Formate-induced phospho-signalling

The mitochondrial serine catabolism to formate induces a metabolic switch to a hypermetabolic state with high rates of glycolysis, purine synthesis and pyrimidine synthesis. While formate is a purine precursor it is not obvious link between formate and pyrimidine synthesis. Methods Here we combine phospho-proteome and metabolic profiling to determine how formate induces pyrimidine synthesis. We discover that formate induces CAD phosphorylation. Mechanistically formate induces mTORC1 activity as quantified by S6K1 phosphorylation, which is known to phosphorylate CAD and increase its enzymatic activity. Treatment with the allosteric mTORC1 inhibitor rapamycin abrogates CAD phosphorylation and pyrimidine synthesis induced by formate. We conclude that formate activates mTORC1 and induces pyrimidine synthesis via increasing CAD activity.