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 dioxygen (O2) and nitrogen oxide (NOx) chemistry utilized by heme-copper oxidases (HCOs), nitric oxide reductases (NORs) and related proteins. HCOs and NOR's are evolutionarily related enzymes which play critical roles in cellular processes within aerobic and anaerobic organisms. They have in common a heme/M (M = Cu or non-heme Fe) active site that reductively cleaves O2 or NO, respectively. The research proposed will contribute to a better understanding of enzyme structure and mechanism by providing a comprehensive and fundamental basis relevant to biological processing of O2, NO and nitrite (NO2-), that extends even beyond the heme and Cu metalloprotein sphere.
Specific aims i nclude (1) the characterization of heme/Cu- O2 adducts, new protonated and low-spin derivatives and elucidation of their (structures) and electronic/bonding properties, (2) the study of reductive O-O cleavage promoted by heme-peroxo-Cu complex systems, especially new low-spin compounds where altering the copper-ligand environment and heme axial 'base'ligands is a part of the approach. Systematically varied reducing agents and acids will be employed in the investigations in order to elucidate those factors crucial for this process, comprising a critical aspect of 'oxygen activation'in chemical or biochemical systems, (3) the employment and study of ligand systems which possess a copper-ligand imidazole-phenol moiety which induces O-O reductive cleavage chemistry for a corresponding heme/copper-O2 assembly. Also, two chemical systems designed to test how CcO (bio)chemistry leads to the actual formation of the copper-ligand His-Tyr crosslink, will be studied in detail. (4) investigation of a chemical system with input variations f the heme axial 'base'ligand, where heme/NO/O2 coordination chemistry will be studied mechanistically with regard to peroxynitrite formation and its subsequent reactivity. This chemistry occurs in NO dioxygenases (NODs), enzymes critically involved in cellular NO homeostasis and possibly in cellular signaling via amino-acid nitration chemistry. (5) the study of chemistry relevant to NORs, heme/Cu assemblies that enable NO reductive coupling. A clear focus will be on the mechanism of formation of putative hypontrite intermediates, their structures and their reactivity leading to N2O and H2O products. Such information is key to the understanding of N-N coupling and N-O cleavage chemistries which are also coupled to protonation. These processes are also of broad interest with respect to other biological metalloenzyme nitrogen oxide processing.
This aim also includes efforts to elucidate the chemistry of heme/Cu mediated nitrite reduction to NO and complementary NO oxidation to nitrite. In-hand heme/Cu assemblies enable this chemistry and further mechanistic probing is necessary;these processes are critical to NO signaling and linked to cellular responses to changes in [O2] concentrations.
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 oxides including nitric oxide and nitrite ion. Te interactions of these biologically important small 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.
|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|
|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 138:7753-62|
|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|
|Hematian, Shabnam; Garcia-Bosch, Isaac; Karlin, Kenneth D (2015) Synthetic heme/copper assemblies: toward an understanding of cytochrome c oxidase interactions with dioxygen and nitrogen oxides. Acc Chem Res 48:2462-74|
|Garcia-Bosch, Isaac; Adam, Suzanne M; Schaefer, Andrew W et al. (2015) A "naked" Fe(III)-(Oâ‚‚Â²â»)-Cu(II) species allows for structural and spectroscopic tuning of low-spin heme-peroxo-Cu complexes. J Am Chem Soc 137:1032-5|
|Kumar, Pankaj; Lee, Yong-Min; Park, Young Jun et al. (2015) Reactions of Co(III)-nitrosyl complexes with superoxide and their mechanistic insights. J Am Chem Soc 137:4284-7|
|Chatterjee, Sudipta; Sengupta, Kushal; Hematian, Shabnam et al. (2015) Electrocatalytic O2-Reduction by Synthetic Cytochrome c Oxidase Mimics: Identification of a "Bridging Peroxo" Intermediate Involved in Facile 4e(-)/4H(+) O2-Reduction. J Am Chem Soc 137:12897-905|
|Sharma, Savita K; Rogler, Patrick J; Karlin, Kenneth D (2015) Reactions of a heme-superoxo complex toward a cuprous chelate and â€¢NO(g): CcO and NOD chemistry. J Porphyr Phthalocyanines 19:352-360|
|Hematian, Shabnam; Kenkel, Isabell; Shubina, Tatyana E et al. (2015) Nitrogen Oxide Atom-Transfer Redox Chemistry; Mechanism of NO(g) to Nitrite Conversion Utilizing Î¼-oxo Heme-Fe(III)-O-Cu(II)(L) Constructs. J Am Chem Soc 137:6602-15|
|Yokoyama, Atsutoshi; Han, Jung Eun; Karlin, Kenneth D et al. (2014) An isoelectronic NO dioxygenase reaction using a nonheme iron(III)-peroxo complex and nitrosonium ion. Chem Commun (Camb) 50:1742-4|
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