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Brian Hoffman


B.S.: University of Chicago; Ph.D.: California Institute of Technology


Morrison Professor of Chemistry

Chemistry of Life Processes Institute (CLP)

Research Statement

We determine the catalytic mechanisms of metalloenzymes through the development and implementation of electron-nuclear double resonance (ENDOR) spectroscopy, a combination of NMR and EPR. This technique is uniquely able to determine active site composition, electronic and geometric structures, not merely for the resting state but, most importantly, for key trapped catlalytic intermediates. This approach is applied to complex multi-metallic catalytic centers, as in the globally important enzyme, nitrogenase, which provides nitrogen as nutrient for most of the planet, as well as to key mononuclear centers, as in the physiologically vital heme enzymes nitric oxide synthase and cytochrome P450.  In parallel, we study biomimetic complexes that  provide constraints that help identify intermediates trapped during catalysis, and that are moreover of intrinsic importance as Jahn-Teller active systems whose H2 complexes exhibit novel dynamic properties. A second area of research is the study of long-range electron transfer between proteins. We focus on the central question: how do conformational dynamics at a protein-protein interface control inter-protein electron transfer? As protein-protein interactions are central to almost all biological processes, this focus links our research to other major problems in biology.

Selected Publications

Impano, Stella; Yang, Hao; Jodts, Richard J.; Pagnier, Adrien; Swimley, Ryan; McDaniel, Elizabeth C.; Shepard, Eric M.; Broderick,William E.; Hoffman, Brian M. "Active-Site Controlled, Jahn-Teller Enabled Regioselectivity in Reductive S-C Bond Cleavage of S-Adenosylmethionine in Radical SAM Enzymes", JACS, (2021) 143 (1), 335-348

Seeler, John F.; Sharma, Ajay; Zaluzec, Nestor J.; Bleher, Reiner; Lai, Barry; Schultz, Emma G.; Hoffman, Brian M.; LaBonne, Carole; Woodruff, Teresa K.; O'Halloran, Thomas, V. "Metal Ion Fluxes Controlling Amphibian Fertilization, Nature Chemistry", (2021), 13, 683–691

Perez-Gonzalez, Ana; Yang, ZhiYong; Lukoyanov, Dmitriy; Dean, Dennis; Seefeldt, Lance; Hoffman, Brian "Exploring the Role of the Central Carbide of the Nitrogenase Active-Site FeMo-cofactor through Selective 13C Labeling and ENDOR Spectroscopy", JACS, (2021), 143 (24), 9183–9190

Seefeldt, Lance C.; Yang, Zhi-Yong; Lukoyanov, Dmitriy A.; Harris, Derek F.; Dean, Dennis R.; Raugei, Simone; Hoffman, Brian M. (2020) “Reduction of Substrates by Nitrogenases”, Chem. Rev. 120 (12) 5082-5106.

Offenbacher, A.R.; Sharma, A.; Doan, P.E.; Klinman, J.P.; Hoffman, B.M. (2020) "The Soybean Lipoxygenase–Substrate Complex: Correlation between the Properties of Tunneling-Ready States and ENDOR-Detected Structures of Ground States", Biochemistry 59 (7) 901-910.

Yang, H.; McDaniel, E. C.; Impano, S.; Byer, A. S.; Jodts, R. J.; Yokoyama, K.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. M. (2019) "The Elusive 5′-Deoxyadenosyl Radical: Captured and Characterized by Electron Paramagnetic Resonance and Electron Nuclear Double Resonance Spectroscopies”, J. Am. Chem. Soc. 141, 12139-12146.

Tsednee, Munkhtsetseg; Castruita, Madeli; Salome, Patrice A.; Sharma, Ajay; Lewwis, Brianne E.; Schmollinger, Stefan R.; Strenkert, Daniela; Holbrook, Kristen; Otegui, Marisa S.; Khatua, Kaustav; Das, Sayani; Datta, Akona; Chen, Si; Ramon, Christina, Ralle, Martina; Weber, Peter K.; Stemmler, Timothy L.; Pett-Ridge, Jennifer; Hoffman, Brian M.; Merchant, Sabeeha S. (2019) "Manganese co-localizes with calcium and phosphorous in Chlamydomonas acidocalcisomes and is mobilized in manganese-deficient conditions”, J. Biol. Chem., 294 (46), 17626-17641.

Ross, Matthew O., MacMillan, Fraser, Wang, Jingzhou, Nisthal, Alex, Lawton, Thomas J., Olafson, Barry D., Mayo, Stephen L., Rosenzweig, Amy C., Hoffman, Brian M. (2019) "Particulate methane monooxygenase contains only mononuclear copper centers", Science, 364, (6440), pp. 566-570.

Seefeldt, Lance C., Peters, John W., Beratan, David N., Bothner, Brian, Minteer, Shelley D., Raugei, Simone and Hoffman, Brian M. (2018) "Control of Electron Transfer in Nitrogenase", Chemical Biology, 47, 54-59.

