{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHMT2, the mitochondrial isoform of serine hydroxymethyltransferase, plays a central role in rewiring cancer cell metabolism by catalyzing the conversion of serine into glycine and a one‐carbon unit that fuels nucleotide biosynthesis. In hypoxic or nutrient‐poor tumor microenvironments—such as in gliomas—upregulation of SHMT2 limits pyruvate kinase activity and reduces oxygen consumption, facilitating cancer cell survival in ischemic regions, while in bladder cancer its increased expression enhances glycine availability and purine synthesis to sustain proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRegulation of SHMT2 activity is tightly linked to post‐translational modifications that affect its oligomeric state and enzymatic performance. In colon cancer models, genetic disruption of SHMT2 (along with its cytosolic counterpart) blocks tumor xenograft formation, underscoring its importance for cancer cell growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, SHMT2 is activated via SIRT5‐mediated desuccinylation, which enhances serine catabolism, while SIRT3 controls its acetylation state—specifically at lysine 95—thereby modulating tetramer assembly, catalytic efficiency, and stability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Structural studies also reveal that binding of its cofactor PLP triggers a dimer‐to‐tetramer transition, distinguishing its regulation from that of the cytosolic enzyme."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its metabolic function, SHMT2 contributes to diverse aspects of tumor progression. Its activity is essential for supplying one‐carbon units needed for nucleotide synthesis in rapidly proliferating cancers, and elevated SHMT2 expression correlates with increased aggressiveness and poorer prognosis in breast and liver cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, SHMT2 can interface with non-metabolic pathways by binding to and modulating complexes such as BRISC, thereby influencing deubiquitylase activity and inflammatory signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Its role is also implicated in fibrotic contexts, where TGF-β induction of SHMT2 supports the heightened glycine requirements for collagen synthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dohoon Kim, Brian P Fiske, Kivanc Birsoy, et al. 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