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Formate Induces a Metabolic Switch in Nucleotide and Energy Metabolism

56 Pages Posted: 20 Sep 2019 Sneak Peek Status: Review Complete

See all articles by Kristell Oizel

Kristell Oizel

Cancer Research UK Beatson Institute

Jacqueline Tait-Mulder

Cancer Research UK Beatson Institute

Jorge Fernandez-de-Cossio-Diaz

Center of Molecular Immunology

Matthias Pietzke

Cancer Research UK Beatson Institute

Holly Brunton

University of Glasgow - Institute of Cancer Sciences

Sandeep Dhayade

Cancer Research UK Beatson Institute

Dimitris Athineos

Cancer Research UK Beatson Institute

Sergio Lilla

Beatson Institute for Cancer Research

Giovanny Rodriguez Blanco

Cancer Research UK Beatson Institute

David Sumpton

Cancer Research UK Beatson Institute

Gillian Mackay

Beatson Institute for Cancer Research

Karen Blyth

Cancer Research UK Beatson Institute

Sara Zanivan

Cancer Research UK Beatson Institute

Johannes Meiser

Luxembourg Institute of Health - Department of Oncology

Alexei Vazquez

Cancer Research UK Beatson Institute

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

Keywords: Formate metabolism, purine metabolism, pyrimidine metabolism, energy metabolism, AMPK, one-carbon metabolism, folate metabolism

Suggested Citation

Oizel, Kristell and Tait-Mulder, Jacqueline and Fernandez-de-Cossio-Diaz, Jorge and Pietzke, Matthias and Brunton, Holly and Dhayade, Sandeep and Athineos, Dimitris and Lilla, Sergio and Rodriguez Blanco, Giovanny and Sumpton, David and Mackay, Gillian and Blyth, Karen and Zanivan, Sara and Meiser, Johannes and Vazquez, Alexei, Formate Induces a Metabolic Switch in Nucleotide and Energy Metabolism (September 18, 2019). CELL-REPORTS-D-19-03419. Available at SSRN: https://ssrn.com/abstract=3456295 or http://dx.doi.org/10.2139/ssrn.3456295
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Kristell Oizel

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Jacqueline Tait-Mulder

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Jorge Fernandez-de-Cossio-Diaz

Center of Molecular Immunology ( email )

Cuba

Matthias Pietzke

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Holly Brunton

University of Glasgow - Institute of Cancer Sciences ( email )

Glasgow, Scotland G12 8LE
United Kingdom

Sandeep Dhayade

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Dimitris Athineos

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Sergio Lilla

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Giovanny Rodriguez Blanco

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

David Sumpton

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Gillian Mackay

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Karen Blyth

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Sara Zanivan

Cancer Research UK Beatson Institute

Switchback Road
Glasgow, G61 1BD
United Kingdom

Johannes Meiser

Luxembourg Institute of Health - Department of Oncology

1 A-B Rue Thomas Edison
Strassen
Luxembourg

Alexei Vazquez (Contact Author)

Cancer Research UK Beatson Institute

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