The goal of this project is to prepare and characterize functional and spectroscopic models for the active sites of the two main metalloenzymes that process hydrogen, the [FeFe]- and [NiFe]-hydrogenases. Such models will provide mechanistic insights into these enzymes and will underpin other advances: (i) define the roles for reduced iron in biological systems, (ii) opportunities for combating diseases caused by organisms that utilize hydrogen in their metabolism, and (ii) lead to new reagents and catalysts for using hydrogen, relevant to the synthesis of many pharmaceuticals. The work focuses mainly on the [FeFe]-hydrogenases, exploiting advances in our modeling both the reduced and oxidized states of this enzyme. An emerging effort builds on a recent breakthrough relevant to the [NiFe]-hydrogenases, which are particularly widespread. Much of the work focuses on the mixed valence Hox state of [FeFe]-hydrogenases, beginning with a recent discovery that H2 is activated by a biomimetic Hox model. The key to this advance is the incorporation of the azadithiolate cofactor into the synthetic analogues. These functionally competent models will be characterized spectroscopically and through isotopical labeling. For the other direction of this enzyme's action - H2 production - we will examine the protonation of reduced biomimetic systems, elucidating factors that control the regiochemistry and redox of the hydrides. Finally, a building block approach is described in the assembly of biomimetic models for the [NiFe]-hydrogenases. Preliminary studies demonstrate the assembly and characterization of a nearly complete active site model. Overall the work promises to clarify the pathways by which nature uses and produces hydrogen. The biochemistry and the underlying inorganic chemistry are highly unusual. Many of these questions cannot be fully addressed with the protein due to the invisibility of hydrogen to crystallography and the presence of interfering chromophores. The work underpins new bioinorganic chemistry involving H2 and hydride ligands.

Public Health Relevance

An H2-based metabolism supports the pathogen H. pylori, estimated to be responsible for 80-90% of all gastric and duodenal cancers. This bacterium infects half of the world's population and 50M Americans. Hydrogen is a constituent of the atmosphere in the human gut.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061153-12
Application #
8401556
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
2000-07-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
12
Fiscal Year
2013
Total Cost
$312,733
Indirect Cost
$91,877
Name
University of Illinois Urbana-Champaign
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
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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