Wednesday, August 20, 2025 8/20/2025

Biophysical basis for enzyme mediated deglycation in protein repair

Award Number: R35GM143004
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: 06/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Biophysical basis for enzyme mediated deglycation in protein repair - Project Summary/Abstract Organisms across all domains of life decorate their protein molecules with an incredible diversity of chemical modifications. Modifications on proteins are critical for their function, affecting protein structure, stability, and interaction partners. Many of the proteins and the enzymes that read, write, and erase these modifications are closely tied to human diseases ranging from neurological disorders to cancer to type 2 diabetes. While these proteins and pathways can be targets to treat these diseases, we lack a high-resolution, mechanistic understanding of how the cell installs, recognizes, and leverages certain post-translational modifications, specifically ubiquitination and spontaneous, non-enzymatic modifications. Our lab is working to understand how protein-protein interactions dynamically regulate post-translational modifications to alter proteome landscape and impact human disease. Protein glycation is an understudied post-translational modification that arises when a sugar covalently attaches to a primary amine. This process occurs spontaneously under normal physiological conditions and is a bio-marker in aging and the development, or worsening, of diseases such as diabetes, Alzheimer's disease, osteoarthritis, and atherosclerosis. Early glycation events are reversible and represent one of the few protein repair mechanisms in the cell. Deglycation is mediated by an unusual “hybrid” kinase/deglycase called Fructosamine-3-kinase (FN3K). FN3K facilitates the removal of protein-linked glycans by directly phosphorylating the attached sugar and destabilizing the sugar-protein linkage. FN3K and FN3K homologs are found in all branches of the tree of life. The glycation of intracellular proteins is not well studied, yet the conservation of FN3K and FN3K-related proteins underscores an important biological role for these enzymes. In this project, my lab will use a multidisciplinary approach, including techniques and expertise in structural biology, enzymology, and systems biology, to address sharply focused mechanistic questions regarding FN3K-mediate protein repair. We hypothesize that an improved mechanistic understanding of FN3K will reveal new biological insight into this ancient repair process, and that we can leverage this insight to better diagnose and treat diseases associated with elevated glycation. In order to distinguish our contributions from those of others, we will integrate reductionist and global approaches to develop a deeper and more complete understanding of the regulation and repair of glycated proteins. Over the five-year funding period, the goals of this project are to: (i) determine the structural and biophysical basis for FN3K-mediated protein repair (ii) systematically characterize the binding kinetics and enzymatic activity of FN3K and FN3K-RP on diverse substrates; (iii) identify sites-specific FN3K deglycation sites and their potential cross-talk with other PTMs. The successful completion of this work will establish the molecular mechanisms that govern the protein deglycation repair process and will ultimately provide needed breakthroughs in biomedical research.


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 = $411,750 )
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	5	8/8/2025	NON-COMPETING CONTINUATION	$41,175
2025	2025	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	5	3/21/2025	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $411,750

Issue Date FY: 2024 ( Subtotal = $411,750 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	4	2/27/2024	NON-COMPETING CONTINUATION	$370,575
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	4	7/31/2024	NON-COMPETING CONTINUATION	$41,175
														Subtotal = $411,750

Issue Date FY: 2023 ( Subtotal = $521,147 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	3	3/1/2023	NON-COMPETING CONTINUATION	$411,750
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	3	8/23/2023	SUPPLEMENT FOR EXPANSION	$109,397
														Subtotal = $521,147

Issue Date FY: 2022 ( Subtotal = $411,750 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	001	2	6/22/2022	NON-COMPETING CONTINUATION	$41,175
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	2	4/4/2022	NON-COMPETING CONTINUATION	$370,575
														Subtotal = $411,750

Issue Date FY: 2021 ( Subtotal = $411,750 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Biomedical Research and Research Training	000	1	6/1/2021	NEW	$411,750
														Subtotal = $411,750

Grand Total All Awards = $2,168,147

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Biophysical basis for enzyme mediated deglycation in protein repair

Award Number: R35GM143004

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: 06/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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