Formate induces a metabolic switch in nucleotide and energy metabolism

Oizel, K. et al. (2020) Formate induces a metabolic switch in nucleotide and energy metabolism. Cell Death and Disease, 11(5), 310. (doi: 10.1038/s41419-020-2523-z) (PMID:32366892) (PMCID:PMC7198490)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Blyth, Professor Karen and Sumpton, Mr David and Lilla, Dr Sergio and Tait-Mulder, Dr Jacqueline and Zanivan, Professor Sara and Vazquez, Alexei and Mackay, Dr Gillian and Athineos, Mr Dimitris
Authors: Oizel, K., Tait-Mulder, J., Fernandez-de-Cossio-Diaz, J., Pietzke, M., Brunton, H., Lilla, S., Dhayade, S., Athineos, D., Blanco, G. R., Sumpton, D., Mackay, G. M., Blyth, K., Zanivan, S. R., Meiser, J., and Vazquez, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Disease
Publisher:Nature Publishing Group
ISSN:2041-4889
ISSN (Online):2041-4889
Copyright Holders:Copyright © The Author(s) 2020
First Published:First published in Cell Death and Disease 11:310
Publisher Policy:Reproduced under a Creative Commons licence

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190874CR-UK Centre renewalKaren VousdenNot Applicable (NA)C596/A18076Institute of Cancer Sciences