Coordinative metabolism of glutamine carbon and nitrogen in proliferating cancer cells under hypoxia

• Published in: Nature communications Vol. 10; no. 1; pp. 201 - 14
• Main Authors: Wang, Yuanyuan, Bai, Changsen, Ruan, Yuxia, Liu, Miao, Chu, Qiaoyun, Qiu, Li, Yang, Chuanzhen, Li, Binghui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.01.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45/320; 631/67/2327; Acetyl Coenzyme A - metabolism; Ammonia; Ammonia - metabolism; Ammonia - toxicity; Animals; Biosynthesis; Cancer; Carbon; Carbon - chemistry; Carbon - metabolism; Cell Hypoxia; Cell Line, Tumor; Cell Survival; Coenzyme A; Female; Glucose - metabolism; Glutamine; Glutamine - chemistry; Glutamine - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Hypoxia; Lactic acid; Lactic Acid - metabolism; Lipogenesis; Metabolic flux; Metabolic Networks and Pathways; Metabolism; Metabolome; Metabolomics; Mice; Mice, Nude; multidisciplinary; Neoplasms - blood; Neoplasms - metabolism; Neoplasms - mortality; Neoplasms - pathology; Nitrogen; Nitrogen - chemistry; Nitrogen - metabolism; Nucleotides - biosynthesis; Orotic Acid - analogs & derivatives; Orotic Acid - metabolism; Science; Science (multidisciplinary); Tumor Microenvironment; Uridine; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-08033-9

Under hypoxia, most of glucose is converted to secretory lactate, which leads to the overuse of glutamine-carbon. However, under such a condition how glutamine nitrogen is disposed to avoid over-accumulating ammonia remains to be determined. Here we identify a metabolic flux of glutamine to secretory dihydroorotate, which is indispensable to glutamine-carbon metabolism under hypoxia. We found that glutamine nitrogen is necessary to nucleotide biosynthesis, but enriched in dihyroorotate and orotate rather than processing to its downstream uridine monophosphate under hypoxia. Dihyroorotate, not orotate, is then secreted out of cells. Furthermore, we found that the specific metabolic pathway occurs in vivo and is required for tumor growth. The identified metabolic pathway renders glutamine mainly to acetyl coenzyme A for lipogenesis, with the rest carbon and nitrogen being safely removed. Therefore, our results reveal how glutamine carbon and nitrogen are coordinatively metabolized under hypoxia, and provide a comprehensive understanding on glutamine metabolism. Glutamine metabolism is increased in proliferating cells under hypoxia potentially generating exceeding nitrogen. Here the authors show that under hypoxia a specific metabolic pathway is activated to push glutamine carbons and excess nitrogen via the reductive pathway to dihyroorotate which is then secreted by the cells and that such pathway is necessary for tumor growth.