In Silico Prediction of Metabolic Fluxes in Cancer Cells with Altered S-adenosylmethionine Decarboxylase Activity
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ORIGINAL PAPER
In Silico Prediction of Metabolic Fluxes in Cancer Cells with Altered S-adenosylmethionine Decarboxylase Activity Olga Dotsenko1 Dmytro Shtofel ●
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Accepted: 28 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract This paper investigates the redistribution of metabolic fluxes in the cell with altered activity of S-adenosylmethionine decarboxylase (SAMdc, EC: 4.1.1.50), the key enzyme of the polyamine cycle and the common target for antitumor therapy. To address these goals, a stoichiometric metabolic model was developed that includes five metabolic pathways: polyamine, methionine, methionine salvage cycles, folic acid cycle, and the pathway of glutathione and taurine synthesis. The model is based on 51 reactions involving 57 metabolites, 31 of which are internal metabolites. All calculations were performed using the method of Flux Balance Analysis. The outcome indicates that the inactivation of SAMdc results in a significant increase in fluxes through the methionine, the taurine and glutathione synthesis, and the folate cycles. Therefore, when using therapeutic agents inactivating SAMdc, it is necessary to consider the possibility of cellular tumor metabolism reprogramming. S-adenosylmethionine affects serine methylation and activates serine-dependent de novo ATP synthesis. Methionine-depleted cell becomes methionine-dependent, searching for new sources of methionine. Inactivation of SAMdc enhances the transformation of S-adenosylmethionine to homocysteine and then to methionine. It also intensifies the transsulfuration process activating the synthesis of glutathione and taurine. Keywords Metabolic flux S-adenosylmethionine decarboxylase Stoichiometric model Polyamine metabolism Flux balance analysis Cancer cell ●
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Introduction Numerous reactions of methylation in cells, including rearrangement of methyl groups on histone tails, methylation of DNA cytosine and mRNA adenine, require Sadenosylmethionine (SAM) as a donor of methyl groups. SAM is a product of a single-carbon metabolic pathway and is involved in the catabolism of serine. Many works indicate that histone and DNA methylation reactions are sensitive to the concentration of SAM [1–3]. Alongside, spermine, spermidine, and other polyamines are created from the decarboxylated form of SAM and putrescine [4, 5]. Since
* Dmytro Shtofel [email protected] 1
Department of Biophysics and Physiology, Vasyl’ Stus Donetsk National University, 600-richchia str. 21, Vinnytsia 21021, Ukraine
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Department of Biomedical Engineering, Vinnytsia National Technical University, Khmelnytske Shose 95, Vinnytsia 21021, Ukraine
polyamines are directly involved in cell activity, the studies focus on the role of these substances in malignant growth [1, 6]. The relations between polyamines and cancer have been investigated for many decades, resulting in extensive and comprehensive studies on enzymes and metabolic pathways. Consequently, many chemotherapy strategies for cancer were
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