| SHMT2 is the mitochondrial isoform of serine hydroxymethyltransferase in the PLP-dependent SHMT family, where it catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and 5,10‑methylenetetrahydrofolate and thereby supplies mitochondrial one‑carbon units that feed nucleotide synthesis, mitochondrial translation, and redox control. The enzyme functions as a homotetramer with a conserved active site built around pyridoxal 5′‑phosphate that binds serine, performs α‑carbon deprotonation, and transfers the one‑carbon unit onto tetrahydrofolate, generating 5,10‑methylenetetrahydrofolate that is subsequently processed by mitochondrial MTHFD enzymes and routed into de novo thymidylate and purine biosynthesis as well as formate export to the cytosolic folate cycle. Within the mitochondrial one‑carbon network, SHMT2 sits upstream of thymidylate synthase and purine biosynthetic reactions and is also required to generate the 5,10‑methylenetetrahydrofolate used for taurinomethyluridine modification at wobble positions of specific mitochondrial tRNAs, linking its catalytic activity directly to maintenance of mitochondrial DNA integrity and efficient mitochondrial translation. Loss or reduction of SHMT2 impairs mitochondrial folate accumulation and formate production, decreases mitochondrial membrane potential and basal respiration, and leads to accumulation of the purine intermediate AICAR, reduced purine nucleotide pools, and slowed proliferation, while overexpression increases proliferation and tumor growth and induces a glycine‑auxotrophic state in which exogenous glycine becomes critical to sustain nucleotide synthesis. In Lung, colorectal, hepatocellular, renal, and breast cancers, SHMT2 is upregulated and forms part of a broader one‑carbon metabolic rewiring that channels serine-derived one‑carbon units into nucleotide biosynthesis and NADPH generation, supports rapid DNA replication, and buffers oxidative stress, and pan‑cancer analyses correlate high SHMT2 expression with poor prognosis and proliferation‑associated transcriptional programs. SHMT2 also acts as a key enzymatic node in mitochondrial one‑carbon metabolism that is druggable with small‑molecule active‑site ligands and allosteric inhibitors, and preclinical work demonstrates that selective SHMT2 blockade depletes nucleotide pools, triggers DNA replication stress, and synergizes with antifolate or thymidylate synthase–targeted therapies. |
