Invited Talk 21st International Conference on Biological Inorganic Chemistry 2025

Molybdenum cofactor model reveals remarkable redox activity at both molybdenum and the pyranopterin dithiolene ligand (123608)

Sharon Josephine Nieter Burgmayer 1 , Jinming Liu 1 , Angelina Rogatch 1 , Benjamin Williams 1 , Jing Yang 2 , Martin L Kirk 2
  1. Chemistry, Bryn Mawr College, Bryn Mawr, Pennsylvania, United States
  2. Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico, United States

The molybdenum (Moco) and tungsten (Tuco) cofactors are uniquely found in pyranopterin dithiolene (PDT) molybdenum and tungsten enzymes, yet the role of the electronically complex PDT ligand in the catalytic cycles of these enzymes has yet to be revealed. Many protein crystal structures of molybdenum enzymes show iron sulfur clusters interacting with different pterin sites through hydrogen bonds, strongly implicating the pyranopterin as a link in in the electron transfer chain during catalysis. This hypothesis motivated development of a reduced pyranopterin dithiolene Mo(4+) model compound and, after more than a decade of effort,1-4 we have synthesized and characterized such a model and investigated its redox properties. A combination of 1D and 2D NMR spectroscopies, augmented by molecular geometry optimization computations, confirm that both R,R- and S,S- diastereomers coexist in the synthetic final product. Redox processes at both the Mo ion and the pyranopterin are detected by cyclic voltammetry. Proton availability has a long-range and strong effect on oxidation outcomes for both 2e- and 1e- oxidants. The two-electron oxidant DCIP oxidizes the pterin component of the ligand in methanol, whereas no reaction occurs in aprotic acetonitrile. Addition of 1 equivalent of the one-electron oxidant Fc+ stoichiometrically oxidizes the Mo(4+) ion to the paramagnetic d1 Mo(5+) species, a result supported by electron paramagnetic resonance (EPR) spectroscopy. However, addition of more than 1 equivalent of Fc+ results in oxidation of the reduced pyranopterin to yield a Mo(4+) complex of the oxidized pyranopterin dithiolene ligand, a result supported by both cyclic voltammetry and electronic absorption titrations. The concrete examples from these model studies suggest how the unique electronic structure of the PDT ligand in Moco and Tuco may enable variable redox reactivity in enzymatic catalysis, highlighting its role as a complex non-innocent biological ligand.

  1. (1) Williams, B. R.; Fu, Y. C.; Yap, G. P. A.; Burgmayer, S. J. N. Structure and Reversible Pyran Formation in Molybdenum Pyranopterin Dithiolene Models of the Molybdenum Cofactor. J. Am. Chem. Soc. 2012, 134 (48), 19584-19587. https://doi-org.proxy.brynmawr.edu/10.1021/ja310018e.
  2. (2) Williams, B. R.; Gisewhite, D.; Kalinsky, A.; Esmail, A.; Burgmayer, S. J. N. Solvent-Dependent Pyranopterin Cyclization in Molybdenum Cofactor Model Complexes. Inorg. Chem. 2015, 54 (17), 8214-8222. https://doi-org.proxy.brynmawr.edu/10.1021/acs.inorgchem.5b00532.
  3. (3) Gisewhite, D. R.; Yang, J.; Williams, B. R.; Esmail, A.; Stein, B.; Kirk, M. L.; Burgmayer, S. J. N.,. J. Am. Chem. Soc. 2018, 140 (40), 12808-12818. https://doi-org.proxy.brynmawr.edu/10.1021/jacs.8b05777.
  4. (4) Gates, C.; Varnum, H.; Getty, C.; Loui, N.; Chen, J.; Kirk, M. L., Yang, J.; Burgmayer, S. J. N. Inorg. Chem. 2022, 61 (35), 13728-13742. https://doi.org/10.1021/acs.inorgchem.2c01234.