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Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.

Gonçalves, E; Sciacovelli, M; Costa, ASH; Tran, MGB; Johnson, TI; Machado, D; Frezza, C; (2018) Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells. Metab Eng , 45 pp. 149-157. 10.1016/j.ymben.2017.11.011. Green open access

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Abstract

Deregulated signal transduction and energy metabolism are hallmarks of cancer and both play a fundamental role in tumorigenesis. While it is increasingly recognised that signalling and metabolism are highly interconnected, the underpinning mechanisms of their co-regulation are still largely unknown. Here we designed and acquired proteomics, phosphoproteomics, and metabolomics experiments in fumarate hydratase (FH) deficient cells and developed a computational modelling approach to identify putative regulatory phosphorylation-sites of metabolic enzymes. We identified previously reported functionally relevant phosphosites and potentially novel regulatory residues in enzymes of the central carbon metabolism. In particular, we showed that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells, restricting carbon entry from glucose to the tricarboxylic acid cycle. Moreover, we confirmed PDHA1 phosphorylation in human FH-deficient tumours. Our work provides a novel approach to investigate how post-translational modifications of enzymes regulate metabolism and could have important implications for understanding the metabolic transformation of FH-deficient cancers with potential clinical applications.

Type: Article
Title: Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells.
Location: Belgium
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ymben.2017.11.011
Publisher version: https://doi.org/10.1016/j.ymben.2017.11.011
Language: English
Additional information: © 2017 The Authors. Published by Elsevier Inc. on behalf of International Metabolic Engineering Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Keywords: Cancer, Metabolism, Modelling, Phosphoproteomics
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Surgical Biotechnology
URI: https://discovery.ucl.ac.uk/id/eprint/10043363
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