Abstract
An experimental and theoretical case study on superoxide reductase explores the protonation states of iron-bound histidines and their relevance for metalloenzyme catalysis.
Highlights
Metal-induced histidine deprotonation may have tremendous effects on metalloprotein catalysis
Using experimental and theoretical techniques, we show that these amino acids remain in their neutral state under physiological conditions, excluding deprotonation
Based on the number of metal centres, superoxide reductases can be divided into two major subclasses:[2] neelaredoxins (Nlr)[10] solely contain the active site (1Fe-SOR), while desulfoferrodoxins (Dfx)[11] harbour an Superoxide O2cÀ is a reactive oxygen species (ROS) that is deleterious to biological systems
Summary
The overall spectral appearance as well as the histidine marker bands, n(C]C) and n(C–N), are essentially unaffected by pH variations This shows that amino acids at the SOR active site titrate far from physiological pH, supporting that protons required in superoxide reduction are derived from water.[2] Speci cally, our ndings indicate that the acid–base equilibrium for imidazolate formation lies outside the stable pH range of SOR. All values are lower compared to histidine in aqueous solution, but clearly incompatible with an acid–base equilibrium below pH 6 for the active site histidines In this context, we have to emphasize that metal-induced pKa lowering in histidine is governed by electron donation to a Lewis acid[17] and, consistently, acidi cation is observed upon adding a second proton to imidazole, yielding the imidazolium cation (pKa 6–7, Fig. 2). Deprotonation of H50 is unlikely as its N-bound proton is H-bonded
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