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Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions

Award Number: R01GM138592
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions - PROJECT SUMMARY Enzymatic reactions comprise the basic building blocks essential to the biochemical processes of cellular metabolism. While most enzymatic reactions are reversible, certain enzymes accelerate a reaction in one direction significantly differently than the reverse direction. The mechanistic determinants of this phenomenon – often referred to as “catalytic bias” – are generally unknown. Our long-term goal of this project is to identify the fundamental principles adopted by redox enzymes (enzymes involved in oxidation-reduction reactions) that provide molecular level control of the catalytic bias. In doing so, we will provide a greater fundamental understanding of the factors that control metabolic processes in all life. Specifically, the objective of this proposal is to delineate determinants that influence the directional reactivity of model Fe containing hydrogenases that are structurally related but exhibit large differences in catalytic bias for the specific reversible hydrogen (H2) oxidation reaction from electron and protons. The central hypothesis is that catalytic bias commonly in redox enzymes results from the relative differential stabilization and destabilization of oxidation states of the respective redox cofactors critical to determining the rate limiting step of the catalytic cycle. The rationale underlying the proposal is that the implementation will result in defining mechanistic determinants of the proposed model system. The proposed work will culminate in elucidating universal, mechanistic factors of catalytic bias that govern a large number of, if not all, redox enzymes. The central hypothesis will be tested by pursuing three specific aims that examine how 1) the reduction potential of the active site proximal accessory redox clusters; 2) the characteristics of the active site cluster protein environment; and 3) the secondary coordination sphere structural dynamics can control reactivity and catalytic bias in cofactor-based oxidation reduction catalysis. To pursue these aims, we will employ an innovative strategy integrating biochemical, structural, spectroscopic, and computational approaches on a unique, one-of-a-kind model hydrogenase platform. The proposed research is significant, because it will delineate molecular determinants that influence the fine-tuning of redox cofactors through the relative stabilization or destabilization of oxidation states to afford certain reactivity fundamental to directing energy and matter in cells. The work will provide additional foundational resources in the form of a blueprint for integrating multiple biophysical and computational approaches.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	5	8/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $329,770 )
2023	2023	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	002	5	8/11/2023	NON-COMPETING CONTINUATION	$334,328
2023	2022	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	001	4	7/28/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$312,644
2023	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Biomedical Research and Research Training	000	3	7/28/2023	NON-COMPETING CONTINUATION	-$317,202
														Subtotal = $329,770

Issue Date FY: 2022 ( Subtotal = $347,477 )
2022	2022	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Biomedical Research and Research Training	000	3	6/14/2022	NON-COMPETING CONTINUATION	$347,477
														Subtotal = $347,477

Issue Date FY: 2021 ( Subtotal = $357,540 )
2021	2021	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Biomedical Research and Research Training	000	2	6/24/2021	NON-COMPETING CONTINUATION	$357,540
														Subtotal = $357,540

Issue Date FY: 2020 ( Subtotal = $367,229 )
2020	2020	WASHINGTON STATE UNIVERSITY	240 FRENCH ADMINISTRATION BLDG	PULLMAN	WA	99164	WHITMAN	USA	Biomedical Research and Research Training	000	1	9/9/2020	NEW	$367,229
														Subtotal = $367,229

Grand Total All Awards = $1,402,016

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Defining the mechanistic determinants of catalytic bias in cofactor-based enzymatic oxidation-reduction reactions

Award Number: R01GM138592

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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