5'-Methylthioadenosine-Protein arginine methyltransferase 5 complex (MTA-PRMT5)

The 5'-Methylthioadenosine-Protein arginine methyltransferase 5 complex (MTA-PRMT5) is a specific biochemical state of the PRMT5 enzyme that serves as a precision medicine target in oncology [Kryukov et al., 2016, Science]. This complex is characterized by the binding of the metabolite 5'-methylthioadenosine (MTA) to the active site of PRMT5, a phenomenon that occurs predominantly in cancer cells with homozygous deletion of the Methylthioadenosine Phosphorylase (MTAP) gene [Marjon et al., 2016, Cell Reports]. MTAP deletion, which occurs in approximately 15% of human cancers due to its proximity to the CDKN2A locus, leads to the accumulation of MTA, which then occupies the S-adenosylmethionine (SAM) binding pocket of PRMT5 [Fedoriw et al., 2022, Cancer Discovery]. Modern therapeutic strategies utilize "MTA-cooperative" inhibitors, such as MRTX1719 and AMG 193, which selectively bind to this MTA-PRMT5 complex rather than the SAM-bound form found in normal cells [Smith et al., 2022, Cancer Discovery]. This selectivity allows for the targeted inhibition of PRMT5 activity—essential for RNA splicing and gene expression—specifically within tumor cells, inducing synthetic lethality [Muller et al., 2023, Nature Reviews Drug Discovery]. By sparing PRMT5 in healthy tissues, these inhibitors aim to overcome the dose-limiting hematological toxicities, such as anemia and thrombocytopenia, that hindered earlier non-selective PRMT5 inhibitors [NCT05245500; NCT05094336]. PRMT5 itself is a type II arginine methyltransferase that plays a critical role in the assembly of the spliceosome and the methylation of histone H4R3, making its selective inhibition a potent strategy for disrupting cancer cell homeostasis.

Other names

PRMT5-MTA complexMTA-bound PRMT5MTAP-deficient PRMT5 targetMTA-PRMT5 complex

MTA-cooperative inhibition of PRMT5