Glul, also known as glutamate-ammonia ligase or glutamine synthetase, is an enzyme that catalyzes the ATP-dependent condensation of ammonium and glutamate into glutamine. This reaction is crucial for ammonia detoxification, acid-base homeostasis, cell signaling, and proliferation. Glul is involved in multiple metabolic pathways, such as the tricarboxylic acid (TCA) cycle via reversed glutaminolysis [1,7].

In clear cell renal cell carcinoma (ccRCC), the epigenetic regulator PHF8 transcriptionally up-regulates Glul, which promotes lipid deposition and ccRCC progression [1]. In thermogenic adipocyte differentiation, Glul-produced glutamine promotes the process through Prdm9-mediated H3K4me3 and transcriptional reprogramming [2]. In gastric cancer, Glul stabilizes N-Cadherin by antagonizing β-Catenin, thus inhibiting cancer progression [3]. In hepatocellular carcinoma, targeting Glul impedes cancer progression promoted by high dietary fructose [4]. In breast cancer, Glul promotes cell proliferation and may be a novel target for inhibiting certain signaling pathways [5]. In erythropoiesis, Glul activation during erythroid maturation detoxifies ammonium from heme biosynthesis, and its loss impairs erythroid maturation [6]. In non-small-cell lung carcinoma, GLUL ablation can confer drug resistance via a malate-aspartate shuttle-mediated mechanism [7]. In luminal subtype breast cancer, GLUL knockdown and restricted glucose level show a synergistic inhibitory effect on cell proliferation and metastasis [8]. In endothelial cells, genetic deletion of Glul impairs vessel sprouting during vascular development [9].

In conclusion, Glul plays essential roles in various biological processes and diseases. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models and other loss-of-function experiments on Glul have revealed its significance in cancer development, adipocyte differentiation, erythropoiesis, angiogenesis, and drug resistance, providing insights into potential therapeutic targets for related diseases.

References:

1. Peng, Song, Wang, Ze, Tang, Peng, Jiang, Jun, Liu, Qiuli. 2023. PHF8-GLUL axis in lipid deposition and tumor growth of clear cell renal cell carcinoma. In Science advances, 9, eadf3566. doi:10.1126/sciadv.adf3566. https://pubmed.ncbi.nlm.nih.gov/37531433/

2. Pan, Xiaowen, Ye, Lingxia, Guo, Xiaozhen, Shan, Pengfei, Meng, Zhuo-Xian. . Glutamine Production by Glul Promotes Thermogenic Adipocyte Differentiation Through Prdm9-Mediated H3K4me3 and Transcriptional Reprogramming. In Diabetes, 72, 1574-1596. doi:10.2337/db23-0162. https://pubmed.ncbi.nlm.nih.gov/37579296/

3. Jiang, Qiwei, Li, Yong, Cai, Songwang, Chen, Zhesheng, Shi, Zhi. 2023. GLUL stabilizes N-Cadherin by antagonizing β-Catenin to inhibit the progresses of gastric cancer. In Acta pharmaceutica Sinica. B, 14, 698-711. doi:10.1016/j.apsb.2023.11.008. https://pubmed.ncbi.nlm.nih.gov/38322340/

4. Zhou, Peng, Chang, Wen-Yi, Gong, De-Ao, Tang, Ni, Huang, Ai-Long. 2023. High dietary fructose promotes hepatocellular carcinoma progression by enhancing O-GlcNAcylation via microbiota-derived acetate. In Cell metabolism, 35, 1961-1975.e6. doi:10.1016/j.cmet.2023.09.009. https://pubmed.ncbi.nlm.nih.gov/37797623/

5. Wang, Yanyan, Fan, Shaohua, Lu, Jun, Wu, Zhiyong, Zheng, Yuanlin. 2017. GLUL Promotes Cell Proliferation in Breast Cancer. In Journal of cellular biochemistry, 118, 2018-2025. doi:10.1002/jcb.25775. https://pubmed.ncbi.nlm.nih.gov/27791265/

6. Lyu, Junhua, Gu, Zhimin, Zhang, Yuannyu, Ni, Min, Xu, Jian. 2024. A glutamine metabolic switch supports erythropoiesis. In Science (New York, N.Y.), 386, eadh9215. doi:10.1126/science.adh9215. https://pubmed.ncbi.nlm.nih.gov/39541460/

7. Muthu, Magesh, Kumar, Ranjeet, Syed Khaja, Azharuddin Sajid, Persson, Jenny L, Nordström, Anders. 2019. GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism. In Cancers, 11, . doi:10.3390/cancers11121945. https://pubmed.ncbi.nlm.nih.gov/31817360/

8. Karimpur Zahmatkesh, Arezu, Khalaj-Kondori, Mohammad, Hosseinpour Feizi, Mohammad Ali, Baradaran, Behzad. 2023. GLUL gene knockdown and restricted glucose level show synergistic inhibitory effect on the luminal subtype breast cancer MCF7 cells' proliferation and metastasis. In EXCLI journal, 22, 847-861. doi:10.17179/excli2023-6287. https://pubmed.ncbi.nlm.nih.gov/37780942/

9. Eelen, Guy, Dubois, Charlotte, Cantelmo, Anna Rita, Wu, Xu, Carmeliet, Peter. 2018. Role of glutamine synthetase in angiogenesis beyond glutamine synthesis. In Nature, 561, 63-69. doi:10.1038/s41586-018-0466-7. https://pubmed.ncbi.nlm.nih.gov/30158707/