Gatm-KO Mouse

Gatm, also known as glycine amidinotransferase, is the rate-limiting enzyme for creatine synthesis. Creatine synthesis is a crucial metabolic pathway, and Gatm functions in the reaction that uses arginine and glycine to produce guanidinoacetate, an intermediate in creatine biosynthesis. This process is essential for maintaining normal cellular energy metabolism, especially in tissues with high-energy demands like muscle [3].

In cancer research, Gatm has been shown to play significant roles. In orthotopic mouse models, GATM-mediated de novo synthesis of creatine promotes colorectal and breast cancer metastasis by upregulating Snail and Slug expression via MPS1-activated Smad2 and Smad3 phosphorylation, and GATM knockdown suppresses cancer metastasis [1]. In FLT3-ITD-mutant acute myeloid leukemia, genetic GATM knockdown with shRNA leads to a significant decrease in cell proliferation and a moderate increase in cell apoptosis, suggesting that targeting Gatm could be a therapeutic strategy [2]. In pancreatic cancer, knockdown of GATM reduces the intracellular level of guanidinoacetic acid, suppresses epithelial-mesenchymal transition (EMT), and inhibits liver metastasis [4]. In obesity-driven breast cancer, deletion of Gatm in adipocytes attenuates obesity-driven tumor growth [5]. Regarding chronic kidney disease (CKD), a Mendelian randomization study shows an association between Gatm and CKD, with increased GATM gene and protein expression corresponding to a diminished risk of CKD, and distinct methylation patterns implying an increased risk [6].

In conclusion, Gatm is essential for creatine synthesis and thus for cellular energy metabolism. Model-based research, especially through gene knockdown in mouse models, has revealed its significant roles in cancer metastasis, leukemia cell maintenance, obesity-associated breast cancer, and the progression of chronic kidney disease. Understanding Gatm's function provides potential therapeutic targets for these diseases.

References:

1. Zhang, Liwen, Zhu, Zijing, Yan, Huiwen, Chen, Gang, Bu, Pengcheng. 2021. Creatine promotes cancer metastasis through activation of Smad2/3. In Cell metabolism, 33, 1111-1123.e4. doi:10.1016/j.cmet.2021.03.009. https://pubmed.ncbi.nlm.nih.gov/33811821/

2. Zhang, Yuan, Newsom, Kimberly J, Zhang, Mei, Kelley, Jeffry S, Starostik, Petr. 2021. GATM-Mediated Creatine Biosynthesis Enables Maintenance of FLT3-ITD-Mutant Acute Myeloid Leukemia. In Molecular cancer research : MCR, 20, 293-304. doi:10.1158/1541-7786.MCR-21-0314. https://pubmed.ncbi.nlm.nih.gov/34635505/

3. Baker, Steven Andrew, Gajera, Chandresh R, Wawro, Adam M, Corces, M Ryan, Montine, Thomas J. 2021. GATM and GAMT synthesize creatine locally throughout the mammalian body and within oligodendrocytes of the brain. In Brain research, 1770, 147627. doi:10.1016/j.brainres.2021.147627. https://pubmed.ncbi.nlm.nih.gov/34418357/

4. Yang, Jinshou, Ren, Bo, Ren, Jie, You, Lei, Zhao, Yupei. 2023. Epigenetic reprogramming-induced guanidinoacetic acid synthesis promotes pancreatic cancer metastasis and transcription-activating histone modifications. In Journal of experimental & clinical cancer research : CR, 42, 155. doi:10.1186/s13046-023-02698-x. https://pubmed.ncbi.nlm.nih.gov/37370109/

5. Maguire, Olivia A, Ackerman, Sarah E, Szwed, Sarah K, Kazak, Lawrence, Cohen, Paul. 2021. Creatine-mediated crosstalk between adipocytes and cancer cells regulates obesity-driven breast cancer. In Cell metabolism, 33, 499-512.e6. doi:10.1016/j.cmet.2021.01.018. https://pubmed.ncbi.nlm.nih.gov/33596409/

6. Liu, Bin, Gao, Xin, Teng, Haolin, Gao, Baoshan, Li, Faping. 2024. Association between GATM gene polymorphism and progression of chronic kidney disease: a mitochondrial related genome-wide Mendelian randomization study. In Scientific reports, 14, 20346. doi:10.1038/s41598-024-68448-x. https://pubmed.ncbi.nlm.nih.gov/39284843/