Enzyme and protein active sites that require two or more metal centers for activity are now prominent features of biochemistry. Examples of biological metal clusters are known that involve Fe atoms (e.g. ferredoxins, sulfite reductase, hemerythrin, ribonucleotide reductase, methane monooxygenase), Cu atoms (e.g. hemocyanin, tyrosinase, ceruloplasmin, CuA in cytochrome oxidase), Mn atoms (e.g. photosystem II, catalase), Ni atoms (urease), and more than one kind of metal, or heteropolynuclear clusters (e.g. superoxide dismutase, Cu, Zn; nitrogenase, Mo, Fe; cytochrome oxidase, heme a3, CuB; hydrogenase, acetyl coenzyme A synthase, carbon monoxide dehydrogenase, Ni, Fe). The diverse functions of the clusters include electron transport, establishment of proton gradients, dioxygen binding, dioxygen activation, aspects of DNA synthesis, hydrolytic reactions, and redox reactions including dinitrogen and dioxygen reduction and dihydrogen, CO and water oxidation. Despite the large number of biological metal clusters that have been characterized, only in a few instances have the unique properties associated with polynuclear active sites been delineated. This is particularly true for heteropolynuclear clusters. The ultimate goals of the proposed research are to understand the advantages associated with catalysis by metal clusters and how each is designed for its specific purpose. This knowledge will provide a detailed understanding of enzyme mechanisms involving metal clusters and will aid in the design of inhibitors of enzymes (e.g. drugs) and industrial catalysts for the chemical reactions involved. This proposal focuses on understanding the structure and function of Ni-containing hydrogenases, which are key enzymes in anaerobic metabolism in microbes and have recently been shown to contain a novel heterodinuclear Ni, Fe active site. Thus, the proposed research also impacts on our understanding of the biological roles of Ni, which include the virility of Helicobacter pylori, a bacterium that has been associated with gastric ulcers and stomach cancer. Specific goals regarding the structure and function of hydrogenase include: (1) establishing the relationship between the active site Ni and Fe centers in the catalytic mechanism, (2) determining the functions of the Ni and Fe site, including the metal ligands, and (3) elucidating the advantages to enzyme catalysis associated with a heterodinuclear site and with incorporation of Se. These goals will be met by using a combination of physical techniques applied to hydrogenases and to model systems that are designed to model specific aspects of the structure or function of the enzyme active site.
| Hosler, Erik R; Herbst, Robert W; Maroney, Michael J et al. (2012) Exhaustive oxidation of a nickel dithiolate complex: some mechanistic insights en route to sulfate formation. Dalton Trans 41:804-16 |
