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Applying asymptotic methods to synthetic biology: modelling the reaction kinetics of the mevalonate pathway

Dalwadi, Mohit P.; Garavaglia, Marco; Webb, Joseph P.; King, John R.; Minton, Nigel P.

Authors

Mohit P. Dalwadi mohit.dalwadi@nottingham.ac.uk

Joseph P. Webb

JOHN KING john.king@nottingham.ac.uk
Professor of Theoretical Mechanics

NIGEL MINTON nigel.minton@nottingham.ac.uk
Professor of Appliedmolecular Microbiology



Abstract

The mevalonate pathway is normally found in eukaryotes, and allows for the production of isoprenoids, a useful class of organic compounds. This pathway has been successfully introduced to Escherichia coli, enabling a biosynthetic production route for many isoprenoids. In this paper, we develop and solve a mathematical model for the concentration of metabolites in the mevalonate pathway over time, accounting for the loss of acetyl-CoA to other metabolic pathways. Additionally, we successfully test our theoretical predictions experimentally by introducing part of the pathway into Cupriavidus necator. In our model, we exploit the natural separation of time scales as well as of metabolite concentrations to make significant asymptotic progress in understanding the system. We confirm that our asymptotic results agree well with numerical simulations, the former enabling us to predict the most important reactions to increase isopentenyl diphosphate production whilst minimizing the levels of HMG-CoA, which inhibits cell growth. Thus, our mathematical model allows us to recommend the upregulation of certain combinations of enzymes to improve production through the mevalonate pathway.

Citation

Dalwadi, M. P., Garavaglia, M., Webb, J. P., King, J. R., & Minton, N. P. (2018). Applying asymptotic methods to synthetic biology: modelling the reaction kinetics of the mevalonate pathway. Journal of Theoretical Biology, 439, https://doi.org/10.1016/j.jtbi.2017.11.022

Journal Article Type Article
Acceptance Date Nov 28, 2017
Online Publication Date Dec 2, 2017
Publication Date Feb 14, 2018
Deposit Date Dec 1, 2017
Publicly Available Date Dec 2, 2017
Journal Journal of Theoretical Biology
Print ISSN 0022-5193
Electronic ISSN 1095-8541
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 439
DOI https://doi.org/10.1016/j.jtbi.2017.11.022
Keywords asymptotic analysis; metabolic pathways; isoprenoid production
Public URL http://eprints.nottingham.ac.uk/id/eprint/48475
Publisher URL https://www.sciencedirect.com/science/article/pii/S0022519317305295
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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