Dynamics of co-substrate pools can constrain and regulate metabolic fluxes
- University of Warwick, United Kingdom
- Weizmann Institute of Science, Israel
- University of Copenhagen, Denmark
Abstract
Cycling of co-substrates, whereby a metabolite is converted among alternate forms via different reactions, is ubiquitous in metabolism. Several cycled co-substrates are well known as energy and electron carriers (e.g. ATP and NAD(P)H), but there are also other metabolites that act as cycled co-substrates in different parts of central metabolism. Here, we develop a mathematical framework to analyse the effect of co-substrate cycling on metabolic flux. In the cases of a single reaction and linear pathways, we find that co-substrate cycling imposes an additional flux limit on a reaction, distinct to the limit imposed by the kinetics of the primary enzyme catalysing that reaction. Using analytical methods, we show that this additional limit is a function of the total pool size and turnover rate of the cycled co-substrate. Expanding from this insight and using simulations, we show that regulation of these two parameters can allow regulation of flux dynamics in branched and coupled pathways. To support these theoretical insights, we analysed existing flux measurements and enzyme levels from the central carbon metabolism and identified several reactions that could be limited by the dynamics of co-substrate cycling. We discuss how the limitations imposed by co-substrate cycling provide experimentally testable hypotheses on specific metabolic phenotypes. We conclude that measuring and controlling co-substrate dynamics is crucial for understanding and engineering metabolic fluxes in cells.
Data availability
All data and models are made available via a dedicated repository (https://doi.org/10.5281/zenodo.7565439) and the following Github page: https://github.com/OSS-Lab/CoSubstrateDynamics/tree/v1.0.0
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Co-substrate dynamics analysis software and datadoi.org/10.5281/zenodo.7565439.
Article and author information
Author details
Funding
Biotechnology and Biological Sciences Research Council (BB/T010150/1))
- Robert West
- Hadrien Delattre
- Orkun Soyer
Novo Nordisk (F18OC0052483)
- Elisenda Feliu
Gordon and Betty Moore Foundation (GBMF9200)
- Orkun Soyer
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, West et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Dynamics of co-substrate pools can constrain and regulate metabolic fluxes
eLife 12:e84379.
https://doi.org/10.7554/eLife.84379
