Our research program is aimed at determining how cysteinates influence function in non-heme iron enzymes. Cysteinate-ligated non-heme iron containing SOR and NHase are involved in the detoxification of superoxide radicals, and the detoxification of nitrile wastes, respectively. Superoxide has been implicated in a number of disease states, including cancer, Alzheimers, Parkinsons, and cardiac damage following a heart attack. The SOR active site closely resembles that of the heme enzyme P450 which oxidizes unactivated hydrocarbons. During this past funding period, we reported the first functional model for SOR, the first example of a thiolate-ligated Felll-OOH, and a model for the unmodified form of NHase. Neither the mechanism of superoxide reduction by SOR, nor the function and mechanism of post-translational NHase cysteinate modification, are well understood. During this funding period we plan to: - investigate the mechanism of formation of our cis and trans Felll-peroxos in order to understand the proton-dependence of these reactions, and determine how the positioning of the thiolate (cis vs trans) influences the available mechanistic pathways. - compare the reactivity of our cis vs. trans thiolate-ligated Felll-OOH with electrophilic and nucleophilic substrates, and H-atom donors, in order to see if an SOR model can promote P450 chemistry. - determine whether thiolate ligands create favorable reaction pathways affording FelV=O, or perhaps even FeV=O species. And, determine whether a trans-thiolate is more efficient than a cis-thiolate at promoting oxidation chemistry by creating a more basic high valent FelV=0 (as was recently proposed for P450). - synthesize a new thiolate-ligated (NSSPy) Fe-peroxide structurally-related to the extensively characterized nitrogen-ligated N4Py Fe-peroxides so that we can determine how thiolates influence function. - synthesize a new trans thiolate-ligand that incorporates steric bulk and H-bonding residues designed to stabilize an Felll-OOH or FelV=O, and/or direct proton delivery to the distal peroxo oxygen. - explore alternative functions of SOR involving SO42-, NO3-, or NO2- reduction. - examine the possibility that post-translational modification of the NHase cysteinates occurs via a mechanism involving an Felll-OOH. -determine how the post-translational oxygenation of two cis NHase cysteinates influences function by examining the reactivity of our unmodified NHase model with oxo-atom and proton donors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM045881-15
Application #
7091100
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Preusch, Peter C
Project Start
1992-02-01
Project End
2010-03-31
Budget Start
2006-04-05
Budget End
2007-03-31
Support Year
15
Fiscal Year
2006
Total Cost
$323,541
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Rees, Julian A; Bjornsson, Ragnar; Kowalska, Joanna K et al. (2017) Comparative electronic structures of nitrogenase FeMoco and FeVco. Dalton Trans 46:2445-2455
Kowalska, Joanna K; Nayyar, Brahamjot; Rees, Julian A et al. (2017) Iron L2,3-Edge X-ray Absorption and X-ray Magnetic Circular Dichroism Studies of Molecular Iron Complexes with Relevance to the FeMoco and FeVco Active Sites of Nitrogenase. Inorg Chem 56:8147-8158
Villar-Acevedo, Gloria; Lugo-Mas, Priscilla; Blakely, Maike N et al. (2017) Metal-Assisted Oxo Atom Addition to an Fe(III) Thiolate. J Am Chem Soc 139:119-129
Rees, Julian A; Martin-Diaconescu, Vlad; Kovacs, Julie A et al. (2015) X-ray Absorption and Emission Study of Dioxygen Activation by a Small-Molecule Manganese Complex. Inorg Chem 54:6410-22
Brines, Lisa M; Coggins, Michael K; Poon, Penny Chaau Yan et al. (2015) Water-soluble Fe(II)-H2O complex with a weak O-H bond transfers a hydrogen atom via an observable monomeric Fe(III)-OH. J Am Chem Soc 137:2253-64
Kovacs, Julie A (2015) Tuning the Relative Stability and Reactivity of Manganese Dioxygen and Peroxo Intermediates via Systematic Ligand Modification. Acc Chem Res 48:2744-53
Coggins, Michael K; Martin-Diaconescu, Vlad; DeBeer, Serena et al. (2013) Correlation between structural, spectroscopic, and reactivity properties within a series of structurally analogous metastable manganese(III)-alkylperoxo complexes. J Am Chem Soc 135:4260-72
Coggins, Michael K; Sun, Xianru; Kwak, Yeonju et al. (2013) Characterization of metastable intermediates formed in the reaction between a Mn(II) complex and dioxygen, including a crystallographic structure of a binuclear Mn(III)-peroxo species. J Am Chem Soc 135:5631-40
Coggins, Michael K; Toledo, Santiago; Kovacs, Julie A (2013) Isolation and characterization of a dihydroxo-bridged iron(III,III)(?-OH)2 diamond core derived from dioxygen. Inorg Chem 52:13325-31
Coggins, Michael K; Brines, Lisa M; Kovacs, Julie A (2013) Synthesis and structural characterization of a series of Mn(III)OR complexes, including a water-soluble Mn(III)OH that promotes aerobic hydrogen-atom transfer. Inorg Chem 52:12383-93

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