SHMT2

SHMT2 (serine hydroxymethyltransferase 2) is the mitochondrial isoform of serine hydroxymethyltransferase and catalyzes the conversion of serine to glycine while generating one-carbon units that enter mitochondrial folate-mediated one-carbon metabolism^[12][13]. This reaction supports nucleotide biosynthesis, methylation-related metabolism, redox homeostasis, and other anabolic processes required for cellular growth and proliferation^[12][1][2]. Mechanistically, SHMT2 functions at the entry point of the mitochondrial serine catabolic pathway and supplies tetrahydrofolate-conjugated one-carbon units that contribute to downstream metabolic reactions and mitochondrial homeostasis^[3][4]. Therefore, SHMT2 has emerged as a central regulator of mitochondrial one-carbon metabolism, a pathway increasingly linked to metabolic adaptation in rapidly proliferating cells and tumors^[2][5]. In disease contexts, elevated SHMT2 expression has been reported across multiple cancers and is associated with tumor progression, cellular proliferation, and unfavorable clinical features^[1][6][7]. Experimental studies further demonstrate that SHMT2 supports mitochondrial respiration and proliferation under metabolic stress conditions, whereas SHMT2 inhibition compromises mitochondrial function and suppresses tumor growth in vitro and in vivo^[3][7][8]. Compared with the related cytosolic isoform SHMT1, which primarily operates in the cytoplasm, SHMT2 is localized to mitochondria and is considered the dominant enzyme driving serine catabolism and growth-associated one-carbon flux in many cancer models^[13][6]. For experimental applications, SHMT2 has attracted substantial interest as a therapeutic target, and both small-molecule and RNA-based inhibitory strategies have shown the ability to disrupt SHMT2-dependent metabolism and reduce cancer cell viability or tumor progression in preclinical models^[5][9][10].

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