Coordination Dynamics of Iron is a Key Player in the Catalysis of Non‐heme Enzymes

Abstract

Mononuclear nonheme iron enzymes catalyze a large variety of oxidative transformations responsible for various biosynthesis and metabolism processes. Unlike their P450 counterparts, non‐heme enzymes generally possess flexible and variable coordination architecture, which can endow rich reactivity for non‐heme enzymes. This Concept highlights that the coordination dynamics of iron can be a key player in controlling the activity and selectivity of non‐heme enzymes. In ergothioneine synthase EgtB, the coordination switch of the sulfoxide radical species enables the efficient and selective C−S coupling reaction. In iron(II)‐ and 2‐oxoglutarate‐dependent (Fe/2OG) oxygenases, the conformational flip of ferryl‐oxo intermediate can be extensively involved in selective oxidation reactions. Especially, the five‐coordinate ferryl‐oxo species may allow the substrate coordination via O or N atom, which may facilitate the C−O or C−N coupling reactions via stabilizing the transition states and inhibiting the unwanted hydroxylation reactions.

Conformational Isomerization of the Fe(III)–OH Species Enables Selective Halogenation in Carrier-Protein-Independent Halogenase BesD and Hydroxylase-Evolved Halogenase

“…Coordination isomerization of the Fe­(IV)-oxo intermediate has been widely proposed in previous computational studies. − Specifically, in BesD, recent QM model calculations postulated that the coordination isomerization of the Fe­(IV)-oxo intermediate can bring the substrate C4–H closer to the Fe­(IV)-oxo species (Figure b), thereby facilitating the following C–H activation . However, the protein environment has been recognized to be crucial to the enzyme catalysis, especially for the substrate positioning. ,,− For instance, the substrate positioning from the QM model calculations varies significantly with the crystal structure and that from our QM/MM calculations (Figure S4).…”

Ergothioneine and its congeners: anti-ageing mechanisms and pharmacophore biosynthesis

“…Hydroxylation of the sulfur atom occurred prior to C ε –S bond formation, C ε –H cleavage is no longer the rate determining step. Notably, a coordination switch of γ-GC sulfenic acid intermediate from sulfur (14) to oxygen atom (15) was proposed ( Wu et al, 2022 ; Zhang et al, 2023 ). It well accommodates the EgtB experimental results, and sheds light on the mechanism of other sulfoxide synthases, including Egt1 and OvoA (C δ –S bond formation enzyme involved in Ovothiol biosynthesis).…”

Unusual catalytic strategy by non-heme Fe(ii)/2-oxoglutarate-dependent aspartyl hydroxylase AspH

“…The mechanisms of 2OG oxygenases have been studied experimentally and computationally (Scheme 1). 80,101–123 The catalytic cycle is initiated by the co-substrate 2OG, then substrate binding to the Fe( ii ) center, followed by O 2 binding producing a Fe( iii )-superoxo anion-radical (Fe( iii )-OO˙ − ) intermediate. 106,124 The latter reacts via a succinyl peroxide intermediate to give a ferryl (Fe( iv )O) intermediate 125–130 with the formation of CO 2 and Fe-linked succinate.…”