This application seeks continued support for an established research program in bioinorganic chemistry directed at a detailed understanding of biologically relevant cluster clusters containing iron, sulfur, and molybdenum, vanadium, or nickel, various types of which are found at all levels of life. The field of this proposal is biomimetic inorganic chemistry, in which it is proposed to synthesize certain of the most complex metallocenters currently recognized in biology. These include the clusters found in nitrogenase and nickel-containing carbon monoxide dehydrogenase, which catalyse the reduction of dinitrogen to ammonia and the interconversion of carbon monoxide and carbon dioxide, respectively, and thus are major factors in the biological utilization of nitrogen, carbon, and oxygen. The main objectives are the P-cluster, molybenum- and vanadium-containing cofactors and the all-iron cofactor of nitrogenase, and the nickel- iron-sulfur catalytic center of carbon monoxide dehydrogenase. Original methods for the synthesis of these entities are proposed using cluster self-assembly, fragment condensation, and core rearrangement. New cluster species prepared in this work will be subjected to detailed physicochemical characterization and reactivity investigations with appropriate substrates. One premise of this work is that the step-by-step formation of these biological clusters implicates reactivity properties intrinsic to the reactants themselves. The research is intended to contribute to the broad and developing area of biosynthesis of metallocenters by showing what synthetic routes are actually feasible for cluster construction in the absence, and possibly in the presence, of proteins. The synthesis of accurate analogues thus may contribute to an understanding of the biosynthesis of native clusters, for which reaction pathways are slowly emerging but molecular steps are unknown.

Public Health Relevance

The proposed research seeks chemical reactions potentially similar to those in living cells that form metal-sulfur-containing molecules of importance to life processes and public health. These processes include the formation of ammonia from atmospheric nitrogen, affording the nitrogen utilized in the formation of DNA and numerous other molecules of life, and of carbon monoxide from carbon dioxide in a process that helps maintain ambient carbon monoxide below toxic levels. The molecules to be prepared should contribute to an understanding of how nature9s catalysts for these processes area formed naturally.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028856-31
Application #
7936925
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Fabian, Miles
Project Start
1980-07-01
Project End
2012-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
31
Fiscal Year
2010
Total Cost
$495,927
Indirect Cost
Name
Harvard University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Lee, Sonny C; Lo, Wayne; Holm, R H (2014) Developments in the biomimetic chemistry of cubane-type and higher nuclearity iron-sulfur clusters. Chem Rev 114:3579-600
Troeppner, O; Huang, D; Holm, R H et al. (2014) Thermodynamics and high-pressure kinetics of a fast carbon dioxide fixation reaction by a (2,6-pyridinedicarboxamidato-hydroxo)nickel(II) complex. Dalton Trans 43:5274-9
Tan, Lay Ling; Holm, R H; Lee, Sonny C (2013) Structural Analysis of Cubane-Type Iron Clusters. Polyhedron 58:206-217
Lo, Wayne; Zhang, Ping; Ling, Chang-Chun et al. (2012) Formation, spectroscopic characterization, and solution stability of an [Fe4S4]2+ cluster derived from ýý-cyclodextrin dithiolate. Inorg Chem 51:9883-92
Zheng, Bo; Chen, Xu-Dong; Zheng, Shao-Liang et al. (2012) Selenium as a structural surrogate of sulfur: template-assisted assembly of five types of tungsten-iron-sulfur/selenium clusters and the structural fate of chalcogenide reactants. J Am Chem Soc 134:6479-90
Zhang, Xiaofeng; Huang, Deguang; Chen, Yu-Sheng et al. (2012) Synthesis of binucleating macrocycles and their nickel(II) hydroxo- and cyano-bridged complexes with divalent ions: anatomical variation of ligand features. Inorg Chem 51:11017-29
Lo, Wayne; Scott, Thomas A; Zhang, Ping et al. (2011) Stabilities of cubane type [FeýýýSýýý(SR)ýýý](2-) clusters in partially aqueous media. J Inorg Biochem 105:497-508
Xi, Bin; Holm, R H (2011) The [MoFe3S4]2+ oxidation state: synthesis, substitution reactions, and structures of phosphine-ligated cubane-type clusters with the S=2 ground state. Inorg Chem 50:6280-8
Huang, Deguang; Makhlynets, Olga V; Tan, Lay Ling et al. (2011) Kinetics and mechanistic analysis of an extremely rapid carbon dioxide fixation reaction. Proc Natl Acad Sci U S A 108:1222-7
Lo, Wayne; Huang, Shaw; Zheng, Shao-Liang et al. (2011) Cubane-type Fe4S4 clusters with chiral thiolate ligation: formation by ligand substitution, detection of intermediates by 1H NMR, and solid state structures including spontaneous resolution upon crystallization. Inorg Chem 50:11082-90

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