Harris, D. F., Yang, Z.-Y., Dean, D. R., Seefeldt, L. C., and Hoffman, B. M. (2018) "Kinetic Understanding of N2 Reduction Versus H2 Evolution at the E4(4H) Janus State in the Three Nitrogenases", Biochemistry, 2018, 57 (39), 5706-5714.

Yang, H., Rittle, J., Marts, A. R., Peters, J. C., and Hoffman, B. M. (2018) "ENDOR Characterization of (N2)FeII(μ-H)2FeI(N2)-: A Spectroscopic Model for N2 Binding by the di-μ-hydrido Nitrogenase Janus Intermediate", Inorg. Chem., 2018, 57, 12323-12330.

Broderick, W. E., Hoffman, B. M., and Broderick, J. B. (2018) "Mechanism of Radical Initiation in the Radical SAM Superfamily", Acc. Chem. Res., 2018, 51, 2611−2619.

Raugei, S., Seefeldt, L. C., and Hoffman, B. M. (2018) "A Critical Computational Analysis Illuminates the Reductive-Elimination Mechanism That Activates Nitrogenase for N2 Reduction", PNAS, 115 (45), E10521-E10530.

Seefeldt, L. C., Hoffman, B. M., Peters, J. W., Raugei, S., Beratan, D. N., Antony, E., and Dean, D. R. (2018) "Energy Transduction in Nitrogenase", Acc. Chem. Res., 51 (9), 2179–2186.

Byer, A. S., Yang, H., McDaniel, E. C., Kathiresan, V., Impano, S., Pagnier, A., Watts, H., Denler, C., Vagstad, A., Piel, J., Duschene, K. S., Shepard, E. M., Shields, T. P., Scott, L. G., Lilla, E. A., Yokoyama, K., Broderick, W. E., Hoffman, B. M., and Broderick, J. B. (2018) "Paradigm Shift for Radical S-Adenosyl-L-Methionine Reactions: The Organometallic Intermediate Omega Is Central to Catalysis", J. Am. Chem. Soc. 140, 8634-8638.

Dong, M., Kathiresan, V., Fenwick, M. K., Torelli, A. T., Zhang, Y., Caranto, J. D., Dzikovski, B., Sharma, A., Lancaster, K. M., Freed, J. H., Ealick, S. E., Hoffman, B. M., and Lin, H. (2018) "Organometallic and Radical Intermediates Reveal Mechanism of Diphthamide Biosynthesis", Science, 359, 1247-1250.

Harris, D. F., Lukoyanov, D. A., Shaw, S., Compton, P., Tokmina-Lukaszewska, M., Bothner, B., Kelleher, N., Dean, D. R., Hoffman, B. M., and Seefeldt, L. C. (2018) "The Mechanism of N2 Reduction Catalyzed by Fe-Nitrogenase Involves Reductive Elimination of H2 ", Biochemistry, 57, 701-710.

Byer, A. S., Yang, H., McDaniel, E. C., Kathiresan, V., Impano, S., Pagnier, A., Watts, H., Denler, C., Vagstad, A., Piel, J., Duschene, K. S., Shepard, E. M., Shields, T. P., Scott, L. G., Lilla, E. A., Yokoyama, K., Broderick, W. E., Hoffman, B. M., and Broderick, J. B. (2018) “A New Paradigm for Radical S‑Adenosyl‑L‑Methionine Reactions: The Organometallic Intermediate Omega Is Central to Catalysis”, J. Am. Chem. Soc., 140, 8634-8638.


Selected Honors/Awards

  • 2020 Robert Burns Woodward Career Lifetime Achievement Award in Porphyrin Chemistry
  • Member, National Academy of Sciences
  • Ritter Lecturer, Miami University (2013)
  • ACS F.A Cotton Medal for Excellence in Chemical Research (2013)
  • RSC Joseph Chatt Award (2012)
  • Alfred Bader Award in Bioinorganic or Bioorganic Chemistry (2012)
  • Fellow, International Society of Magnetic Resonance (ISMAR) (2009)
  • Frontiers in Biological Chemistry Award (2008)
  • Zavoisky Prize from the Russian Academy of Sciences (2007)
  • Charles E. and Emma H. Morrison Professor of Chemistry (2007)
  • Fellow, American Association for the Advancement of Science
  • Fellow, American Academy of Arts & Sciences (2002)
  • Gold Medal International EPR/ERS Society (1999)
  • Bruker Prize, Royal Society of Chemistry (1997)
  • Chair, Bioinorganics Subdivision, American Chemical Society (1991-93)
  • Chair, NIH-BMT Study Section (1990-92)
  • Career Development Award, National Institutes of Health (1972-77)
  • Alfred P. Sloan Fellow (1971-73)
  • NAS-NRC Fellow, Massachusetts Institute of Technology
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