Affinage

SHMT2

Serine hydroxymethyltransferase, mitochondrial · UniProt P34897

Length
504 aa
Mass
56.0 kDa
Annotated
2026-06-10
81 papers in source corpus 36 papers cited in narrative 38 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHMT2 is a pyridoxal-5'-phosphate-dependent serine hydroxymethyltransferase that catalyzes the first committed step of mitochondrial one-carbon metabolism, converting serine and tetrahydrofolate to glycine and one-carbon-laden THF derivatives that feed multiple downstream pathways (PMID:29452640). The 10-formyl-THF it generates is used by MTFMT to produce formylmethionyl-tRNAs required for mitochondrial translation initiation, and SHMT2-null cells fail to maintain these tRNA pools and lose mitochondrially encoded proteins (PMID:29452640); Shmt2 knockout is embryonic-lethal with mitochondrial respiratory defects traced to deficient fMet-tRNA, and reduced expression impairs mitochondrial folate accumulation, elevates mtDNA uracil content, and disrupts mitochondrial dTMP synthesis and membrane potential (PMID:29323231, PMID:34383924). Loss of one-carbon output collapses NADPH and glutathione pools, driving ROS accumulation, cytochrome c release and intrinsic apoptosis that formate supplementation rescues (PMID:35422087). The glycine and one-carbon flux SHMT2 produces couples its metabolism to growth signaling and chromatin state: glycine activates Akt/mTOR to drive liver regeneration and lipogenesis (PMID:30964837, PMID:35212811), while SAM derived from one-carbon units fuels DNA/histone methylation that silences tumor suppressors and supports m6A RNA modification of oncogenic transcripts (PMID:33569544, PMID:37932821). SHMT2 activity is tuned by post-translational modification, including SIRT5-mediated desuccinylation at K280 that directly activates the enzyme (PMID:29180469) and MAPK1 phosphorylation at Ser90 that stabilizes the protein by blocking STUB1-dependent ubiquitination, thereby sustaining SAM-dependent m6A modification (PMID:38460155). Beyond catalysis, SHMT2 serves as the targeting subunit of the BRISC/BRCC36 K63-deubiquitylase complex regulating substrate ubiquitylation and type I interferon receptor signaling (PMID:29791506), and a defatty-acylation event mediated by HDAC11 modulates IFNAR ubiquitination independently of enzymatic activity (PMID:30819897). Crystal structures define the active-site architecture engaged by antifolates (lometrexol, pemetrexed) and by glycyrrhetinic acid derivatives at the folate pocket, and metformin acts as a PLP-competitive inhibitor that destabilizes catalytic oligomers (PMID:31127856, PMID:35602963, PMID:34439169).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2009 High

    Established that SHMT2 is not strictly mitochondrial: an alternative transcript lacking exon 1 produces a cytoplasmic/nuclear isoform that contributes to nuclear de novo thymidylate synthesis, defining isoform-specific compartmentalization.

    Evidence Nuclear import assays, subcellular fractionation, and nuclear thymidylate activity assays in Shmt1-/- mice

    PMID:19513116

    Open questions at the time
    • Relative physiological contribution of the cytoplasmic isoform versus mitochondrial isoform in normal tissues not quantified
    • Regulation of the alternative transcript not defined
  2. 2015 High

    Showed SHMT2 confers a survival advantage under ischemia by limiting PKM2 activity and oxygen consumption, while creating a metabolic dependency on GLDC to clear toxic glycine catabolites.

    Evidence Genetic knockdown/overexpression, metabolic tracing, and xenografts in glioma cells

    PMID:25855294

    Open questions at the time
    • Molecular basis of SHMT2-PKM2 crosstalk not resolved
    • Generality of GLDC co-dependency across tumor types untested
  3. 2018 High

    Resolved the essential mitochondrial role of SHMT2: it supplies 10-formyl-THF for fMet-tRNA synthesis required for mitochondrial translation initiation, distinguishing this from cytoplasmic one-carbon functions by genetic epistasis.

