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Formate induces a metabolic switch in nucleotide and energy metabolism

Authors :
Sandeep Dhayade
Sara Zanivan
Kristell Oizel
Matthias Pietzke
Karen Blyth
Dimitris Athineos
David Sumpton
Holly Brunton
Giovanny Rodriguez Blanco
Alexei Vazquez
Gillian M. Mackay
Sergio Lilla
Johannes Meiser
Jorge Fernandez-de-Cossio-Diaz
Jacqueline Tait-Mulder
Source :
Cell Death & Disease, Cell Death and Disease, Vol 11, Iss 5, Pp 1-14 (2020), SSRN Electronic Journal
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

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 intraperitoneal injection of formate. We conclude that formate is a potent regulator of purine, pyrimidine and energy metabolism.

Details

ISSN :
20414889
Database :
OpenAIRE
Journal :
Cell Death & Disease, Cell Death and Disease, Vol 11, Iss 5, Pp 1-14 (2020), SSRN Electronic Journal
Accession number :
edsair.doi.dedup.....1b0827e2416027cbf35c2ca3dc4bb22f