Department of Biophysics and Physiology, Vasyl' Stus Donetsk National University, 600-richchia str. 21, Vinnytsia, 21021, Ukraine.
Department of Biomedical Engineering, Vinnytsia National Technical University, Khmelnytske Shose 95, Vinnytsia, 21021, Ukraine.
Cell Biochem Biophys. 2021 Mar;79(1):37-48. doi: 10.1007/s12013-020-00949-8. Epub 2020 Oct 11.
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.
本文研究了 S-腺苷甲硫氨酸脱羧酶（SAMdc，EC：4.1.1.50）活性改变时细胞内代谢通量的重新分配，SAMdc 是多胺循环的关键酶，也是抗肿瘤治疗的共同靶点。为了实现这些目标，开发了一个包含五个代谢途径的代谢通量平衡分析模型：多胺、蛋氨酸、蛋氨酸补救循环、叶酸循环和谷胱甘肽和牛磺酸合成途径。该模型基于 51 个涉及 57 种代谢物的反应，其中 31 种是内部代谢物。所有计算均采用通量平衡分析方法进行。结果表明，SAMdc 的失活会导致蛋氨酸、牛磺酸和谷胱甘肽合成以及叶酸循环的通量显著增加。因此，当使用抑制 SAMdc 的治疗剂时，有必要考虑细胞肿瘤代谢重新编程的可能性。S-腺苷甲硫氨酸影响丝氨酸甲基化并激活依赖丝氨酸的从头 ATP 合成。蛋氨酸耗竭的细胞变得依赖蛋氨酸，寻找新的蛋氨酸来源。SAMdc 的失活增强了 S-腺苷甲硫氨酸向同型半胱氨酸然后向蛋氨酸的转化。它还加强了转硫途径，激活了谷胱甘肽和牛磺酸的合成。
