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Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

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Science  17 Nov 2017:
Vol. 358, Issue 6365, pp. 941-946
DOI: 10.1126/science.aam9305

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Cancer cells put ammonia back to work

Ammonia, often considered a metabolic waste product, can be recycled to build new amino acids. Rapidly proliferating cells produce extracellular nitrogen. Spinelli et al. used metabolic tracing of 15N to follow the fate of extracellular ammonia and its incorporation into more than 200 components of the nitrogen metabolome (see the Perspective by Dang). Accumulation of ammonia enabled glutamate dehydrogenase to function in reductive amination, which allowed incorporation of nitrogen from ammonia back into amino acids. Experiments in mice also showed incorporation of ammonia into glutamate, aspartate, and proline.

Science, this issue p. 941; see also p. 862

Abstract

Ammonia is a ubiquitous by-product of cellular metabolism; however, the biological consequences of ammonia production are not fully understood, especially in cancer. We found that ammonia is not merely a toxic waste product but is recycled into central amino acid metabolism to maximize nitrogen utilization. In our experiments, human breast cancer cells primarily assimilated ammonia through reductive amination catalyzed by glutamate dehydrogenase (GDH); secondary reactions enabled other amino acids, such as proline and aspartate, to directly acquire this nitrogen. Metabolic recycling of ammonia accelerated proliferation of breast cancer. In mice, ammonia accumulated in the tumor microenvironment and was used directly to generate amino acids through GDH activity. These data show that ammonia is not only a secreted waste product but also a fundamental nitrogen source that can support tumor biomass.

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