Methylthioadenosine phosphorylase (MTAP)

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and purine salvage pathways, responsible for converting 5'-methylthioadenosine (MTA) into adenine and 5-methylthioribose-1-phosphate. In healthy cells, this process prevents the accumulation of MTA and ensures the recycling of essential metabolites. The MTAP gene is located on chromosome 9p21.3, a region frequently deleted in approximately 15% of all human cancers because of its proximity to the CDKN2A/B tumor suppressor locus. The loss of MTAP leads to a significant accumulation of its substrate, MTA, which acts as a potent endogenous inhibitor of protein arginine methyltransferase 5 (PRMT5). This metabolic vulnerability creates a therapeutic window known as synthetic lethality, where MTAP-deleted tumor cells become hypersensitive to the pharmacological inhibition of PRMT5 or methionine adenosyltransferase 2A (MAT2A). Consequently, drug development efforts are focused on identifying small molecules that selectively target these vulnerabilities in MTAP-deficient malignancies while sparing normal, MTAP-proficient cells.

Other names

5'-methylthioadenosine phosphorylaseMTA phosphorylaseMeSAdo phosphorylaseS-methyl-5'-adenosine phosphorylase

Synthetic lethality via PRMT5 inhibition or MAT2A inhibition in MTAP-deleted cells