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Dynamics of co-substrate pools can constrain and regulate metabolic fluxes
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West, Robert, Delattre, Hadrien, Noor, Elad, Feliu, Elisenda and Soyer, Orkun S. (2023) Dynamics of co-substrate pools can constrain and regulate metabolic fluxes. eLife, 12 . 12:e84379. doi:10.7554/eLife.84379 ISSN 2050-084X.
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Official URL: https://doi.org/10.7554/eLife.84379
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.
Item Type: | Journal Article | ||||||||||||
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Alternative Title: | |||||||||||||
Subjects: | Q Science > QH Natural history > QH426 Genetics Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | ||||||||||||
Library of Congress Subject Headings (LCSH): | Cell metabolism, Biochemical engineering, Metabolism, Metabolites -- Research | ||||||||||||
Journal or Publication Title: | eLife | ||||||||||||
Publisher: | eLife Sciences Publications Ltd. | ||||||||||||
ISSN: | 2050-084X | ||||||||||||
Official Date: | 17 February 2023 | ||||||||||||
Dates: |
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Volume: | 12 | ||||||||||||
Article Number: | 12:e84379 | ||||||||||||
DOI: | 10.7554/eLife.84379 | ||||||||||||
Status: | Peer Reviewed | ||||||||||||
Publication Status: | Published | ||||||||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||
Copyright Holders: | © 2023, West et al. | ||||||||||||
Date of first compliant deposit: | 17 February 2023 | ||||||||||||
Date of first compliant Open Access: | 9 March 2023 | ||||||||||||
RIOXX Funder/Project Grant: |
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