐ray crystal structure showing a CDO with a bound cysteine persulfenate, and also supported by data on the oxidation of thiols catalyzed by Ni(II) compounds. Our results show that the O2 activation mechanism with a Ni‐substituted active site follows the same pattern as native CDOs albeit with much higher energy barriers for the formation of the intermediates suggesting that the reaction might not be biologically feasible. Conversely, the immediate cleavage of the persulfenate SO bond in the alternative mechanism suggests that cysteine persulfenate might not be a true intermediate in catalytic cycle of CDOs.