Utilizing synthetic models to understand active site assembly in pathogenic bacteria

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Heterobimetallic iron/manganese active sites are found in several enzymes, such as purple acid phosphatase, ribonucleotide reductase class Ic (R2c), and R2-like ligand binding oxidase (R2lox). How Nature assembles heterobimetallic FeMn cofactors has been a long-standing puzzle due to the low bioavailability and weaker the binding affinity of MnII versus FeII. The heterobimetallic specificity of R2c and R2lox has yet to be reproduced with small-molecule models, leading to the hypothesis that FeMn cofactors overcome the thermodynamic preference of FeII over MnII with specific secondary or tertiary protein features. Herein, we report that selective formation of the heterobimetallic FeIIMnII complex can be accomplished in the absence of the influence of the protein scaffold. Treatment of the binucleating ligand Py4DMcT (L) with equimolar amounts of FeII and MnII along with two equivalents of acetate (OAc) in a one-pot reaction affords the [LFeIIMnII(OAc)2]2+ complex in 80% yield, while the diiron complex [LFeII-FeII(OAc)2]2+ was only produced in 8% yield. The formation of FeIIMnII is favored regardless of order of addition of FeII, MnII, and acetate. X-ray diffraction (XRD) of single crystals of [LFeIIMnII(OAc)2]2+ reveals an unsymmetrically coordinated acetate ligand - a feature shared by both R2c and R2lox, which differentiates the two metal binding sites. Metal binding studies performed with quantitative 1H-NMR demonstrate that the successful assembly of the FeIIMnII heterobimetallic complex originates from (a) the selective binding of FeII as the first metal, which creates a Fe-deficient/Mn-rich environment that facilitate the loading of MnII as the second metal, and (b) the inability of the ligand L to house a bimetallic manganese complex, as evidenced by single-crystal XRD and DFT calculation. Our modeling study demonstrates that selective assembly of FeIIMnII bimetallic site can be accomplished through primary ligand preference without violating the classic Irving-Williams series.


Mathematical and Physical Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)


chemistry, bioinorganic, iron, manganese