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Formate-induced phospho-signalling

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myeloid Cell, Blood

DISEASE(S): Myeloid Leukemia

SUBMITTER: Sara Zanivan

LAB HEAD: Sara Zanivan

PROVIDER: PXD019347 | Pride | 2020-09-28

REPOSITORIES: Pride

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The conversion of formate into purines stimulates mTORC1 leading to CAD-dependent activation of pyrimidine synthesis.

Tait-Mulder Jacqueline J Hodge Kelly K Sumpton David D Zanivan Sara S Vazquez Alexei A

Cancer & metabolism 20200921

<h4>Background</h4>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 clear how formate induces pyrimidine synthesis.<h4>Methods</h4>Here we combine phospho-proteome and metabolic profiling to determine how formate induces pyrimidine synthesis.<h4>Results</h4>We discover that formate induces phosphorylation of carbamoyl phosphate sy ...[more]

PMID: 32974014

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