The project focuses on the mechanisms of action of enzymes called hydrogenases, of which there are two, [NiFe]- and the [FeFe]-hydrogenases, reflecting the metals at the active sites. These enzymes, which underpin H2-dependent metabolism of many pathogens in the human gut, act on two substrates protons (H+) and H2. Several related families of enzymes are known. The results are further relevant to fundamental catalyst technology. The work aims to clarify the structure and reactivity of the Ni-C, Ni-SI, Ni-R and Ni-L states of the [NiFe]-hydrogenases and the Hred state of the [FeFe]-hydrogenases. Special attention is directed at the location and behavior H2-derived substrates that are usually invisible to protein spectroscopy and are undetectable by protein crystallography. The active sites of these enzymes are highly unusual, featuring several distinctive cofactors, such as CO, cyanide, and, in the [FeFe] case, an aminodithiolate. The work employs the tools of organometallic chemistry to produce models (replicas) of the active sites. Molecular-level insights into behavior of the hydrogenic ligands will be examined by NMR spectroscopy and X-ray crystallography with attention to stereochemistry, redox potentials, acid-base behavior, and kinetic properties. The first theme examines methods for stabilizing nickelIII, characteristic of N-C state, using organometallic ligands that emulate the donor properties of thiolate ligands. The second theme examines the role of the cyanide cofactors bound to Fe, with attention to developing tools to modify the behavior of these groups.
This aim builds on preliminary evidence that boron reagents enable biomimetic activation of hydrogen in iron cyanides. The third theme, with a primary focus on the [FeFe] enzymes, elucidates the factors that lead to bidirectionality, the ability of models to both produce and oxidized H2. The last theme, which also emphasizes [FeFe]-hydrogenase, examines hypotheses that seek to explain the unusual structure-function of the reduced state of the enzyme. This theme will lead to new ligand scaffolds that stabilize terminal hydride ligands.

Public Health Relevance

Hydrogen is a metabolic substrate and product for both pathogenic and beneficial members of human gut flora. This metabolism is mediated by hydrogenase enzymes. Through the work proposed herein we will elucidate the function of these enzymes on a molecular level, with emphasis on interactions involving iron and hydrogen.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM061153-13
Application #
8630785
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Champaign
State
IL
Country
United States
Zip Code
61820
Zhao, Peihua; Gray, Danielle L; Rauchfuss, Thomas B (2016) Rational Synthesis of the Carbonyl(perthiolato)diiron [Fe2(S3CPh2)(CO)6] and Related Complexes. Eur J Inorg Chem 2016:2681-2683
Schilter, David; Camara, James M; Huynh, Mioy T et al. (2016) Hydrogenase Enzymes and Their Synthetic Models: The Role of Metal Hydrides. Chem Rev 116:8693-749
Li, Yulong; Rauchfuss, Thomas B (2016) Synthesis of Diiron(I) Dithiolato Carbonyl Complexes. Chem Rev 116:7043-77
Zhou, Xiaoyuan; Barton, Bryan E; Chambers, Geoffrey M et al. (2016) Preparation and Protonation of Fe2(pdt)(CNR)6, Electron-Rich Analogues of Fe2(pdt)(CO)6. Inorg Chem 55:3401-12
Chambers, Geoffrey M; Huynh, Mioy T; Li, Yulong et al. (2016) Models of the Ni-L and Ni-SIa States of the [NiFe]-Hydrogenase Active Site. Inorg Chem 55:419-31
Ulloa, Olbelina A; Huynh, Mioy T; Richers, Casseday P et al. (2016) Mechanism of H2 Production by Models for the [NiFe]-Hydrogenases: Role of Reduced Hydrides. J Am Chem Soc 138:9234-45
Gilbert-Wilson, Ryan; Siebel, Judith F; Adamska-Venkatesh, Agnieszka et al. (2015) Spectroscopic Investigations of [FeFe] Hydrogenase Maturated with [(57)Fe2(adt)(CN)2(CO)4](2-). J Am Chem Soc 137:8998-9005
Angamuthu, Raja; Chen, Chi-Shian; Cochrane, Tyler R et al. (2015) N-Substituted Derivatives of the Azadithiolate Cofactor from the [FeFe] Hydrogenases: Stability and Complexation. Inorg Chem 54:5717-24
Zhao, Peihua; Bertke, Jeffery A; Rauchfuss, Thomas B (2015) Crystal structure of [μ2-3,3-dimethyl-4-(propan-2-yl-idene)thietane-2,2-dithiol-ato-κ(4) S:S':S:S']bis[tricarbonyl-iron(I)](Fe-Fe). Acta Crystallogr E Crystallogr Commun 71:1296-9
Rauchfuss, Thomas B (2015) Diiron azadithiolates as models for the [FeFe]-hydrogenase active site and paradigm for the role of the second coordination sphere. Acc Chem Res 48:2107-16

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