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A novel and simple mechanism by which cells can sense enzymatic flux

Award Number: R01GM148497
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: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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A novel and simple mechanism by which cells can sense enzymatic flux - Project Summary Metabolism is a tightly controlled and complex process in which different nutrients are taken up and processed to meet variable needs. The regulation of uptake and processing requires that many nutrients and metabolites are sensed. This poses a challenge since some of the molecules that are being sensed are simultaneously subject to processing. This has led to the suspicion that metabolic pathways may directly sense the flux through the pathway, instead of sensing only the concentration of nutrients or metabolites. Recent work has confirmed this by identifying a flux-sensing system in bacteria, although the mechanism used is complex and may not translate to other systems. In preliminary work on the galactose utilization (GAL) pathway of Saccharomyces cerevisiae, we have identified a novel putative mechanism for connecting enzymatic activity to signaling, providing a simple way for metabolic flux to be measured. Because this mechanism is simple, we suspect that it may occur in many pathways. We now propose to investigate this hypothetical mechanism in detail. The GAL pathway is an ideal system in which to identify and mechanistically characterize flux sensing. It is a classic model system for signaling in eukaryotes, and we have extensive methods and genetic tools available. Systematic high- throughput quantitative measurements will be used to develop and refine computational models, which in turn will be used to both guide and interpret experiments and to give insight into the physiological role of both flux and concentration sensors. The insights we gain from the GAL pathway will then simplify the discovery of flux sensors in other pathways. Next, we will bring the tools and models we develop to characterize GAL signaling to bear on identifying and characterizing the sensor modalities in the pathway responsible for metabolizing nitrogen in S. cerevisiae. Based on literature findings, we suspect that this pathway also contains a flux sensor. We anticipate that identifying flux sensors in these pathways will immediately provide insight into the potential for flux sensing in human metabolic pathways, and lead to the identification of promising new therapeutic targets.


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 = $315,388 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	11/20/2024	NON-COMPETING CONTINUATION	$315,388
														Subtotal = $315,388

Issue Date FY: 2024 ( Subtotal = $350,592 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	6/10/2024	NON-COMPETING CONTINUATION	$35,060
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	11/8/2023	NON-COMPETING CONTINUATION	$315,532
														Subtotal = $350,592

Issue Date FY: 2023 ( Subtotal = $350,747 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/19/2023	NEW	$350,747
														Subtotal = $350,747

Grand Total All Awards = $1,016,727

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A novel and simple mechanism by which cells can sense enzymatic flux

Award Number: R01GM148497

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: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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