Bcat1, short for branched-chain amino acid transaminase 1, is an enzyme that initiates the catabolism of branched-chain amino acids (BCAAs) like leucine. It is involved in key metabolic pathways, such as transferring α-amino groups from BCAAs to α-ketoglutarate, regulating intracellular α-ketoglutarate (αKG) homeostasis, and influencing the tricarboxylic acid cycle. Bcat1 has shown significance in multiple biological processes including cell growth, motility, and metabolism, making genetic models crucial for its study [2,3].

In cancer research, gene knockout studies have been revealing. In glioblastoma, loss of Bcat1 combined with α-ketoglutarate (AKG) treatment led to metabolic synthetic lethality in IDH wildtype (WT) GBM cells, as Bcat1 loss increased the NAD+/NADH ratio, impaired oxidative phosphorylation, mTORC1 activity, and nucleotide biosynthesis, and these effects were augmented by AKG [1]. In acute myeloid leukaemia (AML), knockdown of Bcat1 in leukaemia cells caused αKG accumulation, EGLN1-mediated HIF1α protein degradation, a growth and survival defect, and abrogation of leukaemia-initiating potential [2]. In triple-negative breast cancer, inhibiting Bcat1-mediated BCAA metabolism using a small-molecule (Eupalinolide B) reduced BCAA synthesis, inhibited SHOC2-RAS-ERK signaling, and induced apoptosis [4].

In conclusion, Bcat1 is essential in regulating BCAA metabolism and related cellular functions. Model-based research, especially through gene knockout experiments, has demonstrated its role in diseases like glioblastoma, AML, and triple-negative breast cancer. Understanding Bcat1 provides insights into disease mechanisms and potential therapeutic strategies targeting BCAA metabolism in these cancers.

References:

1. Zhang, Bo, Peng, Hui, Zhou, Mi, Wang, Yingfei, Luo, Weibo. . Targeting BCAT1 Combined with α-Ketoglutarate Triggers Metabolic Synthetic Lethality in Glioblastoma. In Cancer research, 82, 2388-2402. doi:10.1158/0008-5472.CAN-21-3868. https://pubmed.ncbi.nlm.nih.gov/35499760/

2. Raffel, Simon, Falcone, Mattia, Kneisel, Niclas, Radlwimmer, Bernhard, Trumpp, Andreas. 2017. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. In Nature, 551, 384-388. doi:10.1038/nature24294. https://pubmed.ncbi.nlm.nih.gov/29144447/

3. Papathanassiu, Adonia E, Ko, Jeong-Hun, Imprialou, Martha, Mauro, Claudio, Behmoaras, Jacques. 2017. BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases. In Nature communications, 8, 16040. doi:10.1038/ncomms16040. https://pubmed.ncbi.nlm.nih.gov/28699638/

4. Huang, Ling, Li, Guanjun, Zhang, Ying, Xiao, Wei, Wang, Jigang. 2024. Small-molecule targeting BCAT1-mediated BCAA metabolism inhibits the activation of SHOC2-RAS-ERK to induce apoptosis of Triple-negative breast cancer cells. In Journal of advanced research, , . doi:10.1016/j.jare.2024.10.021. https://pubmed.ncbi.nlm.nih.gov/39490614/