Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass

Science. 2017 Nov 17;358(6365):941-946. doi: 10.1126/science.aam9305. Epub 2017 Oct 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amination
  • Ammonia / metabolism*
  • Animals
  • Aspartic Acid / metabolism
  • Biocatalysis
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / pathology*
  • Cell Proliferation
  • Female
  • Glutamate Dehydrogenase / genetics
  • Glutamate Dehydrogenase / metabolism*
  • Humans
  • MCF-7 Cells
  • Mice
  • Proline / metabolism
  • RNA, Small Interfering / metabolism
  • Tumor Microenvironment


  • RNA, Small Interfering
  • Aspartic Acid
  • Ammonia
  • Proline
  • Glutamate Dehydrogenase
  • GLUD1 protein, human
  • GLUD2 protein, human