The long-term research objective is to design, synthesize and investigate model compound systems which can help elucidate fundamental aspects of structure, metal ligation, spectroscopy and reactivity relevant to the chemistry utilized by heme-copper oxidases (HCOs) and nitric oxide reductases (NORs). These evolutionarily related enzymes play critical roles in the bioenergetics of aerobic and anaerobic organisms, and have in common a heme/M (M = copper or non-heme iron) active site which reductively cleaves dioxygen (O2) or nitric oxide (NO, nitrogen monoxide), respectively. The research proposed can contribute to a better understanding of enzyme structure and mechanism and provide fundamental insights into the biological processing of dioxygen and NO, the chemistry and biochemistry of nitrogen oxides, as well as address issues related to nitrogen oxides in the environment.
Specific aims i nclude (1) the characterization of heme-peroxo-Cu complexes, new protonated and new low-spin derivatives and elucidation of their peroxo- connectivity and electronic structures, (2) the study of reductive O-O cleavage promoted by already well characterized heme-peroxo-Cu complex systems, and elucidation of the factors crucial for this process, comprising a critical aspect of 'oxygen activation'in chemical or biochemical systems, (3) the design of new ligands for copper which possess a linked phenol-imidazole moiety, to elucidate how such a group may take part in O-O cleavage chemistry, i.e., HCO function. Other new binucleating ligands for heme/Cu will be designed to test how in nature the enzyme His-Tyr crosslink might form, (4) investigation of heme/NO/O2 coordination chemistry - including the apparent reversible formation of a dinitrosyl heme complex and modeling heme protein actions such as occur in enzyme NO-dioxygenases, (5) new approaches to the study of NO reductase activity of heme/non-heme diiron and heme/Cu complexes, including design of a number of dimetal chemical systems for the systematic interrogation of their ability to reductively couple two NO molecules to produce nitrous oxide (N2O), and (6) detailed investigations of the metal-binding dynamics of nitrogen monoxide in heme, heme/copper and heme/non-heme diiron complexes - such photoinitiated reactions can provide a detailed understanding of the kinetics, thermodynamics, and metal preference/migration of these small molecules in interactions with heme/non-heme metal sites, as is relevant to HCO and NOR biological chemistry.
The proposed research will contribute to a deeper understanding of the connection between heme, non- heme iron and copper biochemistries, and their utilization of molecular oxygen and nitrogen monoxide. The interactions of these biologically important small gaseous molecules with such metal dependent enzymes are critical in normal functioning and health. Potential long-term applications of this basic research include development of enzyme inhibitors as drugs and relevant disease therapeutic strategies.
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|Garcia-Bosch, Isaac; Cowley, Ryan E; Díaz, Daniel E et al. (2017) Substrate and Lewis Acid Coordination Promote O-O Bond Cleavage of an Unreactive L2CuII2(O22-) Species to Form L2CuIII2(O)2 Cores with Enhanced Oxidative Reactivity. J Am Chem Soc 139:3186-3195|
|Adam, Suzanne M; Garcia-Bosch, Isaac; Schaefer, Andrew W et al. (2017) Critical Aspects of Heme-Peroxo-Cu Complex Structure and Nature of Proton Source Dictate Metal-O(peroxo) Breakage versus Reductive O-O Cleavage Chemistry. J Am Chem Soc 139:472-481|
|Sharma, Savita K; Schaefer, Andrew W; Lim, Hyeongtaek et al. (2017) A Six-Coordinate Peroxynitrite Low-Spin Iron(III) Porphyrinate Complex-The Product of the Reaction of Nitrogen Monoxide (·NO(g)) with a Ferric-Superoxide Species. J Am Chem Soc 139:17421-17430|
|Wijeratne, Gayan B; Hematian, Shabnam; Siegler, Maxime A et al. (2017) Copper(I)/NO(g) Reductive Coupling Producing a trans-Hyponitrite Bridged Dicopper(II) Complex: Redox Reversal Giving Copper(I)/NO(g) Disproportionation. J Am Chem Soc 139:13276-13279|
|Schaefer, Andrew W; Kieber-Emmons, Matthew T; Adam, Suzanne M et al. (2017) Phenol-Induced O-O Bond Cleavage in a Low-Spin Heme-Peroxo-Copper Complex: Implications for O2 Reduction in Heme-Copper Oxidases. J Am Chem Soc 139:7958-7973|
|Quist, David A; Diaz, Daniel E; Liu, Jeffrey J et al. (2017) Activation of dioxygen by copper metalloproteins and insights from model complexes. J Biol Inorg Chem 22:253-288|
|Kumar, Pankaj; Lee, Yong-Min; Hu, Lianrui et al. (2016) Factors That Control the Reactivity of Cobalt(III)-Nitrosyl Complexes in Nitric Oxide Transfer and Dioxygenation Reactions: A Combined Experimental and Theoretical Investigation. J Am Chem Soc 138:7753-7762|
|Sharma, Savita K; Kim, Hyun; Rogler, Patrick J et al. (2016) Isocyanide or nitrosyl complexation to hemes with varying tethered axial base ligand donors: synthesis and characterization. J Biol Inorg Chem 21:729-43|
|Hong, Seungwoo; Kumar, Pankaj; Cho, Kyung-Bin et al. (2016) Mechanistic Insight into the Nitric Oxide Dioxygenation Reaction of Nonheme Iron(III)-Superoxo and Manganese(IV)-Peroxo Complexes. Angew Chem Int Ed Engl 55:12403-7|
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