    Evidence SHMT2 knockout cell lines, isotope tracing, genetic epistasis, fMet-tRNA pool measurement; complemented by embryonic-lethal Shmt2 knockout mice with respiratory defects

    PMID:29323231 PMID:29452640

    Open questions at the time
    • How fMet-tRNA depletion propagates to specific OXPHOS complex assembly defects not fully mapped
    • Tissue-specific thresholds for translation failure unknown
  4. 2018 High

    Defined a non-enzymatic moonlighting role: SHMT2 (with SHMT1) is an adaptor for the BRCC36/BRISC K63-deubiquitinase, linking one-carbon enzymes to ubiquitin signaling and substrate turnover.

    Evidence DiffPOP proteomics, mass spectrometry, siRNA knockdown, and Co-IP using HIV-1 Tat as a model substrate

    PMID:29791506

    Open questions at the time
    • Endogenous physiological BRISC substrates beyond viral Tat not enumerated here
    • Structural basis of SHMT2 targeting within BRISC not resolved in this study
  5. 2017 High

    Identified post-translational control of catalysis: SIRT5 desuccinylates SHMT2 at K280 to directly activate it, establishing succinylation as an enzymatic on/off switch with tumor-growth consequences.

    Evidence Co-IP, in vitro desuccinylation, K280 mutagenesis, activity assays, and xenografts

    PMID:29180469

    Open questions at the time
    • The succinyltransferase that opposes SIRT5 not identified in this study
    • Stoichiometry of K280 modification in vivo unknown
  6. 2019 High

    Demonstrated an enzymatic-activity-independent regulatory function: HDAC11 defatty-acylates SHMT2 to control IFNAR ubiquitination and surface levels, coupling SHMT2 to type I interferon signaling.

    Evidence Proteomics substrate ID, biochemical defatty-acylation validation, and HDAC11 knockdown in cells and mice

    PMID:30819897

    Open questions at the time
    • Mechanistic link between SHMT2 acylation state and IFNAR ubiquitin machinery not fully detailed
    • Relationship to the BRISC adaptor function not integrated
  7. 2019 High

    Provided structural basis for pharmacological targeting by solving SHMT2-antifolate and SHMT2-glycyrrhetinic acid co-crystal structures, mapping the folate-binding active site and inhibitor hydrogen-bond networks.

    Evidence X-ray crystallography of inhibitor complexes with in vitro inhibition assays and chemical proteomics target ID

    PMID:31127856 PMID:35602963

    Open questions at the time
    • Selectivity over SHMT1 incomplete for several compounds
    • Cellular target engagement at therapeutic doses not established in these structural studies
  8. 2020 High

    Connected SHMT2 metabolic output to epigenetic reprogramming: SAM generated from serine metabolism drives DNA/histone methylation that silences tumor suppressors, cooperating with BCL2 in lymphomagenesis.

    Evidence BCL2-cooperation mouse models, SHMT2 perturbation, and DNA/histone methylation analysis

    PMID:33569544

    Open questions at the time
    • Specificity of SAM-driven methylation toward particular loci not mechanistically explained
    • Quantitative contribution of mitochondrial versus cytosolic SAM unresolved
  9. 2020 Medium

    Revealed cytoplasmic scaffolding roles distinct from catalysis: SHMT2 binds cytosolic p53 to block its HDM2-mediated degradation and suppress autophagy, and binds β-catenin via K64 to stabilize it.

    Evidence Co-IP, siRNA knockdown, K64 mutagenesis, and autophagy rescue experiments in cancer cells

    PMID:33456583 PMID:33990700

    Open questions at the time
    • Single-lab Co-IP findings without reciprocal structural validation
    • How a predominantly mitochondrial protein accesses cytosolic p53/β-catenin pools not reconciled
  10. 2021 High

    Defined metformin's anticancer mechanism on SHMT2 as PLP-competitive inhibition that destabilizes catalytic oligomers, with SHMT2-null cells rendered insensitive to the drug.

