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

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2024 · $350,592

## Abstract

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.

## Key facts

- **NIH application ID:** 10766231
- **Project number:** 5R01GM148497-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Michael Springer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $350,592
- **Award type:** 5
- **Project period:** 2023-02-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10766231

## Citation

> US National Institutes of Health, RePORTER application 10766231, A novel and simple mechanism by which cells can sense enzymatic flux (5R01GM148497-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10766231. Licensed CC0.

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