DEPARTMENT OF CHEMISTRY

Affiliations

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

• Yang, H.; Drena, A.; Cutsail Iii, G. E.; Peters, J. C.; Hoffman, B. M. EPR and 31P ENDOR Characterization of Pseudo-Jahn–Teller Dynamics and N₂ Activation in Functional Nitrogenase Models, P₃EM(N₂) (M = Fe, Co; E = Si, B, C). Inorganic chemistry 2025, 64 (36), 18346-18355. DOI: 10.1021/acs.inorgchem.5c02760.
•  Volpe, R. P.; Sen, A.; Sharma, A.; Kathiresan, V.; Hoffman, B. M.; Cox, R. T. Prophylactically Feeding Manganese to Drosophila Confers Sex-Specific Protection from Acute Ionizing Radiation Independent of MnSOD2 Levels. Antioxidants (Basel) 2025, 14 (2), 134. DOI: 10.3390/antiox14020134.
• Palczewski, M. B.; Kuschman, H. P.; Hoffman, B. M.; Kathiresan, V.; Yang, H.; Glynn, S. A.; Wilson, D. L.; Kool, E. T.; Montfort, W. R.; Chang, J.; et al. Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome.
• Londoño, A. F.; Sharma, A.; Sealy, J.; Rana, V. S.; Foor, S. D.; Matrosova, V. Y.; Gaidamakova, E. K.; Volpe, R. P.; Daly, M. J.; Hoffman, B. M.; et al.
• Davydov, R.; Lukoyanov, D. A.; Harris, D. F.; Dean, D. R.; Seefeldt, L. C.; Hoffman, B. M. Proton transfer during reduction of the catalytic metallo-cofactors of the three nitrogenase isozymes.
• Yang, H.; Ho, M. B.; Lundahl, M. N.; Mosquera, M. A.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. M. ENDOR Spectroscopy Reveals the "Free" 5'-Deoxyadenosyl Radical in a Radical SAM Enzyme Active Site Actually is Chaperoned by Close Interaction with the Methionine-Bound [4Fe-4S]
• Pagnier, A.; Balci, B.; Shepard, E. M.; Yang, H.; Drena, A.; Holliday, G. L.; Hoffman, B. M.; Broderick, W. E.; Broderick, J. B. Role of ammonia-lyases in the synthesis of the dithiomethylamine ligand during [FeFe]-hydrogenase maturation.
• Fu, B.; Yang, H.; Kountz, D. J.; Lundahl, M. N.; Beller, H. R.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. H.; Balskus, E. P. Discovery of a New Class of Aminoacyl Radical Enzymes Expands Nature’s Known Radical Chemistry.
• Drena, A.; Fraker, A.; Thompson, N. B.; Doan, P. E.; Hoffman, B. M.; McSkimming, A. Terminal Hydride Complex of High-Spin Mn.
• Tucci, F. J.; Jodts, R. J.; Hoffman, B. M.; Rosenzweig, A. C. Product analog binding identifies the copper active site of particulate methane monooxygenase.
• Lundahl, M. N.; Yang, H.; Broderick, W. E.; Hoffman, B. M.; Broderick, J. B. Pyruvate formate-lyase activating enzyme: The catalytically active 5'-deoxyadenosyl radical caught in the act of H-atom abstraction.
• 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.
• 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
• Lukoyanov, D. A.; Yang, Z. Y.; Perez-Gonzalez, A.; Raugei, S.; Dean, D. R.; Seefeldt, L. C.; Hoffman, B. M.
• 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.; et al. Effects of Desiccation and Freezing on Microbial Ionizing Radiation Survivability: Considerations for Mars Sample Return.
• 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.
• 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.
• Impano, S.; Yang, H.; Jodts, R. J.; Pagnier, A.; Swimley, R.; McDaniel, E. C.; Shepard, E. M.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. M. Active-Site Controlled, Jahn-Teller Enabled Regioselectivity in Reductive S-C Bond Cleavage of S-Adenosylmethionine in Radical SAM Enzymes.
• Martinez, J. L.; Lutz, S. A.; Yang, H.; Xie, J.; Telser, J.; Hoffman, B. M.; Carta, V.; Pink, M.; Losovyj, Y.; Smith, J. M. Structural and spectroscopic characterization of an Fe(VI) bis(imido) complex.
• Yang, H.; McDaniel, E. C.; Impano, S.; Byer, A. S.; Jodts, R. J.; Yokoyama, K.; Broderick, W. E.; Broderick, J. B.; Hoffman, B. M. The Elusive 5'-Deoxyadenosyl Radical: Captured and Characterized by Electron Paramagnetic Resonance and Electron Nuclear Double Resonance Spectroscopies.

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