# Protein-metabolite interaction networks for functional characterization of metabolites.

> **NIH NIH R35** · MICHIGAN STATE UNIVERSITY · 2024 · $384,052

## Abstract

Project Summary
Metabolites are central to orchestrating all cellular processes, yet functions of many metabolites remain
unknown. The predominant mode of metabolite action is regulating protein activities. Hence, one way to
understand a metabolite's role is to identify its protein targets.
 My research program investigates how organisms exploit metabolites to regulate protein activities and,
consequently, cellular processes by untargeted identification of protein-metabolite complexes. We are especially
interested in identifying enzyme-ligand pairings contributing to metabolic adaptations. I address this question
from the perspective of a biochemist and an expert in mass-spectrometry. To obtain a snapshot of the protein-
metabolite interactome in a single experiment, my group developed PROMIS; an original biochemical approach
that relies on the co-fractionation of proteins and associated small-molecule ligands. The protein-metabolite
interaction (PMI) networks are queried for novel regulatory interactions followed by in-detail functional analysis.
One of the key findings coming from our work is uncovering the role of proteinogenic dipeptides in the regulation
of central carbon metabolism in yeast and plants; specific dipeptides act at different points of flux control. These
findings represent just the tip of the iceberg considering the hundreds of metabolites present in PMI datasets
generated by my group and spanning four model organisms including gram-negative bacteria Escherichia coli,
budding yeast Saccharomyces cerevisiae, plant Arabidopsis thaliana, and roundworm Caenorhabditis elegans.
 Over the next five years, the focus of my research program is to build on the experimental toolbox and
wealth of PMI data to uncover the evolutionary conservation of these PMI networks and to functionally
characterize previously unknown metabolite-protein pairings associated with processes essential to organismal
health. To address these goals, I will lead projects under three broad themes (1) assembly and validation of the
organism-specific and pan-organismal protein-metabolite interactome, (2) extending the analysis to the unknown
compounds present in the protein-complexes and introducing computational methods to predict PMIs and (3)
further functional characterization of the roles of dipeptides in regulating central carbon metabolism in
Arabidopsis.
 The knowledge gained over the next five years in the proposed projects will expand our understanding
of the regulatory roles of metabolites. The envisaged organism-specific and pan-organismal protein-metabolite
interactomes will provide a solid foundation for us and others to uncover novel small-molecule regulators and
their modes of action. Functional dissection of the dipeptide-enzyme interaction networks will contribute to the
mechanistic understanding of the central question in biology of how organisms remodel their metabolism to
changing environments. The outcome of my research may lead to innovation in ...

## Key facts

- **NIH application ID:** 10841941
- **Project number:** 1R35GM153298-01
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Aleksandra Skirycz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $384,052
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10841941

## Citation

> US National Institutes of Health, RePORTER application 10841941, Protein-metabolite interaction networks for functional characterization of metabolites. (1R35GM153298-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10841941. Licensed CC0.

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