Movement of unique biological catalytic reactivity to small synthetic molecules, while a formidable challenge, is an extremely intriguing and informative endeavor providing critical insights into the native reactivity. The broad and long-term objective of this research is elucidation of the structural and electronic properties of Cu-O2 species formed in biological mononuclear, binuclear and trinuclear Cu-sites and subsequent characterization of their oxidative reactivity. The methodology is that of the synthetic analog approach to the active sites of metallobiomolecules, whereby low molecular weight complexes are synthesized and examined at a small molecule level of detail to reveal intrinsic properties of the metal complexes uncoupled from the influences of the protein matrix. The premise is that the formation and subsequent reactivity of biological intermediates should be reproducible in small synthetic complexes if appropriate ligation environments are engineered, and if deleterious bimolecular reactions of the reactive intermediates are avoided. Creation of spectroscopically congruent, functional models is the ultimate goal so that specific aspects of proposed biological mechanisms may be investigated at a small molecule level of detail.
The specific aims are as follows: Structural, spectroscopic and reactivity characterization of [Cu(I)LDAL(MeCN)]1+-O2 products using simple peralkylated diamines ligands (LDA) to provide chemical precedence for possible biological intermediates and spectroscopic benchmarks by which such intermediates may be identified. Reactivity characterization of new intermediates may lead to new bio-inspired oxidation catalysts. Defining the mechanistic relationship of catalytically functional galactose oxidase model complexes to the native system. Development of more oxidatively resistant model complexes will aid in the mechanistic and kinetic studies. Integration of histidine terminated peptides into the ligand framework will provide more biologically relevant functional models of galactose oxidase. Functional modeling of the reactivity of mononuclear trigonally-ligated copper sites to investigate the type of environments that promote O2 activation, the type of Cu-O2 intermediates formed, and the mechanism of phenolate group oxidative modification, an emerging theme in mononuclear copper enzymes. Development of a mechanistic relationship between lipoxygenase, a mononuclear iron enzyme, and mononuclear iron models that exhibit oxidation behavior most consistent with CH hydrogen atom abstraction.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM050730-06
Application #
2903552
Study Section
Metallobiochemistry Study Section (BMT)
Project Start
1994-07-01
Project End
2003-06-30
Budget Start
1999-07-01
Budget End
2000-06-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Stanford University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Herres-Pawlis, Sonja; Haase, Roxana; Verma, Pratik et al. (2015) Formation of hybrid guanidine-stabilized bis(?-oxo)dicopper cores in solution: Electronic and steric perturbations. Eur J Inorg Chem 2015:5426-5436
Citek, Cooper; Lin, Bo-Lin; Phelps, Tim E et al. (2014) Primary amine stabilization of a dicopper(III) bis(?-oxo) species: modeling the ligation in pMMO. J Am Chem Soc 136:14405-8
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Hoffmann, Alexander; Citek, Cooper; Binder, Stephan et al. (2013) Catalytic phenol hydroxylation with dioxygen: extension of the tyrosinase mechanism beyond the protein matrix. Angew Chem Int Ed Engl 52:5398-401
Lyons, Christopher T; Stack, T Daniel P (2013) Recent advances in phenoxyl radical complexes of salen-type ligands as mixed-valent galactose oxidase models. Coord Chem Rev 257:528-540
Nakazawa, Jun; Smith, Brian J; Stack, T Daniel P (2012) Discrete complexes immobilized onto click-SBA-15 silica: controllable loadings and the impact of surface coverage on catalysis. J Am Chem Soc 134:2750-9
Citek, Cooper; Lyons, Christopher T; Wasinger, Erik C et al. (2012) Self-assembly of the oxy-tyrosinase core and the fundamental components of phenolic hydroxylation. Nat Chem 4:317-22
Pratt, Russell C; Lyons, Christopher T; Wasinger, Erik C et al. (2012) Electrochemical and spectroscopic effects of mixed substituents in bis(phenolate)-copper(II) galactose oxidase model complexes. J Am Chem Soc 134:7367-77
Verma, Pratik; Pratt, Russell C; Storr, Tim et al. (2011) Sulfanyl stabilization of copper-bonded phenoxyls in model complexes and galactose oxidase. Proc Natl Acad Sci U S A 108:18600-5
McCrory, Charles C L; Devadoss, Anando; Ottenwaelder, Xavier et al. (2011) Electrocatalytic O2 reduction by covalently immobilized mononuclear copper(I) complexes: evidence for a binuclear Cu2O2 intermediate. J Am Chem Soc 133:3696-9

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