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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Fabian, Miles
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Harvard University
Schools of Arts and Sciences
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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
Majumdar, Amit; Holm, R H (2011) Specific incorporation of chalcogenide bridge atoms in molybdenum/tungsten-iron-sulfur single cubane clusters. Inorg Chem 50:11242-51
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

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