The activation of dioxygen in biological systems is a question of great importance because of its involvement in many metabolic processes. Although the mechanism of oxygen activation in heme systems such as cytochrome P450 and peroxidases is becoming quite well understood, much less is known of the corresponding mechanisms for non-heme systems. These latter enzymes are involved in aromatic and aliphatic metabolism, collagen formation, the synthesis of neurochemicals and antibiotics, and participate in reactions that range from oxidative cleavage of aromatic rings, aliphatic and aromatic hydroxylation, to ring cyclizations involving heteroatoms. For many mononuclear nonheme iron enzymes, the reaction with O2 occurs only after substrate or cofactor interacts with the active site iron, e.g. catechol for catechol dioxygenases, substrate thiol for isopenicillin N synthase, and the alpha-ketoacid cofactor for prolyl hydroxylase, clavaminate synthase and other alpha-ketoglutarate-dependent oxygenases. It is proposed that a common general mechanism unites the chemistry of these enzymes, but the details of the dioxygen activation step vary from enzyme because of the divergent natures of the substrates and/or cofactors. Important questions include, 1) how is O2 activated by these enzymes, and 2) what is the nature of high valent intermediates that are involved in the reactions? Spectroscopic (NMR, EPR, resonance Raman, Mossbauer, EXAFS) and mechanistic studies are proposed for a number of enzymes to elucidate details of the active site structure and the mechanism of action. These include intradiol cleaving catechol dioxygenases, isopenicillin N synthase, p- hydroxyphenylpyruvate dioxygenase, and clavaminate synthase (ketoacid- dependent enzymes). Model complexes will be synthesized and used as models to interpret spectroscopic features of the enzymes. More importantly, the key mechanistic steps of the oxidations will be modeled. Areas of particular interest are: 1) biomimetic oxidative cleavage of catechols, 2) development of models for the isopenicillin N synthase and the alpha- ketoacid-dependent oxygenase reactions, 3) characterization of transient high valent intermediates. As in the past, the synergistic interaction of the biochemical and inorganic aspects of the proposal is important for the success of the program.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Minnesota Twin Cities
Other Domestic Higher Education
United States
Zip Code
England, Jason; Bigelow, Jennifer O; Van Heuvelen, Katherine M et al. (2014) An Ultra-Stable Oxoiron(IV) Complex and Its Blue Conjugate Base. Chem Sci 5:1204-1215
Wang, Dong; Ray, Kallol; Collins, Michael J et al. (2013) Nonheme Oxoiron(IV) Complexes of Pentadentate N5 Ligands: Spectroscopy, Electrochemistry, and Oxidative Reactivity. Chem Sci 4:282-291
Hayden, Joshua A; Farquhar, Erik R; Que, Lawrence et al. (2013) NO binding to Mn-substituted homoprotocatechuate 2,3-dioxygenase: relationship to Oýýý reactivity. J Biol Inorg Chem 18:717-28
McDonald, Aidan R; Guo, Yisong; Vu, Van V et al. (2012) A Mononuclear Carboxylate-Rich Oxoiron(IV) Complex: a Structural and Functional Mimic of TauD Intermediate 'J' Chem Sci 3:1680-1693
Srnec, Martin; Wong, Shaun D; England, Jason et al. (2012) ýý-Frontier molecular orbitals in S = 2 ferryl species and elucidation of their contributions to reactivity. Proc Natl Acad Sci U S A 109:14326-31
Van Heuvelen, Katherine M; Fiedler, Adam T; Shan, Xiaopeng et al. (2012) One-electron oxidation of an oxoiron(IV) complex to form an [O?FeV?NR]+ center. Proc Natl Acad Sci U S A 109:11933-8
Fielding, Andrew J; Lipscomb, John D; Que Jr, Lawrence (2012) Characterization of an O2 adduct of an active cobalt-substituted extradiol-cleaving catechol dioxygenase. J Am Chem Soc 134:796-9
Mas-Balleste, Ruben; McDonald, Aidan R; Reed, Dana et al. (2012) Intramolecular gas-phase reactions of synthetic nonheme oxoiron(IV) ions: proximity and spin-state reactivity rules. Chemistry 18:11747-60
Wong, Shaun D; Bell 3rd, Caleb B; Liu, Lei V et al. (2011) Nuclear resonance vibrational spectroscopy on the Fe(IV)=O S=2 non-heme site in TMG3tren: experimentally calibrated insights into reactivity. Angew Chem Int Ed Engl 50:3215-8
Li, Feifei; Meier, Katlyn K; Cranswick, Matthew A et al. (2011) Characterization of a high-spin non-heme Fe(III)-OOH intermediate and its quantitative conversion to an Fe(IV)?O complex. J Am Chem Soc 133:7256-9

Showing the most recent 10 out of 118 publications