The proposed research is designed to address specific questions of molecular and electronic structure, and chemical reactivity to gain a fundamental understanding of the catalytic activity of the Ni-containing protein acetyl coenzyme A synthase (ACS) through the synthesis, characterization and elucidation of reactivity of model complexes. This methodology will permit characterization of the intrinsic properties of structure and function of the metal sites at the molecular level of detail decoupled from the protein architecture. Recent results from structural biology have established details of the active site structure making now the optimum time to address this problem as the targets are well defined. Individual reactions will be systematically interrogated using the protocols of mechanistic inorganic chemistry including product analyses, kinetic measurements, stereochemical and radical clock probe investigations. The long-term goal of this project is to develop a detailed mechanistic understanding of how the structural, electronic and chemical properties of nickel sites in proteins are optimized for their intended catalytic transformations. The proposed research impacts our understanding of the biological implications of the essential trace element nickel that include the virility of Helicobacter pylori which has been associated with peptic ulcer disease, gastric carcinoma, and gastric lymphoma, and carcinogenesis through production of oxidizing species that degrade DMA. Additionally, acetogenic and methanogenic bacteria, organisms that contain ACS, may be important to human digestive function and dysfunction as they occupy a large volume of the colon. More broadly, a deeper understanding of ACS catalysis will advance fundamental understanding of redox-based Ni toxicity.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Delaware
Schools of Arts and Sciences
United States
Zip Code
Riordan, Charles G (2010) Coordination chemistry of poly(thioether)borate ligands. Coord Chem Rev 254:1815-1825
Ariyananda, Piyal W G; Kieber-Emmons, Matthew T; Yap, Glenn P A et al. (2009) Synthetic analogs for evaluating the influence of N-H...S hydrogen bonds on the formation of thioester in acetyl coenzyme A synthase. Dalton Trans :4359-69
Riordan, Charles G (2009) The multidisciplinary field of bioorganometallic chemistry. Dalton Trans :4273
Mock, Michael T; Kieber-Emmons, Matthew T; Popescu, Codrina V et al. (2009) A Series of Cyanide-Bridged Binuclear Complexes. Inorganica Chim Acta 362:4553-4562
Dougherty, William G; Rangan, Krishnan; O'Hagan, Molly J et al. (2008) Binuclear complexes containing a methylnickel moiety: relevance to organonickel intermediates in acetyl coenzyme A synthase catalysis. J Am Chem Soc 130:13510-1
Eckert, Nathan A; Dougherty, William G; Yap, Glenn P A et al. (2007) Methyl transfer from methylcobaloxime to (triphos)Ni(PPh(3)): relevance to the mechanism of acetyl coenzyme A synthase. J Am Chem Soc 129:9286-7
Craft, Jennifer L; Mandimutsira, Beaven S; Fujita, Koyu et al. (2003) Spectroscopic and computational studies of a Ni(+)-CO model complex: implications for the acetyl-CoA synthase catalytic mechanism. Inorg Chem 42:859-67