(30 lines maximum) 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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Macromolecular Structure and Function A Study Section (MSFA)
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Anderson, Vernon
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Johns Hopkins University
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Kieber-Emmons, Matthew T; Ginsbach, Jake W; Wick, Patrick K et al. (2014) Observation of a Cu(II)(2) (?-1,2-peroxo)/Cu(III)(2) (?-oxo)(2) equilibrium and its implications for copper-dioxygen reactivity. Angew Chem Int Ed Engl 53:4935-9
Hematian, Shabnam; Siegler, Maxime A; Karlin, Kenneth D (2014) Nitric oxide generation from heme/copper assembly mediated nitrite reductase activity. J Biol Inorg Chem 19:515-28
Sharma, Vivek; Karlin, Kenneth D; Wikstrom, Marten (2013) Computational study of the activated O(H) state in the catalytic mechanism of cytochrome c oxidase. Proc Natl Acad Sci U S A 110:16844-9
Das, Dipanwita; Lee, Yong-Min; Ohkubo, Kei et al. (2013) Acid-induced mechanism change and overpotential decrease in dioxygen reduction catalysis with a dinuclear copper complex. J Am Chem Soc 135:4018-26
Li, Yuqi; Sharma, Savita K; Karlin, Kenneth D (2013) New heme-dioxygen and carbon monoxide adducts using pyridyl or imidazolyl tailed porphyrins. Polyhedron 58:
Garcia-Bosch, Isaac; Sharma, Savita K; Karlin, Kenneth D (2013) A selective stepwise heme oxygenase model system: an iron(IV)-oxo porphyrin ýý-cation radical leads to a verdoheme-type compound via an isoporphyrin intermediate. J Am Chem Soc 135:16248-51
Kieber-Emmons, Matthew T; Qayyum, Munzarin F; Li, Yuqi et al. (2012) Spectroscopic elucidation of a new heme/copper dioxygen structure type: implications for O···O bond rupture in cytochrome c oxidase. Angew Chem Int Ed Engl 51:168-72
Kieber-Emmons, Matthew T; Li, Yuqi; Halime, Zakaria et al. (2011) Electronic structure of a low-spin heme/Cu peroxide complex: spin-state and spin-topology contributions to reactivity. Inorg Chem 50:11777-86
Wang, Jun; Schopfer, Mark P; Puiu, Simona C et al. (2010) Reductive coupling of nitrogen monoxide (*NO) facilitated by heme/copper complexes. Inorg Chem 49:1404-19
Schopfer, Mark P; Wang, Jun; Karlin, Kenneth D (2010) Bioinspired heme, heme/nonheme diiron, heme/copper, and inorganic NOx chemistry: *NO((g)) oxidation, peroxynitrite-metal chemistry, and *NO((g)) reductive coupling. Inorg Chem 49:6267-82

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