O 2 Activation and Enzymatic C–H Bond Activation Mediated by a Dimanganese Cofactor
Year: 2025
Type: article
Abstract: Dioxygen (O 2 ) is a potent oxidant used by aerobic organisms for energy transduction and critical biosynthetic processes. Numerous metalloenzymes harness O 2 to mediate C–H bond hydroxylation reactions, but most commonly feature iron or copper ions in their active site cofactors. In contrast, many manganese-activated enzymes─such as glutamine synthetase and isocitrate lyase─perform redox neutral chemical transformations and very few are known to activate O 2 or C–H bonds. Here, we report that the dimanganese-metalated form of the cambialistic monooxygenase SfbO (Mn 2 –SfbO) can efficiently mediate enzymatic C–H bond hydroxylation. The activity of the dimanganese form of SfbO toward substrate hydroxylation is comparable to that of its heterobimetallic Mn/Fe form but exhibits distinct kinetic profiles. Kinetic, spectroscopic, and structural studies invoke a mixed-valent dimanganese cofactor (Mn II Mn III ) in O 2 activation and evidence a stoichiometric role for superoxide in maturing an O 2 -inert Mn II 2 cofactor. Computational studies support a hypothesis wherein superoxide addition to the Mn II 2 cofactor installs a critical bridging hydroxide ligand that stabilizes higher-valent manganese oxidation states. These findings establish the viability of proteinaceous dimanganese cofactors in mediating complex, multistep redox transformations.
DOI: 10.1021/jacs.4c16271
Language: English
Subfield: Inorganic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
Awards: G1286236842, G1286251239, G2371548206, G2464961839, G303061748, G30714459, G3083819904, G382641700, G42916606, G5570207115, Spectroscopic Investigations of Metalloenzyme Mechanisms, G650090426, G6550344761, G7283024673, G8229677252, G8925327636, G9000034938, G9000263589, A Synchrotron Radiation Structural Biology Resource, ALS Efficiently Networking Advanced Beam Line Experiments (ALS-ENABLE), Discovery and Characterization of Manganese-dependent Monooxygenases, G911061179, G969889393
OpenAlex ID: W4405956047