PT  - JOURNAL ARTICLE
AU  - Emanuel Gonçalves
AU  - Marco Sciacovelli
AU  - Ana S. H. Costa
AU  - Timothy Isaac Johnson
AU  - Daniel Machado
AU  - Christian Frezza
AU  - Julio Saez-Rodriguez
TI  - Post-translational regulation of metabolism in fumarate hydratase deficient cancer cells
AID  - 10.1101/149716
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 149716
4099  - http://biorxiv.org/content/early/2017/06/13/149716.short
4100  - http://biorxiv.org/content/early/2017/06/13/149716.full
AB  - Deregulated signal transduction pathways and energy metabolism are hallmarks of cancer and both play a fundamental role in the process of 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 show that pyruvate dehydrogenase (PDHA1) enzymatic activity is inhibited by increased phosphorylation in FH-deficient cells. 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.