Gart, short for Glycinamide ribonucleotide transformylase, is a trifunctional polypeptide with phosphoribosylglycinamide formyltransferase, phosphoribosylglycinamide synthetase, and phosphoribosylaminoimidazole synthetase activity. It is crucial for de novo purine biosynthesis and is highly conserved in vertebrates. Gart is involved in multiple signaling pathways, such as the Wnt/β -catenin pathway, and plays important roles in various biological processes including cell proliferation, migration, and energy homeostasis [1,2,3,4,5,6]. Genetic models, like gene knockout (KO) or conditional knockout (CKO) mouse models, can be valuable for studying Gart's functions in vivo.

In colorectal cancer, Gart has a novel methyltransferase function with its enzymatic activity center at the E948 site. It enhances the stability of RUVBL1 through methylating its K7 site, aberrantly activating the Wnt/β -catenin signaling pathway to promote tumor stemness. Pemetrexed, a GART -targeting compound, can suppress tumor growth [1]. In multiple myeloma, GART promotes cell proliferation and tumor stemness by activating the HSP90α/CDK6/β -catenin axis, and its inhibitor pemetrexed can suppress cell proliferation and tumor growth in a CDX model [4]. In non -small cell lung cancer, knockdown of GART inhibits cell proliferation and migration by inhibiting the activation of the PAICS -Akt -β -catenin pathway [6]. In colitis, inhibition of GART induces cellular apoptosis and suppresses the migration of intestinal epithelial cells through the MEKK3 -MKK3 -p38 MAPK pathway, affecting the p53 and PUMA regulation [5]. In breast cancer, inhibition of GART, a key enzyme in the purine de novo biosynthetic pathway, induces ERα degradation and prevents cell proliferation [7].

In conclusion, Gart is essential for de novo purine biosynthesis and is involved in multiple signaling pathways. Studies using KO/CKO mouse models (or other in vivo models inferred from the findings) have revealed its significant roles in various diseases, including colorectal cancer, multiple myeloma, non -small cell lung cancer, colitis, and breast cancer. Understanding Gart's functions provides potential therapeutic targets for these diseases.