# Mechanisms of metabolite signaling

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $423,500

## Abstract

ABSTRACT
Much evidence has accumulated over the past several decades that metabolism does more than just provide
the building blocks and energy to fuel biological functions. Instead, it is increasingly clear that metabolism has
a profound effect in determining the behaviors of cells, tissues and organisms. We hypothesize that many of
these effects are mediated by direct physical interactions whereby metabolites act on macromolecules, like
proteins, to alter their functions. Unfortunately, the available methodologies for discovering such interactions
are limited in scale, throughput and sensitivity. For this reason, we developed the MIDAS platform, which
uses simple biophysical principles to discover interactions with very high sensitivity and selectivity. MIDAS
has enabled the discovery of many novel metabolite-protein interactions, some of which we have shown to
exert functionally important effects in cell models. We now propose to implement MIDAS in a much more
systematic way, including collaborative efforts to define the metabolite interactions of the ubiquitin-
proteasome system and the autophagy machinery. Metabolite interactions with RNA are known to be
functionally important in bacteria, which use RNA elements known as riboswitches to couple direct metabolite
binding to changes in RNA function. We have used MIDAS to identify metabolite ligands for some previously
“orphan” riboswitches and will functionally characterize such interactions. More importantly, we
hypothesized that RNA-metabolite interactions also exist and drive cellular behaviors in human cells. We
used an integrated platform of transcriptome screening and RNA-adapted MIDAS to discover several
intriguing putative interactions between metabolites and human mRNAs. We have validated and
demonstrated the functionality of one of these interactions, with cAMP binding and stimulating the translation
of the COX7B mRNA. We will collaboratively determine the structure and function of this interaction and it
will serve as a model for the many such interactions that we propose are important in mediating metabolic
signaling in human cells. We anticipate that these two modes of metabolite regulation, via proteins and RNA,
are fundamental to the metabolic effects on cell behavior, and the understanding that we will gain over time
will be transformative.

## Key facts

- **NIH application ID:** 10841777
- **Project number:** 2R35GM131854-06
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jared P Rutter
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,500
- **Award type:** 2
- **Project period:** 2019-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841777

## Citation

> US National Institutes of Health, RePORTER application 10841777, Mechanisms of metabolite signaling (2R35GM131854-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10841777. Licensed CC0.

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