Methionine adenosyltransferase 2 alpha (MAT2A) (MAT2A)

Methionine adenosyltransferase 2 alpha (MAT2A) is the rate-limiting enzyme that catalyzes the synthesis of S-adenosylmethionine (SAM), the cell's universal methyl donor, from methionine and ATP [1, 2, 11]. SAM is essential for the methylation of DNA, RNA, and proteins, playing a fundamental role in gene expression, signal transduction, and the methionine cycle [3, 9, 15]. The enzyme is often overexpressed in various human cancers to support the high metabolic demands of rapid proliferation and epigenetic reprogramming [1, 5, 10]. In particular, MAT2A has emerged as a major therapeutic target for synthetic lethality in tumors harboring the deletion of the methylthioadenosine phosphorylase (MTAP) gene [4, 6]. MTAP loss leads to the accumulation of methylthioadenosine (MTA), which partially inhibits the methyltransferase PRMT5, rendering these cells uniquely sensitive to further SAM depletion [4, 11]. Clinical candidates like IDE397 and AG-270 are designed to selectively inhibit MAT2A, thereby disrupting the survival of MTAP-deficient cancer cells while minimizing effects on normal tissues [11]. The development of MAT2A inhibitors represents a precision medicine approach that leverages metabolic vulnerabilities created by specific genetic alterations in cancer [1, 4].

Other names

S-adenosylmethionine synthetaseMAT2MATIIMethionine adenosyltransferase IIAMS2MAT-II

MAT2A inhibition leading to intracellular depletion of S-adenosylmethionine (SAM) and consequent disruption of methyltransferase-mediated epigenetic regulation and protein function [3, 4, 11]