# A Multienzyme Metabolic Complex for Glucose Metabolism

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE COUNTY · 2021 · $289,259

## Abstract

Project Summary/Abstract
The long-term objective of this proposal is to understand the molecular-level mechanism of metabolic flux
regulation in human cells. In this proposal, we will investigate the subcellular localization-function relationship
of human multienyzme metabolic complex that regulate glucose metabolism in human cells. Despite
considerable advances in our knowledge of glycolytic enzymes and their complexes, it is still challenging to
explain how the direction of glucose flux is spatially and/or temporally regulated at metabolic nodes between
energy metabolism and anabolic biosynthetic pathways. Now, we provide compelling evidence that all the
cytosolic, rate-determining enzymes in glucose metabolism are spatially organized into a multienzyme complex,
namely the “glucosome,” in various sizes in the cytoplasm of human cells. We hypothesize that the spatial
assembly of glucosomes regulates the direction of glucose flux in a size-dependent manner at subcellular
levels. In Aim1, we will determine a precise metabolic function of each size of glucosome clusters at
subcellular levels, thus providing a quantitative principle for their collective metabolic outcomes at ensemble
levels. Quantitative secondary ion mass spectrometric imaging and 13C-metabolic flux assays will be performed
to determine size-specific partition coefficients of glucosome clusters as their metabolic functions. In Aim 2, we
will provide mechanistic insights of how multiple metabolic pathways are reciprocally regulated as a network to
govern metabolic shunts at subcellular levels. Intracellular fluorescence resonance energy transfer microscopy
and in vitro immunoprecipitation will be used to map the network of protein-protein interactions and its
alterations in differently sized clusters. In Aim 3, we will address how glucosome clusters are spatially altered
to functionally contribute to the cell cycle progression. Flow cytometry, time-lapse fluorescence live-cell
imaging, cell synchronization and mass spectrometry will be employed to functionally correlate the sizes of
glucosome clusters with the cell cycle. We envision that metabolic activities of the rate-determining enzymes in
glucose metabolism are spatially regulated inside glucosome clusters to govern the direction of glucose flux in
cells. The proposed research will significantly advance our understanding of glucose flux regulation at
subcellular levels and thus its dysregulation in human metabolic diseases, like cancer and diabetes.
Collectively, this new level of understanding will divulge the importance of a heretofore unrecognized metabolic
compartment as a novel target for therapeutic intervention.

## Key facts

- **NIH application ID:** 10059257
- **Project number:** 5R01GM125981-04
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE COUNTY
- **Principal Investigator:** Songon An
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $289,259
- **Award type:** 5
- **Project period:** 2017-12-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10059257

## Citation

> US National Institutes of Health, RePORTER application 10059257, A Multienzyme Metabolic Complex for Glucose Metabolism (5R01GM125981-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10059257. Licensed CC0.

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