Research described in this proposal will be aimed at: Understanding how structure influences function and/or the characteristic properties of metalloenzyme active sites. Understanding how protein constraint can influence both the reactivity, and geometric/electronic structure of metalloenzymes. More specifically: Studies will continue to focus on the design and synthesis of analogues for the iron and cobalt sites of nitrile hydratases. Synthetic models, possessing a variety of structures, will be synthesized (using a versatile, one-pot synthesis), structurally characterized (using X-ra crystallography), and then screened for key biophysical properties such as (1) a S=1/2 spin-state (epr, magnetism (both solution and solid state)), and (2) a intense visible band near 700 nm. Reactions between our synthetic models and enzyme substrates (RCN),inhibitor (N3-), and inactivator (NO), will then be monitored both spectrophotometricall and by EPR. By systematically altering the structure of our models, and probing the influence that these changes have on the electronic, and reactivity, properties, we will determine if there is any correlation between structure an reactivity, and determine if spin-state and other electronic properties have a important influence on reactivity. Ligand constraints will be incorporated into our models, as a model for protei constraints, so that we can probe the influence that protein constraints can have on structure and reactivity. For example, by using a ligand with a fixed """"""""backbone"""""""" length, angles can be constrained, and, in some cases, opened, so a to create a substrate binding site (entatic state). Similar constraints may be responsible for the reactivity of metalloenzymes. Studies aimed at understanding structure/reactivity relationships in other cysteine-ligated metalloenzymes, such as hydrogenase, and liver alcohol dehydrogenase, will also be pursued.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM045881-10
Application #
6386177
Study Section
Physical Biochemistry Study Section (PB)
Program Officer
Preusch, Peter C
Project Start
1992-02-01
Project End
2002-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
10
Fiscal Year
2001
Total Cost
$237,748
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
135646524
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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