    Evidence Competitive binding with recombinant enzyme, docking/MD, differential scanning fluorimetry, CRISPR knockout, and isotope tracing

    PMID:34439169

    Open questions at the time
    • Contribution of SHMT2 inhibition relative to metformin's other targets in vivo not quantified
    • Affinity relative to physiological PLP not benchmarked
  11. 2021 High

    Extended SHMT2's mtDNA-protective role in vivo: reduced expression impairs mitochondrial folate accumulation and dramatically increases uracil misincorporation in liver mtDNA, linking one-carbon flux to mitochondrial genome integrity.

    Evidence Shmt2+/- mice with mitochondrial folate quantification, mtDNA uracil measurement, and respiration assays

    PMID:34383924

    Open questions at the time
    • Threshold of folate/dTMP loss causing functional mtDNA mutation not defined
    • Reversibility of mtDNA damage upon SHMT2 restoration untested
  12. 2022 High

    Established glycine/formate output as an upstream input to mTOR signaling, with SHMT2 inhibition collapsing mTOR, triggering autophagic TCF3 degradation and disrupting tonic BCR signaling in lymphoma.

    Evidence Genome-scale CRISPR screens, pharmacological inhibitors, metabolite measurement, and mTOR/TCF3/BCR readouts in vitro and in vivo

    PMID:34624079

    Open questions at the time
    • Direct molecular sensor linking formate/glycine to mTOR not identified
    • Generalizability beyond Burkitt lymphoma not established
  13. 2022 Medium

    Linked SHMT2 to SAM-dependent m6A RNA modification, showing it stabilizes oncogenic transcripts (PPAT) through IGF2BP2-dependent m6A, broadening its epigenetic reach to the epitranscriptome.

    Evidence SHMT2 perturbation, m6A assays, SAM measurement, and IGF2BP2 interaction studies

    PMID:35798250

    Open questions at the time
    • Single-lab finding; direct causality between SAM levels and target-specific m6A not isolated from global methylation effects
  14. 2023 Medium

    Generalized the m6A-stabilization mechanism to c-myc mRNA, with SHMT2-driven SAM enhancing METTL3/IGF2BP2-dependent m6A to promote esophageal cancer progression and immune escape.

    Evidence MeRIP, SHMT2 silencing, SAM measurement, writer/eraser/reader knockdown, and xenografts

    PMID:37932821

    Open questions at the time
    • Single-lab; specificity of SHMT2-derived SAM for individual transcripts not mechanistically dissected
  15. 2024 High

    Identified MAPK1-mediated Ser90 phosphorylation as a stabilizing modification that blocks STUB1-dependent degradation, coupling a kinase signal to SHMT2 protein levels and downstream SAM/m6A output.

    Evidence Compound screen, phospho-proteomics, Ser90 mutagenesis, ubiquitination and STUB1 interaction assays, MeRIP-Seq and RNA-Seq

    PMID:38460155

    Open questions at the time
    • Phosphatase opposing Ser90 not identified
    • Whether MAPK1-SHMT2 axis operates in non-cancer contexts unknown
  16. 2024 Medium

    Uncovered an RNA-binding moonlighting activity: SHMT2 directly binds GAGGG motifs in the ADAM10 5'UTR to enhance eIF2-dependent translation initiation, independent of its catalytic role.

    Evidence RNA pulldown/RIP, in vitro translation, 5'UTR reporter assays, and APP/PS1 mouse model

    PMID:38183387

    Open questions at the time
    • Single-lab; breadth of SHMT2's RNA target repertoire beyond ADAM10 not defined
    • Structural basis of RNA recognition not resolved
  17. 2025 Medium

    Provided structural and mechanistic confirmation that SHMT2 is the targeting subunit of a 16-subunit BRISC dimer, with molecular glues that block SHMT2-BRCC36 interactions selectively suppressing interferon-stimulated gene expression.

    Evidence Biochemical and structural characterization of inhibitor-bound BRISC dimer with structure-guided mutagenesis (preprint)

    Open questions at the time
    • Preprint not peer-reviewed
    • Physiological regulation of SHMT2's partitioning between BRISC and metabolic roles not addressed
  18. 2025 Medium

    Implicated SHMT2 loss in neurodegeneration via homocysteine accumulation that engages AARS1 and suppresses histone lactylation, with overexpression rescuing degeneration in Huntington's disease models.

