SHMT1

SHMT1 (serine hydroxymethyltransferase 1) is the cytosolic isoform of serine hydroxymethyltransferase and a pyridoxal phosphate-dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate into glycine and 5,10-methylenetetrahydrofolate, thereby supplying one-carbon units required for thymidylate, purine, and methionine biosynthesis within cellular folate metabolism^[1][2]. Mechanistically, SHMT1 functions as a central component of cytosolic one-carbon metabolism, linking serine-glycine interconversion to nucleotide production and supporting cellular proliferation through regulation of folate-dependent biosynthetic pathways^[3][4]. In disease-associated settings, altered dependence on cytosolic one-carbon flux has been linked to tumor growth, and experimental suppression of SHMT1 impairs pyrimidine biosynthesis and reduces tumor growth in vivo in models characterized by limited intracellular folate retention^[3]. Compared with the mitochondrial isoform SHMT2, which primarily supports mitochondrial one-carbon metabolism and is frequently upregulated in proliferating and malignant tissues, SHMT1 predominantly operates in the cytosolic compartment and contributes to distinct metabolic requirements of folate-mediated biosynthesis^[4][5]. Functional overlap between SHMT isoforms has been reported in thymidylate biosynthesis, yet their subcellular localization and metabolic context remain different, emphasizing the importance of isoform-specific investigation in experimental systems^[6]. For research applications, SHMT has emerged as a pharmacological target in one-carbon metabolism, and small-molecule inhibitors such as (+)-SHIN-1 have been developed to inhibit human SHMT activity, providing useful tools for mechanistic studies of folate-dependent metabolism and cancer-associated metabolic reprogramming^[7][8].