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Studies on Enzyme Activation and Novel Modes of Inhibition

Award Number: R35GM134881
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: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 08/14/2025

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Studies on Enzyme Activation and Novel Modes of Inhibition - Progress in studies of enzyme mechanisms has slowed in recent years, in part because investigators have failed to clearly define all of the important questions that must be addressed in order to move towards final conclusions about these reaction mechanisms. Many of the studies described in this grant are designed to leverage the potential for creative work directed towards answering the following question: How do enzymes achieve their specificity in transition state (TS) binding? This potential has been harnessed in studies in Buffalo on the mechanism of action of triosephosphate isomerase (TIM), orotidine 5'-monophosphate decarboxylase (OMPDC) and glycerol 3-phosphate dehydrogenase (GPDH). These enzymes undergo dianion-driven conformational changes from loose, unliganded, open enzymes to stiff, structured, catalytically active closed forms, which act as “switches” that turn on the expression of tight transition state binding interactions. Four key question are addressed in this grant, with the goals of generalizing earlier conclusions from TIM, OMPDC, and GPDH to other enzymes, and of initiating new studies to develop novel inhibitors of TIM and OMPDC from pathogenic organisms. Key Question 1: What other protein catalysts utilize binding interactions of their nonreacting substrate fragments to drive enzyme-activating conformational changes? These experiments will probe whether the binding energy from the adenosine ring of the substrate for adenylate kinase, or from the NAD cofactor of the substrate for alcohol dehydrogenase, which drive conformational changes during catalysis by these enzymes, act as a switch to turn on tight transition state binding interactions. Key Question 2: What interactions between the catalytic and activation sites of TIM, OMPDC and GPDH enable utilization of the intrinsic substrate binding energy for catalysis? Experiments are described to characterize a network of amino acid side chains involved in catalysis by GPDH, and to characterize the mechanism for activation of OMPDC by the utilization of binding interactions between the enzyme and the ribosyl hydroxyl groups of the substrates orotidine 5'-monophosphate (OMP) and 5-F-OMP. Key Question 3: Are computational methods sufficiently advanced to model the effect of site-directed mutations on the activation barrier for reactions catalyzed by TIM and GPDH? Calculations will be carried out in collaboration with Professor Lynn Kamerlin in Uppsala, Sweden, to determine whether existing EVB methods are able to model the results of extensive mutagenesis studies on these enzymes, with the goal of expanding the limits of these computational methods. Key Question 4: What is the potential for selection of peptides that show species specificity for inhibition of TIM and OMPDC from pathogenic organisms? Experiments are proposed, in collaboration with Professor Hiroaki Suga at the University of Tokyo, Japan, to identify species-specific inhibitors for TIM from Trypanosoma brucei and OMPDC from Plasmodium falciparum, and to characterize the important inhibitor-protein interactions by X-ray crystallography and computational docking studies.


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 = $287,269 )
2025	2025	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	002	6	8/7/2025	COMPETING CONTINUATION	$287,269
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	003	5	8/8/2025	NON-COMPETING CONTINUATION	$0
2025	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	5	11/6/2024	NON-COMPETING CONTINUATION	$0
2025	2024	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	5	1/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $287,269

Issue Date FY: 2024 ( Subtotal = $395,263 )
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	5	1/2/2024	NON-COMPETING CONTINUATION	$355,738
2024	2024	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	5	5/20/2024	NON-COMPETING CONTINUATION	$39,525
														Subtotal = $395,263

Issue Date FY: 2023 ( Subtotal = $395,330 )
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	4	4/4/2023	NON-COMPETING CONTINUATION	$39,533
2023	2023	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	4	12/15/2022	NON-COMPETING CONTINUATION	$355,797
														Subtotal = $395,330

Issue Date FY: 2022 ( Subtotal = $395,420 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	3	12/22/2021	NON-COMPETING CONTINUATION	$355,877
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	3	6/24/2022	NON-COMPETING CONTINUATION	$39,543
														Subtotal = $395,420

Issue Date FY: 2021 ( Subtotal = $395,484 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	2	2/12/2021	NON-COMPETING CONTINUATION	$39,549
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	2	12/10/2020	NON-COMPETING CONTINUATION	$355,935
														Subtotal = $395,484

Issue Date FY: 2020 ( Subtotal = $462,579 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	001	1	7/8/2020	SUPPLEMENT FOR EXPANSION	$67,036
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	520 LEE ENTRANCE STE 211	AMHERST	NY	14228	ERIE	USA	Biomedical Research and Research Training	000	1	12/24/2019	NEW	$395,543
														Subtotal = $462,579

Grand Total All Awards = $2,331,345

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Studies on Enzyme Activation and Novel Modes of Inhibition

Award Number: R35GM134881

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: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 08/14/2025

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