Formate induces a metabolic switch in nucleotide and energy metabolism

Kristell Oizel, Jacqueline Tait-Mulder, Jorge Fernandez-de-Cossio-Diaz, Matthias Pietzke, Holly Brunton, Sergio Lilla, Sandeep Dhayade, Dimitri Athineos, Giovanny Rodriguez Blanco, David Sumpton, Gillian M. Mackay, Karen Blyth, Sara R. Zanivan, Johannes Meiser, Alexei Vazquez*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)

Abstract

Formate is a precursor for the de novo synthesis of purine and deoxythymidine nucleotides. Formate also interacts with energy metabolism by promoting the synthesis of adenine nucleotides. Here we use theoretical modelling together with metabolomics analysis to investigate the link between formate, nucleotide and energy metabolism. We uncover that endogenous or exogenous formate induces a metabolic switch from low to high adenine nucleotide levels, increasing the rate of glycolysis and repressing the AMPK activity. Formate also induces an increase in the pyrimidine precursor orotate and the urea cycle intermediate argininosuccinate, in agreement with the ATP-dependent activities of carbamoyl-phosphate and argininosuccinate synthetase. In vivo data for mouse and human cancers confirms the association between increased formate production, nucleotide and energy metabolism. Finally, the in vitro observations are recapitulated in mice following and intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.

Original languageEnglish
Article number310
JournalCell Death and Disease
Volume11
Issue number5
DOIs
Publication statusPublished - 1 May 2020

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