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Brian M. Hoffman


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


Charles E. and Emma H. Morrison Professor of Chemistry

Professor of Molecular Biosciences

Chemistry of Life Processes Institute (CLP)

Interdisciplinary Biological Sciences Graduate Program (IBiS)

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 and electronic and geometric structures, not merely for the resting state but, most importantly, for key trapped catalytic intermediates. Characterization of key intermediates reveals mechanism!

Our work has made decisive contributions to all the major metalloenzymes, including nitrogenase, cytochrome c oxidase, hydrogenases, peroxidases, aconitase, heme and non-heme mono- and dioxygenases, methane monooxygenases (Fe and Cu), ribonucleotide reductase, and [4Fe,4S] cluster-containing radical S-adenosylmethionine (radical-SAM) enzymes. Foremost perhaps among the array of projects reflected in recent publications are ongoing studies of five central issues at the intersection of Inorganic Chemistry and biology: (i) biological ‘nitrogen fixation’ – the reduction of N2 to two NH3 molecules by the enzyme nitrogenase – the source of ~50% of the N atoms in humans today; (ii) catalysis of H-atom transfer by enzymes of the vast radical SAM superfamily, comprising over 500,000 members, which initiate radical reactions by homolytic cleavage of SAM to form the highly reactive 5’-deoxyadenosyl radical (5’-dAdo•); (iii) activation of O2 by Cu sties, and the oxidation of the greenhouse gas, CH4 by particulate methane monooxygenase; (iv) the biological role of Mn2+ through in vivo ENDOR studies; (v) correlated studies of synthetic, biomimetic complexes 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.

Selected Publications

Badding, E. D.; Srisantitham, S.; Lukoyanov, D. A.; Hoffman, B. M.; Suess, D. L. M. Connecting the Geometric and Electronic Structures of the Nitrogenase Iron- Molybdenum Cofactor through Site-Selective 57Fe Labelling. Nat. Chem. 2023, 15, 658- 665. DOI: 10.1038/s41557-023-01154-9.

Jodts, R. J.; Wittkop, M.; Ho, M. B.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. M.; Mosquera, M. A. Computational Description of Alkylated Iron-Sulfur Organometallic Clusters. J. Am. Chem. Soc. 2023, 145, 13879-13887. DOI: 10.1021/jacs.3c03062.

Lukoyanov, D. A.; Yang, Z. Y.; Perez-Gonzalez, A.; Raugei, S.; Dean, D. R.; Seefeldt, L. C.; Hoffman, B. M. 13C ENDOR Characterization of the Central Carbon within the Nitrogenase Catalytic Cofactor Indicates That the CFe6 Core Is a Stabilizing "Heart of Steel". J. Am. Chem. Soc. 2022, 144, 18315-18328. DOI: 10.1021/jacs.2c06149.

Ho, M. B.; Jodts, R. J.; Kim, Y.; McSkimming, A.; Suess, D. L. M.; Hoffman, B. M. Characterization by ENDOR Spectroscopy of the Iron–Alkyl Bond in a Synthetic Counterpart of Organometallic Intermediates in Radical Sam Enzymes. J. Am. Chem. Soc. 2022, 144, 17642-17650. DOI: 10.1021/jacs.2c07155.

Horne, W. H.; Volpe, R. P.; Korza, G.; DePratti, S.; Conze, I. H.; Shuryak, I.; Grebenc, T.; Matrosova, V. Y.; Gaidamakova, E. K.; Tkavc, R.; Sharma, A.; Gostincar, C.; Gunde- Cimerman, N.; Hoffman, B. M.; Setlow, P.; Daly, M. J. Effects of Desiccation and Freezing on Microbial Ionizing Radiation .Survivability: Considerations for Mars Sample Return. Astrobiology 2022, 22, 1337-1350. DOI: 10.1089/ast.2022.0065.

Lundahl, M. N.; Sarksian, R.; Yang, H.; Jodts, R. J.; Pagnier, A.; Smith, D. F.; Mosquera, M. A.; van der Donk, W. A.; Hoffman, B. M.; Broderick, W. E.; Broderick, J. B. "Mechanism of Radical S-Adenosyl-L-Methionine Adenosylation: Radical Intermediates and the Catalytic Competence of the 5'-Deoxyadenosyl Radical." J. Am. Chem. Soc. (2022), 144, 5087-5098

Davydov, R.; Herzog, A. E.; Jodts, R. J.; Karlin, K. D.; Hoffman, B. M. "End-on Copper(I) Superoxo and Cu(Ii) Peroxo and Hydroperoxo Complexes Generated by Cryoreduction/Annealing and Characterized by Epr/Endor Spectroscopy. " J. Am. Chem. Soc. (2022)

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

  • American Institute of Chemists Gold Medal Award (2022)
  • 2020 Robert Burns Woodward Career Lifetime Achievement Award in Porphyrin Chemistry (2020)
  • 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