ACTIVE TOPICS
Synthetic Models of Nonheme Fe Dioxygenases of Environmental Importance
The ability of microbes to breakdown and assimilate organic compounds of both natural and human origin requires metalloenzymes that convert xenobiotic substrates into smaller metabolites. These enzymes are often mononuclear nonheme iron dioxygenases, which incorporate both atoms of O2 into the substrate. Inspired by these remarkable enzymes, the Fiedler lab aims to develop synthetic active-site models to advance our understanding of O2 activation in both biological and synthetic contexts. These synthetic platforms have allowed us to isolate transient intermediates of relevance to the catalytic mechanism. Examination of these species with an assortment of spectroscopic and computational techniques yields fundamental insights into dioxygenase catalysis.
RELEVANT PAPERS
Devkota, L.; Xiong, J.; Fischer, A.A.; Murphy, K.; Kumar, P.; Balensiefen, E.L.; Lindeman, S.V.; Popescu, C.V.;* Fiedler, A.T.* “Observation of Oxygenated Intermediates in Functional Mimics of Aminophenol Dioxygenase.” Journal of Inorganic Biochemistry 2024, 259, 112632.
Kumar, P.; Devkota, L.; Casey, M.C.; Fischer, A.A.; Lindeman, S.V.; Fiedler, A.T.* “Reversible Dioxygen Binding to Co(II) Complexes with Noninnocent Ligands” Inorganic Chemistry 2022, 61, 16664-16677.
Kumar, P.; Lindeman, S.V.; Fiedler, A.T.* “Cobalt Superoxo and Alkylperoxo Complexes Derived from Reaction of Ring-Cleaving Dioxygenase Models with O2.” Journal of the American Chemical Society 2019, 141, 10984-10987.
Biomimetic Studies of Sulfur Oxidation Reactions by Nonheme Fe Enzymes
Enzymes that utilize O2 to catalyze the oxidation of sulfur-containing compounds play critical roles in amino acid metabolism, signaling pathways, and the biosynthesis of nutrients that protect against oxidative stress in humans. These enzymes often require a nonheme iron cofactor that coordinates substrate(s) and activates O2 for sulfur dioxygenation or C-S bond formation. The Fiedler group seeks to prepare synthetic models of three types of enzymes that oxidize sulfur-based compounds: (i) sulfoxide synthases, (ii) ergothioneine dioxygenase (ETDO), and (iii) persulfide dioxygenase (PDO, also known as ETHE1).
RELEVANT PAPERS
Ekanayake, D.M.; Fischer, A.A.; Elwood, M.E.; Guzek, A.M.; Lindeman, S.V.; Popescu, C.V.;* Fiedler, A.T.* “Nonheme Iron-Thiolate Complexes as Structural Models of Sulfoxide Synthase Active Sites.” Dalton Transactions 2020, 49, 17745-17757.
Fischer, A.A.; Miller, J.R.; Jodts, R.J.; Ekanayake, D.M.; Lindeman, S.V.; Brunold, T.C.;* Fiedler, A.T.* “Spectroscopic and Computational Comparisons of Thiolate-Ligated Ferric Nonheme Complexes to Cysteine Dioxygenase: Second-Sphere Effects on Substrate (Analogue) Positioning.” Inorganic Chemistry 2019, 58, 16487-16499.
Fischer, A.A.; Lindeman, S.V.; Fiedler, A.T.* “A Synthetic Model of the Nonheme Iron–Superoxo Intermediate of Cysteine Dioxygenase.” Chemical Communications 2018, 54, 11344-11347.
Computational Studies of Nitrile Hydratase
Nitrile hydratases (NHases) catalyze the conversion of nitriles to the corresponding amide. These versatile metalloenzymes that have found applications in many industrial, pharmaceutical, and environmental contexts. The active sites of NHases feature a low-spin, nonheme Fe(III) or Co(III) center in an unusual coordination environment consisting of three cysteine residues and two amidate N-donors from the protein backbone. Two of the cysteine-derived ligands undergo post-translational oxygenation to sulfenate (CysSO) and sulfinate (CysSO2) donors. The Fiedler group collaborates with the research groups of Dr. Brian Bennett (Marquette) and Dr. Rick Holz (Colorado School of Mines) to elucidate important aspects of NHase catalysis. This collaborative team has examined the identity of catalytic intermediates, the role of H-bonding networks, and the enzyme maturation process. As part of this work, the Fiedler group has developed novel theoretical approaches to accurately predict EPR g-values for low-spin Fe(III) systems.
