Chemistry of Nickel(III/II)-Thiolate Complexes: Insight into the Structure and Mechanism of Ni-Containing SOD

University Of Georgia Research Foundation Inc, Athens GA

Investigators

Abstract

With this award, the Chemistry of Life Processes Program in the Division of Chemistry is funding Professor Todd C. Harrop at the University of Georgia to study model nickel-thiolate complexes that mimic the imporant enzyme superoxide dismutase. Nickel-containing superoxide dismutase (NiSOD) is the only redox-active nickel-enzyme that is present in aerobes despite the presence of ROS (reactive oxygen species)-sensitive cysteine-S-ligands at its active site. This project involves the preparation and investigation of synthetic models of the nickel-containing active site of NiSOD that are capable of aerobic function. In particular, the project will examine the role of the entities that are bound to nickel, in dictating the catalytic properties of the active site. Plans are in place to provide hands-on research opportunities in the fundamental chemical sciences to groups traditionally underrepresented in the STEM disciplines. One such plan, with which there was prior success, is to provide a summer research internship and lifelong career mentorship to undergraduate chemistry majors from Historically Black Colleges and Universities (HBCUs) in the southeast region. The PI and his group will also participate in the University of Georgia Young Dawgs program where high school students from the Clarke County public school system are provided STEM research internships. The objective of this research is to prepare synthetic model complexes of the nickel center found at the active site of NiSOD, and to investigate the mechanistic role that the coordinated peptide-N and cysteinate-S ligands play in the redox mechanism of this enzyme. Nickel-cysteine sites in biology are central catalysts that participate in reactions of global impact including the detoxification of reactive oxygen species (ROS), fixation of cellular carbon, and the generation of alternative energy supplies, i.e., hydrogen evolution/consumption. Nickel enzymes and their corresponding synthetic models are thus ideal systems to promote chemical transformations of high economic and environmental importance. However, the majority of these nickel-enzymes are found in strict anaerobic organisms. Despite the sensitive nature of cysteine-S with ROS, these donor atoms appear inert to ROS during turnover in the enzyme. Advanced synthetic techniques will be employed to construct N/S-containing ligand frames and their corresponding Ni(III/II) complexes that accurately reproduce the NiSOD active site. Key factors in the design of these constructs are the incorporation of an axial N-donor and the ability to fine-tune the nucleophilicity of the S-ligands in order to promote Ni-based versus S-based redox chemistry. Spectroscopic, structural and computational techniques will be utilized. The project aims to determine the geometric and electronic structural properties of these Ni(III/II)-N/S complexes and investigate their reactivity with ROS and other reactive small molecules, such as NO, to shed light on the redox mechanism taking place at this unique nickel site.