Morgan, Amy E and Salcedo-Sora, J Enrique and Mc Auley, Mark T (2023) A new mathematical model of folate homeostasis in E. coli highlights the potential importance of the folinic acid futile cycle in cell growth. Biosystems, 235. ISSN 0303-2647
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Abstract
Folate (vitamin B9) plays a central role in one-carbon metabolism in prokaryotes and eukaryotes. This pathway
mediates the transfer of one-carbon units, playing a crucial role in nucleotide synthesis, methylation, and amino
acid homeostasis. The folinic acid futile cycle adds a layer of intrigue to this pathway, due to its associations with
metabolism, cell growth, and dormancy. It also introduces additional complexity to folate metabolism. A logical
way to deal with such complexity is to examine it by using mathematical modelling. This work describes the
construction and analysis of a model of folate metabolism, which includes the folinic acid futile cycle. This model
was tested under three in silico growth conditions. Model simulations revealed: 1) the folate cycle behaved as a
stable biochemical system in three growth states (slow, standard, and rapid); 2) the initial concentration of serine
had the greatest impact on metabolite concentrations; 3) 5-formyltetrahydrofolate cyclo-ligase (5-FCL) activity
had a significant impact on the levels of the 7 products that carry the one-carbon donated from folates, and the
redox couple NADP/NADPH; this was particularly evident in the rapid growth state; 4) 5-FCL may be vital to the
survival of the cells by maintaining low levels of homocysteine, as high levels can induce toxicity; and 5) the
antifolate therapeutic trimethoprim had a greater impact on folate metabolism with higher nutrient availability.
These results highlight the important role of 5-FCL in intracellular folate homeostasis and mass generation under
different metabolic scenarios.
| Item Type: | Article |
|---|---|
| Faculty / Department: | Faculty of Human and Digital Sciences > School of Health and Sport Sciences |
| Depositing User: | Amy Morgan |
| Date Deposited: | 07 Dec 2023 14:29 |
| Last Modified: | 07 Dec 2023 14:29 |
| URI: | https://hira.hope.ac.uk/id/eprint/4083 |
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