RELEVANT PAPERS
Pathiranage, W.LK.; Gumataotao, N.; Fiedler, A.T.;* Holz, R.C.;* Bennett, B.* “Identification of an Intermediate Species along the Nitrile Hydratase Reaction Pathway by EPR Spectroscopy.” Biochemistry 2021, 60, 3771-3782.
Stein, N.; Gumataotao, N.; Hajnas, N.; Wu, R.; Lankathilaka, K.P.W.; Bornscheuer, U.T.; Liu, D.; Fiedler, A.T.*; Holz, R.C.*; Bennett, B.* “Multiple States of Nitrile Hydratase from Rhodococcus equi TG328-2: Structural and Mechanistic Insights from EPR and DFT Studies.” Biochemistry 2017, 56, 3068-3077.
Transition Metal Complexes with Unique Electronic Structures
The Fiedler group has applied advanced physical inorganic methods to transition-metal complexes with unique electronic and/or magnetic features. In particular, we have sought to increase our understanding of the factors that control magnetic anisotropy (or zero-field splitting, ZFS), which is critical for the design of single molecule magnets. These studies examined Co(II) and Ni(II) complexes with (imino)semiquinone radical ligands, which are relevant to the catalytic cycles of ring-cleaving dioxygenases. Related efforts have focused on four- and five-coordinate M(II)-X complexes (M = Co, Fe; X = F, Cl, Br, I) supported by hydrotris(pyrazol-1-yl)borate (Tp) ligands. These studies tested the hypothesis that that paramagnetic complexes with heavy-atom ligands (Z > 30) will generally display larger anisotropy (a “heavy-atom effect”).
These studies have been pursed in collaboration with Dr. Josh Telser (Roosevelt University) and scientists at the MagLab in Tallahassee, FL (Drs. Krzystek and Mykhaylo Ozerov). The relationship between geometric structure and magnetic properties were also examined using state-of-the art ab initio calculations performed by our group.
RELEVANT PAPERS
Devkota, L.; SantaLucia, D.J; Wheaton, A.M.; Pienkos, A.J.; Lindeman, S.V.; Krzystek, J.; Ozerov, M.; Berry, J.F.; Telser, J.;* Fiedler, A.T.* “Spectroscopic and Magnetic Studies of Co(II) Scorpionate Complexes: Is there a Halide Effect on Magnetic Anisotropy?” Inorganic Chemistry 2023, 62, 5984-6002.
Kumar, P.; SantaLucia, D.J.; Kaniewska-Laskowska, K.; Lindeman, S. V.; Ozarowski, A.; Krzystek, J.; Ozerov, M.; Telser, J.; Berry, J.F.;* Fiedler, A.T.* “Probing the Magnetic Anisotropy of Co(II) Complexes Featuring Redox-Active Ligands.” Inorganic Chemistry 2020, 59, 16178-16193.
New Ligand Scaffolds for Metalloenzyme Mimics
The preparation of structural and functional metalloenzyme models requires new ligand frameworks that account for the diversity of enzyme active sites. To this end, the Fiedler lab has designed several ligands that mimic the facial 3-His coordination geometry found in some nonheme iron dioxygenases, such as β-diketone dioxygenase (Dke1), gentisate dioxygenase, and cysteine dioxygenase. We have also prepared N3 facially-coordinating ligands that possess outer sphere H-bond donors to account for important role of second-sphere residues in metalloenzyme catalysis.
RELEVANT PAPERS
Ekanayake, D.M.; Sheridan, P.E.; Lindeman, S.V.; Fiedler, A.T.* “Diverse Coordination Geometries Derived from Trisaminocyclohexane Ligands with Appended Outer-Sphere Hydrogen Bond Donors.” European Journal of Inorganic Chemistry 2023, 26, e202300434.
Wang, D.; Lindeman, S.V., Fiedler, A.T.* “Intramolecular Hydrogen Bonding in Cu(II) Complexes with 2,6-Pyridinedicarboxamide Ligands: Synthesis, Structural Characterization, and Physical Properties.” European Journal of Inorganic Chemistry 2013, 4473-4484.
