Abstract:
The study of the metabolism of tumor cells has broadened the understanding of the mechanisms and effects of tumor associated metabolic disorders at various stages of tumor formation due to the emergence of new biochemical, molecular biology methods and mathematical methods that enhanced predictive capabilities of computer simulation. However, existing data remains very dispersed and not systemically integrated. The purpose of the work was to investigate the redistribution of metabolic flows in the cell by inactivating S-adenosylmethionine decarboxylase (SAMdc, EC: 4.1.1.50), the key enzyme of the polyamide cycle and the common target of antitumor therapy.
To address these goals, a stoichiometric metabolic model was developed that included five metabolic cycles: polyamines, methionine, methionine regeneration cycle, folic acid cycle, and the synthesis of glutathione and taurine. The model is based on 51 reactions involving 59 metabolites (31 of them are internal metabolites). All calculations were performed using the method of analysis of stationary flows (FluxBalanceAnalysis, FBA). Within this method, the number of elementary modalities (EFM) and flow control (CEF) were calculated. This work proposes to extend the capabilities of the analysis of interactions using the flow control coefficients (CEF) by simulating both overexpression and suppression of the synthesis of SAMdc. The model was developed in the CellNetAnalyzer 2017.
According to the simulation results, inactivation of SAMdc will reduce the flow through the enzymes for the synthesis and acetylation of spermine and spermidine. At the same time, significant reduction of flows is predicted only when SAMdc is inactivated by more than 50%. We determined that SAMdc controls the methionine cycle more significantly than the polyamines cycle. The obtained results indicate that the inactivation of SAMdc will result in a significant increase in flows through the methionine cycle and the taurine synthesis cycle for glutathione, a folate cycle. Therefore, when using therapeutic agents aimed to inactivate SAMdc, it is necessary to consider the possibility of the reprogramming of cellular tumor metabolism, the role of S-adenosylmethionine (SAM) in the methylation and catabolism of serine, the amount of which in these conditions will increase. In addition, the decrease in the activity of SAMdc creates the possibility of increased synthesis of glutathione metabolite, protecting tumor cells from oxidative stress.
