Understanding Mechanisms of Nitrogen Incorporation into the Glioma Metabolome
The paradigm of malignant transformation by IDH1 mutations holds that (R)-2-hydroxyglutarate produced by IDH1 mutant enzymes directly modulates the activity of oncogenic or tumor suppressive dioxygenase enzymes to promote tumorigenesis. Recently, we showed that (R)-2-hydroxyglutarate can also regulate the activity of another class of enzymes known as transaminases (McBrayer et al, 2018). Specifically, we found that (R)-2-hydroxyglutarate directly inhibits the branched chain amino acid transaminases BCAT1 and BCAT2. These enzymes play central roles in nitrogen metabolism in glial cells and our work revealed that (R)-2-hydroxyglutarate accumulation impairs the BCAT-dependent synthesis of nitrogenous metabolites.
These findings provide a mechanistic explanation for metabolic differences observed between IDH1 mutant and wild-type brain tumors but, at the same time, prompt fundamental questions about nitrogen metabolism programs in cancer. How do tumor cells couple the catabolism of specific amino acids to the synthesis of key nitrogenous metabolites? How do tumor cells engage compensatory amino acid catabolism pathways to adapt to nitrogen limitation? The answers to these questions have been obscured by conventional depictions of metabolic pathways from carbon-centric standpoints. We aim to answer these questions using metabolomic profiling and isotope tracing approaches in in vitro and in vivo glioma models to systematically map nitrogen metabolism pathways. These studies are expected to illuminate novel patterns of nitrogen incorporation in IDH1 mutant brain tumors as well as other cancers that display BCAT-independent metabolic phenotypes.
