Serine hydroxymethyltransferase, mitochondrial (SHMT2)

Human serine hydroxymethyltransferase 2 (SHMT2) is a critical mitochondrial enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate [1, 3]. This reaction serves as a primary source of one-carbon units essential for the de novo biosynthesis of purines and thymidylate, which are necessary for DNA replication and repair [11, 12]. Beyond its role in nucleotide synthesis, SHMT2 is vital for maintaining cellular redox balance by supporting the production of NADPH and glutathione, thereby protecting cells from oxidative stress, particularly under hypoxic conditions [1, 15]. SHMT2 is frequently overexpressed in a variety of malignancies, including hepatocellular carcinoma, breast cancer, and gliomas, where its upregulation is strongly associated with rapid cell proliferation, tumor aggressiveness, and poor clinical prognosis [3, 9, 13]. Due to its central role in metabolic reprogramming, SHMT2 has emerged as a significant therapeutic target in oncology [1, 15]. Current drug development efforts focus on small-molecule inhibitors like SHIN1 and SHIN2, as well as multi-targeted antifolates, which aim to disrupt cancer cell metabolism and induce apoptosis by depleting essential biosynthetic precursors [6, 15, 16].

Other names

Mitochondrial serine hydroxymethyltransferaseGlycine hydroxymethyltransferaseSHMTmSHMT

Inhibition of SHMT2 enzyme activity, typically by binding to the folate-binding pocket or active site, which disrupts the conversion of serine to glycine and the generation of one-carbon units required for nucleotide synthesis and redox homeostasis [1, 4, 6, 15].