Formate induces a metabolic switch in nucleotide and energy metabolism
Open Access
- 4 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (5), 1-14
- https://doi.org/10.1038/s41419-020-2523-z
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.Keywords
Funding Information
- Cancer Research UK (C596/A21140, C596/A17196, C596/A18076)
- Deutsche Forschungsgemeinschaft (ME 4636/2-1)
This publication has 42 references indexed in Scilit:
- Mitochondrial One-Carbon Pathway Supports Cytosolic Folate Integrity in Cancer CellsCell, 2018
- Increased formate overflow is a hallmark of oxidative cancerNature Communications, 2018
- Mitochondrial translation requires folate-dependent tRNA methylationNature, 2018
- Mammals divert endogenous genotoxic formaldehyde into one-carbon metabolismNature, 2017
- Serine one-carbon catabolism with formate overflowScience Advances, 2016
- One-Carbon Metabolism in Health and DiseaseCell Metabolism, 2016
- Mitochondrial dysfunction remodels one-carbon metabolism in human cellseLife, 2016
- Reversal of Cytosolic One-Carbon Flux Compensates for Loss of the Mitochondrial Folate PathwayCell Metabolism, 2016
- Improved vectors and genome-wide libraries for CRISPR screeningNature Methods, 2014
- Compartmentalization of Mammalian Folate-Mediated One-Carbon MetabolismAnnual Review of Nutrition, 2010