Regulation of Thiamine (Vitamin B1)-Dependent Metabolism in Mammals by p53

• Published in: Biochemistry (Moscow) Vol. 85; no. 7; pp. 801 - 807
• Main Authors: Bunik, V. I., Aleshin, V. A., Zhou, X., Krishnan, S., Karlsson, A.
• Format: Journal Article
• Language: English
• Published: Moscow Pleiades Publishing 01.07.2020; Springer; Springer Nature B.V
• Subjects: A549 Cells; Adenocarcinoma; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - metabolism; Aspartate; Aspartate aminotransferase; Binding sites; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Cyclin-dependent kinase inhibitor p21; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Dehydrogenase; Dehydrogenases; Deoxyribonucleic acid; Derivatives; DNA; Energy Metabolism; Enzymes; Genes; Genetic aspects; Genetic transcription; Glutamate; Glutamate dehydrogenase; Glutamate Dehydrogenase - metabolism; Humans; Isocitrate dehydrogenase; Isoenzymes; Ketoglutarate Dehydrogenase Complex - metabolism; Ketoglutaric acid; Life Sciences; Lung cancer; Malate dehydrogenase; Medicin och hälsovetenskap; Metabolic response; Metabolism; Microbiology; Mitochondria; NAD; NADP; Oxidation-Reduction; Oxoglutarate dehydrogenase (lipoamide); p53 Protein; Pyrimidines; Thiamine; Thiamine - metabolism; Thiamine diphosphate; Thiamine Pyrophosphate - metabolism; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Vitamin B; Vitamin B1; Vitamins; Russia; A549 cells; glutathione; succinyl phosphonate; thiamine-dependent metabolism; cisplatin; p21; p53
• ISSN: 0006-2979; 1608-3040; 1608-3040
• DOI: 10.1134/S0006297920070081

Transcriptional factor p53 is a master regulator of energy metabolism. Energy metabolism strongly depends on thiamine (vitamin B1) and/or its natural derivatives. Thiamine diphosphate (ThDP), which is a major thiamine derivative, affects p53 binding to DNA. In order to elucidate the mechanism of regulation of thiamine-dependent metabolism by p53, we assessed putative p53-binding sites near transcription starting points in genes coding for transporters and enzymes, whose function is associated with thiamine and/or its derivatives. The predictions were validated by studying cell metabolic response to the p53 inducer cisplatin. Expression of p53 and its known target, p21, has been evaluated in cisplatin-treated and control human lung adenocarcinoma A549 cells that possess functional p53 pathway. We also investigated the activity of enzymes involved in the thiamine-dependent energy metabolism. Along with upregulating the expression of p53 and p21, cisplatin affected the activities of metabolic enzymes, whose genes were predicted as carrying the p53-binding sites. The activity of glutamate dehydrogenase GDH2 isoenzyme strongly decreased, while the activities of NADP + -dependent isocitrate dehydrogenase (IDH) and malic enzymes, as well as the activity of 2-oxoglutarate dehydrogenase complex at its endogenous ThDP level, were elevated. Simultaneously, the activities of NAD + -dependent IDH, mitochondrial aspartate aminotransferase, and two malate dehydrogenase isoenzymes, whose genes were not predicted to have the p53-binding sequences near the transcription starting points, were upregulated by cisplatin. The p53-dependent regulation of the assayed metabolic enzymes correlated with induction of p21 by p53 rather than induction of p53 itself.