The origin of oncometabolites and an overview of the analysis workflow used.

(A) (left) Mutant isocitrate dehydrogenases (IDH) enzymes show a neomorphic enzymatic activity to convert α-KG (α-ketoglutarate) into 2-HG (2-hydroxyglutarate), a small oncometabolite. The presence of mutant IDH1 or IDH2 proteins results in increased amounts of 2-HG, which then alters a number of downstream cellular activities. 2-HG competitively inhibits α-KG binding to several histone demethylases. (Middle, Right) Loss of succinate dehydrogenase (SDH) and fumarate hydratase (FH) enzymatic activity due to the mutation results in accumulated concentration of intracellular succinate and fumarate, respectively. (B) Overview of the work presented here. First, recurrently mutated enzymes which could produce potential oncometabolites are identified across the nine cancer types. Once the recurrently mutated enzymes were identified, oncometabolites were predicted by simulating flux changes between LoF cancer vs. normal in silico GEM (LoF analysis), and applying the chemoinformatics approach to predict promiscuous catalytic activities of enzymes resulting from their GoF mutations (GoF analysis).