Gatm-flox Mouse

Gatm, also known as glycine amidinotransferase or AGAT, is the rate-limiting enzyme in the creatine biosynthesis pathway. Creatine synthesis involves a series of reactions where Gatm, along with guanidinoacetate N-methyltransferase (GAMT), synthesizes creatine from arginine, glycine, and S-Adenosyl methionine [4]. Creatine metabolism is important for energy homeostasis in various tissues, and Gatm-mediated creatine synthesis occurs locally throughout the mammalian body, including in oligodendrocytes of the brain [4].

In cancer research, Gatm has been shown to play significant roles. In orthotopic mouse models, upregulation of Gatm in liver metastases promotes colorectal and breast cancer metastasis. Dietary creatine uptake or Gatm-mediated de novo synthesis enhances cancer metastasis by upregulating Snail and Slug expression via MPS1-activated Smad2 and Smad3 phosphorylation, and Gatm knockdown suppresses cancer metastasis and improves mouse survival [1]. In FLT3-ITD-mutant acute myeloid leukemia, FLT3-ITD activates the STAT5 signaling pathway, upregulating Gatm expression. Pharmacologic FLT3-ITD inhibition or genetic GATM knockdown reduces intracellular creatinine levels, leading to decreased cell proliferation and increased apoptosis in mutant cell lines, suggesting that targeting Gatm could be a therapeutic strategy [3]. In pancreatic cancer, high GATM expression is positively correlated with advanced N stage, and GATM knockdown reduces intracellular guanidinoacetic acid (GAA) levels, suppresses epithelial-mesenchymal transition (EMT), and inhibits liver metastasis [5]. In obesity-driven breast cancer, Gatm in adipocytes is required for obesity-driven tumor progression, and deletion of Gatm in adipocytes attenuates tumor growth [6].

In summary, Gatm is crucial for creatine biosynthesis, which has far-reaching implications in energy-related biological processes. Through gene-knockout (KO) and conditional-knockout (CKO) mouse models, research has revealed its important roles in cancer metastasis and tumor progression, highlighting its potential as a therapeutic target in cancer treatment. Additionally, studies on Gatm polymorphism suggest its role in statin-induced myopathy and chronic kidney disease, further expanding its significance in different disease areas [2,7].