title: Switching between Inner- and Outer-Sphere PCET Mechanisms of Small-Molecule Activation: Superoxide Dismutation and Oxygen/Superoxide Reduction Reactivity Deriving from the Same Manganese Complex.
abstract: Readily exchangeable water molecules are commonly found in the active sites of oxidoreductases, yet the overwhelming majority of studies on small-molecule mimics of these enzymes entirely ignores the contribution of water to the reactivity. Studies of how these enzymes can continue to function in spite of the presence of highly oxidizing species are likewise limited. The mononuclear MnIIcomplex with the potentially hexadentate ligand N-(2-hydroxy-5-methylbenzyl)-N,N',N'-tris(2-pyridinylmethyl)-1,2-ethanediamine (LOH) was previously found to act as both a H2O2-responsive MRI contrast agent and a mimic of superoxide dismutase (SOD). Here, we studied this complex in aqueous solutions at different pH values in order to determine its (i) acid-base equilibria, (ii) coordination equilibria, (iii) substitution lability and operative mechanisms for water exchange, (iv) redox behavior and ability to participate in proton-coupled electron transfer (PCET) reactions, (v) SOD activity and reductive activity toward both oxygen and superoxide, and (vi) mechanism for its transformation into the binuclear MnIIcomplex with(H)OL-LOHand its hydroxylated derivatives. The conclusions drawn from potentiometric titrations, low-temperature mass spectrometry, temperature- and pressure-dependent17O NMR spectroscopy, electrochemistry, stopped-flow kinetic analyses, and EPR measurements were supported by the structural characterization and quantum chemical analysis of proposed intermediate species. These comprehensive studies enabled us to determine how transiently bound water molecules impact the rate and mechanism of SOD catalysis. Metal-bound water molecules facilitate the PCET necessary for outer-sphere SOD activity. The absence of the water ligand, conversely, enables the inner-sphere reduction of both superoxide and dioxygen. The LOHcomplex maintains its SOD activity in the presence of•OH and MnIV-oxo species by channeling these oxidants toward the synthesis of a functionally equivalent binuclear MnIIspecies.
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Isabell
authors.initials: I
authors.lastname: Kenkel
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Alicja
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Dürr
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Zahl
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Dücker-Benfer
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Jens
authors.identifier: 0000-0002-2895-4979
authors.initials: J
authors.lastname: Langer
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Milos R
authors.initials: MR
authors.lastname: Filipović
authors.affiliation: Department of Chemistry and Biochemistry, Auburn University , Auburn, Alabama 36849, United States.
authors.forename: Meng
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Puchta
authors.affiliation: Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523-1872, United States.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Fiedler
authors.affiliation: Department of Chemistry, Colorado State University , Fort Collins, Colorado 80523-1872, United States.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Shores
authors.affiliation: Department of Chemistry and Biochemistry, Auburn University , Auburn, Alabama 36849, United States.
authors.forename: Christian R
authors.identifier: 0000-0001-7293-1267
authors.initials: CR
authors.lastname: Goldsmith
authors.affiliation: Department of Chemistry and Pharmacy, University Erlangen-Nuremberg , 91058 Erlangen, Germany.
authors.forename: Ivana
authors.identifier: 0000-0002-1651-3359
authors.initials: I
authors.lastname: Ivanović-Burmazović