    Evidence RNA-seq/metabolomics in HD organoids and YAC128 mice, SHMT2 manipulation, homocysteine and histone lactylation measurement, motor testing

    PMID:41805887

    Open questions at the time
    • Single-lab; the homocysteine-AARS1-lactylation chain is novel and lacks independent confirmation
    • Direct relevance to human HD pathology not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SHMT2's catalytic, scaffolding (BRISC, p53, β-catenin), and RNA-binding activities are partitioned and prioritized within and outside the mitochondrion under physiological conditions remains unresolved.
  • No unified model reconciles compartment-specific moonlighting functions with the dominant mitochondrial enzymatic role
  • Most non-canonical interactions rest on single-lab Co-IP without reciprocal or structural validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 2 GO:0140313 molecular sequestering activity 2 GO:0003723 RNA binding 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-4839726 Chromatin organization 2 R-HSA-9612973 Autophagy 2
Partners
BRCC36CTNNB1MAPK1SAMM50SETSIRT5STUB1TP53
Complex memberships
BRISC/BRCC36 deubiquitylase complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 SHMT2 activity limits pyruvate kinase (PKM2) activity and reduces oxygen consumption, conferring a survival advantage under ischemic conditions; excess glycine not cleared by GLDC (glycine decarboxylase) is converted to toxic aminoacetone and methylglyoxal, making high-SHMT2 cells dependent on GLDC activity. Genetic knockdown/overexpression, metabolic tracing, cell viability assays in glioma cells and mouse xenograft models Nature High 25855294
2017 SIRT5 desuccinylates SHMT2 at lysine 280, directly activating its enzymatic activity; hypersuccinylation at K280 inhibits SHMT2 enzymatic activity and suppresses tumor cell growth in vitro and in vivo. Co-immunoprecipitation, in vitro desuccinylation assay, site-directed mutagenesis (K280), enzymatic activity assays, xenograft tumor models Cancer research High 29180469
2018 SHMT2 catalyzes the first step of mitochondrial one-carbon metabolism, producing 10-formyl-THF used by MTFMT to generate formylmethionyl-tRNAs required for proper mitochondrial translation initiation; SHMT2-null cells fail to maintain formylmethionyl-tRNA pools and mitochondrially encoded proteins. Genetic screens, SHMT2 knockout cell lines, isotope tracing, genetic epistasis (impaired cytoplasmic one-carbon metabolism or blockade of one-carbon efflux does not phenocopy SHMT2 loss), measurement of formylmethionyl-tRNA pools Molecular cell High 29452640
2009 SHMT2 encodes two transcripts: one encoding a protein that localizes exclusively to mitochondria (SHMT2), and a second lacking exon 1 (SHMT2alpha) that encodes a protein localizing to the cytoplasm and nucleus during S-phase, providing redundancy for nuclear de novo thymidylate biosynthesis. Nuclear import assays, subcellular fractionation, activity assays in isolated nuclei from Shmt1-/- mice, demonstration of residual thymidylate synthesis activity attributable to SHMT2alpha PloS one High 19513116
2019 HDAC11 acts as a lysine defatty-acylase on SHMT2 (>10,000-fold more efficient than its deacetylase activity); defatty-acylation of SHMT2 does not affect its enzymatic activity but instead regulates type I IFN receptor (IFNAR) ubiquitination and cell surface levels, thereby modulating type I interferon signaling. Proteomics identification of substrate, biochemical validation of defatty-acylation, enzyme activity assays, HDAC11 knockdown in cell culture and mice, measurement of IFNAR ubiquitination and surface levels Proceedings of the National Academy of Sciences of the United States of America High 30819897
