In nitrogenases, iron-sulfur clusters transcend their usual role as electron transfer sites, by performing the multielectron reduction of N2 to NH3. This enzyme thus shows the amazing catalytic potential of iron-sulfur clusters in biological systems. In addition to its unique ability to reduce N2, the FeMoco active site of nitrogenase has a carbide (C4-), a feature that is new in biological chemistry. Intermediates in the biosynthesis and catalytic mechanism are likely to have hydride, carbene, N2, and hydrazine moieties, which are unknown in other enzymes. Learning the relationship between the structure and function of nitrogenase is aided by synthetic molecules that have specifi similarities to the FeMoco. Though they are simplified, they make it possible to test structural features one at a time without the complication of the other cofactors and protein. Our guiding hypothesis is that carbide holds and releases low-coordinate iron, which can form Fe-N2 and Fe-H intermediates. In this hypothesis, sulfide donors in the FeMoco give reactive high-spin electronic configurations. We will test these ideas using synthetic iron clustes with combinations of sulfide, nitride, carbene and carbide bridges. Synthetic compounds with these features will show the feasibility of the proposed functional groups on iron-sulfur clusters, establish the spectroscopic signatures of these functional groups, and show whether their behavior is consistent with the models for FeMoco biosynthesis and mechanism. In the proposed research, we will create synthetic iron-containing compounds with each of the following novel functionalities: unsaturated iron-sulfur clusters, iron-sulfide-hydride clusers, high- spin iron-carbene and carbide clusters, and N2-cleaving iron complexes. The isolation and characterization of these compounds is made possible by the use of bulky supporting groups. The bulky groups also facilitate crystallization, and enhance solubilit in solvents that can be used at low temperature. Crystallography, kinetic studies, electrochemistry, and reactivity will be used to elucidate the atomic-level detail of the elementary steps of small-molecule binding and reduction. The synthetic complexes will be evaluated by ENDOR, infrared, Raman, M?ssbauer, and X-ray absorption spectroscopies to provide a link between the structures of novel model compounds and the known data for nitrogenases. We anticipate that the proposed work will lead to valuable precedents for reaction pathways in nitrogenases. Although much is known about the mechanisms of multielectron oxidation reactions in bioinorganic chemistry, the knowledge about multielectron biological reductions lags far behind, and there is particular need for research on small-molecule reactions of iron-sulfur clusters. Therefore, there is fundamental importance in learning how the iron-sulfide cluster in nitrogenase binds and transforms small molecules that are essential for life. In the long run, understanding the mechanisms of small-molecule reduction in biological systems may also lead to new catalysts for use in chemical synthesis, giving an even broader impact.

Public Health Relevance

Enzymes that contain iron and sulfur produce many of the molecules that are essential for life, but are not understood well. The iron-sulfur enzyme nitrogenase converts nitrogen in the atmosphere into more useful molecules, and life as we know it is dependent upon this process of nitrogen fixation. This project aims to show the chemical principles underlying the mechanism of nitrogen fixation, which may also lead to new catalysts for transforming organic and inorganic molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM065313-10
Application #
8761476
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2004-04-01
Project End
2018-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Broere, Daniël L J; Mercado, Brandon Q; Holland, Patrick L (2018) Selective Conversion of CO2 into Isocyanate by Low-Coordinate Iron Complexes. Angew Chem Int Ed Engl 57:6507-6511
Chen, Jingguang G; Crooks, Richard M; Seefeldt, Lance C et al. (2018) Beyond fossil fuel-driven nitrogen transformations. Science 360:
McWilliams, Sean F; Bill, Eckhard; Lukat-Rodgers, Gudrun et al. (2018) Effects of N2 Binding Mode on Iron-Based Functionalization of Dinitrogen to Form an Iron(III) Hydrazido Complex. J Am Chem Soc 140:8586-8598
Pelmenschikov, Vladimir; Gee, Leland B; Wang, Hongxin et al. (2018) High-Frequency Fe-H Vibrations in a Bridging Hydride Complex Characterized by NRVS and DFT. Angew Chem Int Ed Engl 57:9367-9371
McWilliams, Sean F; Bunting, Philip C; Kathiresan, Venkatesan et al. (2018) Isolation and characterization of a high-spin mixed-valent iron dinitrogen complex. Chem Commun (Camb) 54:13339-13342
Broere, Daniel L J; Mercado, Brandon Q; Bill, Eckhard et al. (2018) Alkali Cation Effects on Redox-Active Formazanate Ligands in Iron Chemistry. Inorg Chem 57:9580-9591
Broere, Daniël L J; Holland, Patrick L (2018) Boron compounds tackle dinitrogen. Science 359:871
Skubi, Kazimer L; Holland, Patrick L (2018) So Close, yet Sulfur Away: Opening the Nitrogenase Cofactor Structure Creates a Binding Site. Biochemistry 57:3540-3541
DeRosha, Daniel E; Holland, Patrick L (2018) Incorporating light atoms into synthetic analogues of FeMoco. Proc Natl Acad Sci U S A 115:5054-5056
Broere, Daniël L J; Mercado, Brandon Q; Lukens, James T et al. (2018) Reversible Ligand-Centered Reduction in Low-Coordinate Iron Formazanate Complexes. Chemistry 24:9417-9425

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