A new mathematical model of folate homeostasis in E. coli highlights the potential importance of the folinic acid futile cycle in cell growth

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.