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.

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: https://nottingham-repository.worktribe.com/output/911457
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0022519317305295
• Contract Date: Dec 1, 2017