(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)
Project #
Application #
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Anderson, Vernon
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Johns Hopkins University
Schools of Arts and Sciences
United States
Zip Code
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)-(O₂²⁻)-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 •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 μ-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

Showing the most recent 10 out of 46 publications