The research in our lab aims to investigate oxygen activation chemistry by metalloenzymes with the goal of discovering new therapeutics for human health and informing synthetic catalyst design for C-H functionalization reactions. The ability of iron-bound enzymes to catalyze challenging chemistry is best illustrated by soluble methane monooxygenase (sMMO), which catalyzes the O₂-dependent conversion of methane to methanol in methanotrophic organisms. In order to break the strongest aliphatic C-H bond in chemistry, sMMO generates Nature’s most powerful oxidant in the form of a unique oxygen-bridged dinuclear iron(IV) intermediate termed Q. Understanding the structure and electronics of Q and other sMMO reaction intermediates is critical to the design of a synthetic biomimetic catalyst that can revolutionize the use of natural gas as a liquid fuel and chemical industry feedstock. We probe the chemical mechanism of sMMO with steady-state and transient kinetic techniques, rapid-freeze-quench (RFQ) trapping of intermediates, and physical inorganic spectroscopies to study the dinuclear iron cluster. The structure-function relationship of the protein is studied with biochemical and biophysical techniques including Protein-Observed ¹⁹F-NMR, protein crystallography and cryo-EM microscopy. The exciting, new avenues in sMMO research include the ability to generate site-directed mutants of the active site containing hydroxylase protein and making a molecular movie of sMMO catalysis through Serial Femtosecond Crystallography (SFX) at X-ray Free Electron Laser (XFEL) facilities.

The central role of oxygen activation chemistry in cellular metabolism is catalyzed by soluble cytoplasmic and integral membrane metalloenzymes. While the former class has yielded great insight into oxygen activation, the latter class is under-explored, despite the prevalence of unique active sites, novel chemistry and vital roles in human diseases. One such enzyme superfamily is the dinuclear iron cluster containing integral membrane desaturases that use O₂ to either desaturate or hydroxylate sterols and coenzyme-A-linked fatty acids. These enzymes play critical roles in cellular lipid metabolism, membrane fluidity and signaling. Our lab aims to investigate the chemical mechanism of the stearoyl CoA-desaturase (SCD) enzymes, which are the sole non-dietary source of unsaturated fatty acids in humans. SCDs may employ a putatively novel mechanism for O₂-activation inferred from the unique nitrogen-rich, 8-histidine diiron active site. The central role of SCD in generating membranes means that SCD expression levels are upregulated in cancer cells and during (+) RNA virus infections for making host-membrane derived replication complexes. Our lab, therefore, also aims to guide a rational in-vitro design of SCD inhibitors as anti-cancer and novel anti-viral therapeutics.

Prior to joining Auburn University

1. Jacobs, A.; Banerjee, R.; Deweese, D.; Braun, A.; Babicz, J.; Gee, L.; Sutherlin, K.; Böttger, L.; Yoda, Y.; Saito, M.; Kitao, S.; Kobayashi, Y.; Seto, M.; Tamasaku, K.; Lipscomb, J. D.; Park, K.; Solomon, E. I. Nuclear Resonance Vibrational Spectroscopic (NRVS) Definition of the Fe(IV)₂ Intermediate Q in Methane Monooxygenase and its Reactivity. J Am Chem Soc 2021, 143, 16007-16029 DOI: 1021/jacs.1c05436
2. Jones, J. C.; Banerjee, R.; Shi, K.; Semonis, M. M.; Aihara, H.; Pomerantz, W. C. K.; Lipscomb, J. D. Soluble Methane Monooxygenase Component Interactions Monitored by ¹⁹F NMR. Biochemistry 2021, 60, 1995-2010. DOI: 1021/acs.biochem.1c00293
3. Banerjee, R.; Lipscomb, J. D. Small-Molecule Tunnels in Metalloenzymes Viewed as Extensions of the Active Site. Acc Chem Res 2021, 54, 2185-2195. DOI: 1021/acs.accounts.1c00058
4. Srinivas, V.; Banerjee, R.; Lebrette, H.; Jones, J. C.; Aurelius, O.; Kim, I. S.; Pham, C. C.; Gul, S.; Sutherlin, K. D.; Bhowmick, A.; John, J.; Bozkurt, E.; Fransson, T.; Aller, P.; Butryn, A.; Bogacz, I.; Simon, P.; Keable, S.; Britz, A.; Tono, K.; Kim, K. S.; Park, S. Y.; Lee, S. J.; Park, J.; Alonso-Mori, R.; Fuller, F. D.; Batyuk, A.; Brewster, A. S.; Bergmann, U.; Sauter, N. K.; Orville, A. M.; Yachandra, V. K.; Yano, J.; Lipscomb, J. D.; Kern, J.; Hogbom, M. High-resolution XFEL structure of the soluble methane monooxygenase hydroxylase complex with its regulatory component at ambient temperature in two oxidation states. J Am Chem Soc 2020, 142, 14249-14266. DOI: 1021/jacs.0c05613
5. Banerjee, R.; Jones, J. C.; Lipscomb, J. D. Soluble methane monooxygenase. Annu Rev Biochem 2019, 88, 409-431. DOI: 1146/annurev-biochem-013118-111529
6. Cutsail, G. E., 3rd; Banerjee, R.; Zhou, A.; Que, L., Jr.; Lipscomb, J. D.; DeBeer, S. High-resolution extended X-ray absorption fine structure analysis provides evidence for a longer Fe...Fe distance in the Q intermediate of methane monooxygenase. J Am Chem Soc 2018, 140, 16807-16820. DOI: 1021/jacs.8b10313
7. Banerjee, R.; Proshlyakov, Y.; Lipscomb, J. D.; Proshlyakov, D. A. Structure of the key species in the enzymatic oxidation of methane to methanol. Nature 2015, 518, 431-434. DOI: 1038/nature14160

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