Serine hydroxymethyltransferase 2 (SHMT2) (SHMT2)

Serine hydroxymethyltransferase 2 (SHMT2) is a mitochondrial enzyme that plays a central role in one-carbon metabolism by catalyzing the reversible conversion of L-serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate [1, 4]. This reaction serves as the primary source of one-carbon units in the mitochondria, which are essential for the de novo synthesis of purines and thymidylate, as well as for mitochondrial translation and redox homeostasis through NADPH production [2, 5]. SHMT2 is frequently overexpressed in a wide range of malignancies, including breast, lung, and colorectal cancers, where its activity supports the high metabolic demands of rapidly proliferating cells and correlates with poor patient prognosis [4, 16]. Beyond its metabolic role, SHMT2 also functions as a component of the BRISC complex, contributing to immune regulation and deubiquitination processes [2, 17]. Therapeutic targeting of SHMT2 is an active area of research, with small-molecule inhibitors like SHIN1 and SHIN2 demonstrating the ability to impair tumor growth by disrupting nucleotide pools and inducing oxidative stress [1, 12]. However, the development of SHMT2-targeted therapies faces challenges such as the need for mitochondrial penetration and potential toxicity arising from the disruption of essential metabolic pathways in normal tissues [4, 14].

Other names

mSHMTGLYASerine methylaseGlycine hydroxymethyltransferaseHEL-S-51eNEDCASB

Inhibition of the enzymatic conversion of L-serine and tetrahydrofolate to glycine and 5,10-methylenetetrahydrofolate, thereby depleting one-carbon units required for nucleotide synthesis and redox maintenance.