Dynamics of co-substrate pools can constrain and regulate metabolic fluxes
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-subst...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-02-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/84379 |
| _version_ | 1797867050663673856 |
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| author | Robert West Hadrien Delattre Elad Noor Elisenda Feliu Orkun S Soyer |
| author_facet | Robert West Hadrien Delattre Elad Noor Elisenda Feliu Orkun S Soyer |
| author_sort | Robert West |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T23:34:06Z |
| format | Article |
| id | doaj.art-8bd63d87193a45329ae6e414df0033f2 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T23:34:06Z |
| publishDate | 2023-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8bd63d87193a45329ae6e414df0033f22023-03-20T16:25:21ZengeLife Sciences Publications LtdeLife2050-084X2023-02-011210.7554/eLife.84379Dynamics of co-substrate pools can constrain and regulate metabolic fluxesRobert West0https://orcid.org/0000-0001-9348-0258Hadrien Delattre1https://orcid.org/0000-0002-5488-8370Elad Noor2https://orcid.org/0000-0001-8776-4799Elisenda Feliu3https://orcid.org/0000-0001-7205-6511Orkun S Soyer4https://orcid.org/0000-0002-9504-3796School of Life Sciences, University of Warwick, Warwick, United KingdomSchool of Life Sciences, University of Warwick, Warwick, United KingdomDepartment of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Mathematics, University of Copenhagen, Copenhagen, DenmarkSchool of Life Sciences, University of Warwick, Warwick, United KingdomCycling 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.https://elifesciences.org/articles/84379S. cerevisiaehumanA. thaliana |
| spellingShingle | Robert West Hadrien Delattre Elad Noor Elisenda Feliu Orkun S Soyer Dynamics of co-substrate pools can constrain and regulate metabolic fluxes eLife S. cerevisiae human A. thaliana |
| title | Dynamics of co-substrate pools can constrain and regulate metabolic fluxes |
| title_full | Dynamics of co-substrate pools can constrain and regulate metabolic fluxes |
| title_fullStr | Dynamics of co-substrate pools can constrain and regulate metabolic fluxes |
| title_full_unstemmed | Dynamics of co-substrate pools can constrain and regulate metabolic fluxes |
| title_short | Dynamics of co-substrate pools can constrain and regulate metabolic fluxes |
| title_sort | dynamics of co substrate pools can constrain and regulate metabolic fluxes |
| topic | S. cerevisiae human A. thaliana |
| url | https://elifesciences.org/articles/84379 |
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