Protein arginine N-methyltransferase 3 (PRMT3) is a cytoplasmic enzyme that utilizes S-adenosyl-L-methionine (AdoMet) to methylate specific proteins, most of which contain GAR (glycine-arginine rich) motifs. PRMT3 has been shown to play a role in the proper maturation of the 80S ribosome by binding to and catalyzing the methylation of rpS2, a component of the 40S ribosomal subunit[2]. The expression of lipogenic proteins was increased by PRMT3 overexpression, but decreased by PRMT3 silencing and use of the PRMT3 knockout (KO) mouse embryonic fibroblast cell line. PRMT3 also increased the transcriptional activity of LXRα by directly binding with LXRα in a methylation-independent manner[3]. In cells, PRMT3 overexpression triggered metabolic reprogramming and enhanced glycolysis and mitochondrial respiration simultaneously in a glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-dependent manner. PRMT3-overexpressing cancer cells were addicted to GAPDH-mediated metabolism and sensitive to the inhibition of GAPDH and mitochondrial respiration. The combination of inhibitors of GAPDH and oxidative phosphorylation induced a synergistic inhibition on cellular growth in vitro and in vivo[4]. XY1 is a very close analogue of SGC707 (a potent, selective, and non-competitive inhibitor of PRMT3 with IC50 of 31 nM), but XY1 is completely inactive against PRMT3 at concentrations as high as 100 μM. XY1 contains a naphthyl group replacing the isoquinoline group, lacks the key hydrogen bond with T466. The naphthyl ring of XY1 could act as a weak hydrogen-bond acceptor, but this should come with a substantial enthalpic penalty. The more than 1000-fold potency loss of XY1 compared with SGC707 supports this analysis. SGC707 and XY1 are a pair of excellent tools for the biomedical community to further elucidate biological functions and disease associations of PRMT3[5].
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