The overall goal of this proposal is to understand how dioxygen is activated by biological diiron centers to carry out metabolically critical transformations. Nonheme diiron enzymes perform a variety of dioxygen-dependent essential functions, including the biosynthesis of DNA (ribonucleotide reductase), iron storage (ferritin), and the hydroxylation of organic substrates (methane monooxygenase, arene hydroxylases, deoxyhypusine hydroxylase). In general, dioxygen activation is proposed to entail a common mechanism involving diiron(III)- peroxo intermediates. Important project goals are to understand how the diiron(III)-peroxo intermediates are converted to corresponding high-valent iron-oxo species that very likely act as the key oxidants for substrate transformation and to describe the structural, electronic, and reactivity properties of the high-valent intermediates. These goals will be accomplished by both biochemical and biomimetic approaches. The biochemical effort will primarily focus on human deoxyhypusine hydroxylase, an enzyme that hydroxylates a deoxyhypusine residue on eukaryotic initiation factor 5A to generate a mature form that is required for eukaryotic cell proliferation and implicated in HIV-1 transcription initiation. This enzyme has a diiron active site and is isolated in an unusually stable diiron(III)-peroxo form that is nevertheless capable of substrate hydroxylation. The diiron active site will be investigated by a combination of biochemical and spectroscopic techniques to gain insight into its mode of action. The biomimetic effort will focus on generating and trapping metastable species that relate to diiron(III)-peroxo and high-valent iron intermediates observed in the redox cycles of the nonheme diiron enzymes. Of particular interest are complexes with unusual Fe(III)-O-Fe(IV) and Fe(IV)-O-Fe(IV) units, motifs associated with the oxidizing species formed during enzyme catalysis. These novel complexes will be characterized by a variety of spectroscopic techniques to determine their structures and electronic properties. Corresponding complexes with Fe(III)-O-Mn(IV) and Fe(IV)-O-Mn(IV) units will also be synthesized to model high-valent intermediates associated with the recently discovered ribonucleotide reductase (RNR) with a FeMn active site (instead of a diiron site) from the parasite Chlamydia trachomatis. Understanding the difference in the reactivity properties of high-valent FeFe and FeMn complexes may contribute to the development of better methods for treating infections from such human pathogens. Nonheme diiron enzymes perform a variety of metabolically critical functions that require O2. For example, ribonucleotide reductase is a key enzyme that controls DNA biosynthesis, while deoxyhypusine hydroxylase is required for the formation of mature eukaryotic initiation factor 5a that is essential for cell proliferation. Understanding how these enzymes work can lead to the development of new drug strategies for treating cancer, AIDS, and infections of human pathogens like chlamydiae.
Nonheme diiron enzymes perform a variety of metabolically critical functions that require O2. For example, ribonucleotide reductase is a key enzyme that controls DNA biosynthesis, while deoxyhypusine hydroxylase is required for the formation of mature eukaryotic initiation factor 5a that is essential for cell proliferation. Understanding how these enzymes work can lead to the development of new drug strategies for treating cancer, AIDS, and infections of human pathogens like chlamydiae.
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|Frisch, Jonathan R; McDonnell, Ryan; Rybak-Akimova, Elena V et al. (2013) Factors affecting the carboxylate shift upon formation of nonheme diiron-O2 adducts. Inorg Chem 52:2627-36|
|Xue, Genqiang; Geng, Caiyun; Ye, Shengfa et al. (2013) Hydrogen-bonding effects on the reactivity of [X-Fe(III)-O-Fe(IV)ýýýO] (X = OH, F) complexes toward C-H bond cleavage. Inorg Chem 52:3976-84|
|Wang, Dong; Que Jr, Lawrence (2013) Oxidation of water by a nonhaem diiron(IV) complex via proton-coupled electron transfer. Chem Commun (Camb) 49:10682-4|
|Park, Kiyoung; Bell 3rd, Caleb B; Liu, Lei V et al. (2013) Nuclear resonance vibrational spectroscopic and computational study of high-valent diiron complexes relevant to enzyme intermediates. Proc Natl Acad Sci U S A 110:6275-80|
|Do, Loi H; Xue, Genqiang; Que Jr, Lawrence et al. (2012) Evaluating the identity and diiron core transformations of a (ýý-oxo)diiron(III) complex supported by electron-rich tris(pyridyl-2-methyl)amine ligands. Inorg Chem 51:2393-402|
|Li, Feifei; Chakrabarti, Mrinmoy; Dong, Yanhong et al. (2012) Structural, EPR, and Mössbauer characterization of (?-alkoxo)(?-carboxylato)diiron(II,III) model complexes for the active sites of mixed-valent diiron enzymes. Inorg Chem 51:2917-29|
|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|
|Chandrasekaran, P; Stieber, S Chantal E; Collins, Terrence J et al. (2011) Prediction of high-valent iron K-edge absorption spectra by time-dependent density functional theory. Dalton Trans 40:11070-9|
|Xue, Genqiang; Pokutsa, Alexander; Que Jr, Lawrence (2011) Substrate-triggered activation of a synthetic [Fe2(?-O)2] diamond core for C-H bond cleavage. J Am Chem Soc 133:16657-67|
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