By Steve Edelson, Executive Editor

Ammonia has long been viewed as a toxic cellular by-product of glutamine metabolism that has little or no functionality. New findings by a group at Pfizer Inc. now suggest this may not always be the case. The team found that in tumors, ammonia functions as a diffusible signal that can trigger autophagy in neighboring cancer cells, which enables them to be better prepared to counter external stressors such as chemotherapeutics.1 The results suggest that disrupting glutamine
metabolism to reduce ammonia could be explored as a therapeutic strategy. The challenge will be figuring out how to therapeutically target the underlying pathways. In the presence of oxygen, normal cells extract as much energy as possible from glucose primarily through mitochondrial oxidative phosphorylation. In contrast, the majority of tumors grow mostly through glycolysis, a less efficient but faster process that involves converting glucose to lactate in the cytosol. As a result, the mitochondria of tumor cells are not used to generate ATP—instead, they work overtime producing intermediates for the
synthesis of nucleic and fatty acids via the tricarboxylic acid (TCA) cycle (see Figure 1, “Ammonia as a stress signal in cancer”).
One of the substrates for the TCA cycle, α-ketoglutarate, is generated from glutamine in the mitochondria following two deamination reactions. As a by-product, two molecules of ammonia are released.