Anti-MAT2A monoclonal antibody, clone FQS21507

S-adenosylmethionine (SAM), generated from methionine and adenosine triphosphate (ATP) catalyzed by methionine adenosyltransferase (MAT), is usually used as the major methyl donor in mammals. The MAT family includes MAT1A, MAT2A and MAT2B, of which MAT2A is mainly located in extrahepatic cells and is responsible for SAM synthesis in extrahepatic normal and cancerous tissues. Although SAM selectively promotes apoptosis in hepatocellular carcinoma and colorectal cancer cells without affecting apoptosis in normal hepatocytes and intestinal epithelial cells, it can act as a methyl donor, affecting the methylation levels of downstream substrates and altering gene expression thereby promoting cancer development. For example, in mammalian mTORC1-driven cancers, mTORC1 elevates SAM levels and provides substrates for RNA methyltransferases, thereby promoting mRNA methylation and cancer cell proliferation. Upon provision of methyl, SAM is converted to S-adenosylhomocysteine (SAH), which in turn is cleaved by SAH hydrolase into homocysteine (Hcy) and adenosine.

Figure 1. MAT-catalysed reaction
(Source: Schlesier J, et al. 2013)

MAT2A is regulated by SAM while synthesizing SAM, and high concentrations of SAM inhibit the utilization of methionine and ATP by MAT2A. The concentration of SAM correlates with post-transcriptional modification of MAT2A mRNA and MAT2A expression. In addition, MAT2B inhibited MAT2A activity when SAM concentration was high; however, MAT2B promoted MAT2A activity under conditions of SAM deficiency. Therefore, when MAT2A is inhibited and the concentration of SAM decreases, the level of MAT2A protein is compensatingly increased, thus stimulating SAM synthesis to maintain the corresponding balance.

Studies have shown that MAT2A plays an important role in tumor development, not only by mediating cancer metabolism to promote tumor development, but also by acting as a transcriptional cofactor and other direct promoters of cancer development. Therefore, MAT2A is regarded as a potential target for cancer therapy, especially after the discovery of the synthetic lethal effect of MAT2A inhibition and methylthioadenosine phosphorylase (MTAP) deficiency in recent years, which has further promoted the development of MAT2A inhibitors. Currently, this class of inhibitors consists mainly of substrate-competitive and metabolic inhibitors for the treatment of patients with MTAP-deficient tumors, and a large number of studies have been devoted to exploring combinatorial strategies.

Anti-methionine adenosyltransferase 2A monoclonal antibody