R. R. Rodriguez¹, I. S. Lushchyk², M. Yu. Obolenska¹

 ¹Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv;
e-mail: northernwizard@yandex.ua;
²National University Kyiv-Mohyla Academy, Ukraine

The work is dedicated to creation of the mathematical model of folate-dependent one-carbon unit metabolism (FOCM) and study of its function in human placenta under homocysteine load and the most common mutations in the genes of methylenetetrahydrofolate reductase (MTHFR) and cystathionine β-synthase (CBS). In the model we have taken into account specific features of placental expression of genes that encode enzymes of FOCM. Using software tools Metatool and COBRAToolbox­ we have identified key metabolites, elementary modes and metabolic fluxes through different reactions of the system. It is shown that the most vulnerable links in the system are the folate cycle and synthesis of precursors of nucleic acids, inosine monophosphate and thymidyne monophosphates, which are changing in the broad range from significant inhibition to activation depending on the imposed conditions. The most stable links in the system are the reactions of glutathione and taurine synthesis. Simulation results coincide with the results obtained in similar experimental conditions. Under certain imposed conditions non-obvious relationships between the system links are revealed, and this becomes the basis for a purposeful test of predictions generated by the model.

Keywords: cystathionine-β-synthase, folate-dependent one-carbon metabolism, homocysteine, metylentetrahydrofolate reductase, polymorphisms, stoichiometric model