Copper enzymes perform diverse reactions that include O2 activation for the monooxygenation, dioxygenation and oxidation of substrates in natural product biosynthesis (related to a number of disease states), the 4 electron reduction of O2 to H2O in iron and copper metabolism and proton pumping for ATP synthesis, and the 2 electron reduction of N2O in denitrification. The active sites in these enzymes have different geometric and electronic structures: antiferromagnetically """"""""coupled"""""""" binuclear copper sites, non-coupled binuclear copper sites, trinuclear copper clusters, heme-copper sites, a tetranuclear copper cluster, and mononuclear copper centers that perform multi-electron reactions in cofactor biogenesis. These active sites and their intermediates exhibit unique spectral features, which reflect their different electronic structures that direct specific reaction coordinates for catalysis. The broad goals of this research program are to use a wide range of spectroscopies (including the development of new methods), coupled to electronic structure calculations, enzymology, and model studies to define the molecular mechanism for each class of copper enzymes and to understand how the differences in active site geometric and electronic structures over these classes determine their diverse specific functions: a) 2 electron activation of O2 for electrophilic aromatic attack in the coupled binuclear copper enzymes;b) 1 electron O2 activation for H atom abstraction by the non-coupled binuclear copper enzymes;c) O2 activation for H-atom abstraction from the strong C-H bond in methane by the recently defined binuclear copper center in particulate methane monooxygenase;d) the coupling of the four one-electron oxidations of substrate to the 4 electron reduction of O2 to H2O by the trinuclear copper cluster containing multicopper oxidases;e) the coupling of the 4 electron reduction of O2 to H2O in the heme-copper oxidases to proton pumping;f) N2O activation by the tetranuclear copper cluster site;g) the activation of O2 or substrate by a reduced or oxidized, respectively, mononuclear copper center. These studies provide molecular level insight into reactivity and define structure/function correlations over the O2 and N2O activating copper enzymes. They are of fundamental importance towards understanding pathogenesis and provide structural and mechanistic insight for drug design, medical device development, and the generation of new catalysts.

Public Health Relevance

Copper proteins play critical roles in Fe, Cu and O2 metabolism, are directly related to a range of genetic diseases (oculocutaneous albinism1, aceruloplasminemia,2 etc.) and health issues (Alzheimer's,3 atherosclerosis,4 control of neurotransmiters,5,6 etc.) and are important in natural product biosynthesis,7,8 biotechnology9 (oxidoreductases,10 biofuel cells11,12), detoxification,13 and the bioremediation of greenhouse gases (N2O,14 CH415,16). Understanding Cu biochemistry on a molecular level provides mechanisms to improve or inhibit these processes, and enable drug design and the development of implantable devices.17

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031450-34
Application #
8719970
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Sechi, Salvatore
Project Start
1982-01-01
Project End
2016-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
34
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Stanford
State
CA
Country
United States
Zip Code
94304
Meier, Katlyn K; Jones, Stephen M; Kaper, Thijs et al. (2018) Oxygen Activation by Cu LPMOs in Recalcitrant Carbohydrate Polysaccharide Conversion to Monomer Sugars. Chem Rev 118:2593-2635
Bhadra, Mayukh; Lee, Jung Yoon C; Cowley, Ryan E et al. (2018) Intramolecular Hydrogen Bonding Enhances Stability and Reactivity of Mononuclear Cupric Superoxide Complexes. J Am Chem Soc 140:9042-9045
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
Johnston, Esther M; Carreira, Cíntia; Dell'Acqua, Simone et al. (2017) Spectroscopic Definition of the CuZ° Intermediate in Turnover of Nitrous Oxide Reductase and Molecular Insight into the Catalytic Mechanism. J Am Chem Soc 139:4462-4476
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
de Poulpiquet, Anne; Kjaergaard, Christian H; Rouhana, Jad et al. (2017) Mechanism of chloride inhibition of bilirubin oxidases and its dependence on potential and pH. ACS Catal 7:3916-3923
Hansson, Henrik; Karkehabadi, Saeid; Mikkelsen, Nils et al. (2017) High-resolution structure of a lytic polysaccharide monooxygenase from Hypocrea jecorina reveals a predicted linker as an integral part of the catalytic domain. J Biol Chem 292:19099-19109
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
Solomon, Edward I (2016) Dioxygen Binding, Activation, and Reduction to H2O by Cu Enzymes. Inorg Chem 55:6364-75

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