2018 SHMT2 (together with SHMT1) serves as an adaptor for the BRCC36 K63Ub-specific deubiquitinase in the BRISC complex, regulating HIV-1 Tat K63-ubiquitylation and its destruction via autophagy; knockdown of SHMT1/2 or BRCC36 increases Tat K63Ub-dependent autophagic degradation. DiffPOP proteomics, mass spectrometry, siRNA knockdown, point mutation of Tat lysines, co-immunoprecipitation PLoS pathogens High 29791506
2019 Crystal structures of human SHMT2 bound to antifolates (lometrexol and pemetrexed) reveal the active site architecture; lometrexol is the most potent hSHMT1/2 inhibitor among the antifolates tested, with distinct hydrogen bond networks for each compound at the highly conserved active site. X-ray crystallography of SHMT2-antifolate complexes, in vitro enzyme inhibition assays FEBS letters High 31127856
2018 Shmt2 knockout mice are embryonic lethal after 13.5 dpc; fibroblasts from Shmt2-deficient embryos display mitochondrial respiration defects and growth retardation, linked to reduced production of N-formylmethionine-tRNA in mitochondria and consequent impaired mitochondrial translation. Genetic knockout in mice, measurement of mitochondrial respiration, cell growth assays, mechanistic link to mitochondrial fMet-tRNA production Scientific reports High 29323231
2021 Metformin acts as a PLP (pyridoxal-5'-phosphate)-competitive inhibitor of SHMT2, occupying the PLP-binding cavity and destabilizing catalytically active SHMT2 oligomers; CRISPR-based disruption of SHMT2 abolishes metformin's inhibitory effect on total SHMT activity, and SHMT2-null cells are insensitive to metformin's cytotoxic and antiproliferative effects. In vitro competitive binding assays with recombinant SHMT1/2, computational docking and molecular dynamics, differential scanning fluorimetry, CRISPR/Cas9 SHMT2 knockout, isotope tracing, viability assays Cancers High 34439169
2022 SHMT2 inhibition reduces intracellular glycine and formate levels, inhibiting the mTOR pathway and triggering autophagic degradation of the oncogenic transcription factor TCF3, thereby collapsing tonic BCR signaling essential for Burkitt lymphoma cell survival. CRISPR-Cas9 genome-scale screens, siRNA knockdown, pharmacological SHMT2 inhibitors, measurement of glycine/formate levels, mTOR pathway analysis, TCF3 protein levels, BCR signaling assays in vitro and in vivo Blood High 34624079
2020 SHMT2 inhibits autophagy by binding cytosolic p53 and preventing its interaction with HDM2, thereby blocking p53 ubiquitin-mediated degradation; depletion of SHMT2 promotes autophagy and inhibits apoptosis under 5-FU treatment in colorectal cancer cells. Co-immunoprecipitation (SHMT2-p53 interaction), siRNA knockdown, autophagy inhibitor rescue experiments, in vitro and in vivo models Oncogene Medium 33990700
2021 Cytoplasmic SHMT2 interacts with β-catenin via its lysine 64 residue, inhibiting ubiquitylation-mediated degradation of β-catenin and promoting its nuclear signaling; TCF4 interacts with β-catenin which in turn increases SHMT2 expression, forming a positive feedback loop. Co-immunoprecipitation, immunofluorescence, site-directed mutagenesis (K64), mRNA-seq, chromatin immunoprecipitation-qPCR, xenograft models Theranostics Medium 33456583
2020 SHMT2 elevates expression by catalyzing serine metabolism to generate SAM, which provides one-carbon units supporting S-adenosyl methionine synthesis; elevated SHMT2 induces changes in DNA and histone methylation, leading to promoter silencing of tumor suppressor genes SASH1 and PTPRM, initiating lymphomagenesis when cooperating with BCL2. Genetic mouse models (BCL2 cooperation), SHMT2 overexpression and inhibition, DNA/histone methylation analysis, lymphoma development assays Nature cancer High 33569544
2019 Crystal structures of glycyrrhetinic acid (GA) derivatives reveal that GA occupies the SHMT2 folate-binding pocket; chemical proteomics identifies SHMT2 as the mitochondrial target of GA, and GA binding inhibits SHMT2 activity, restricting mitochondrial OXPHOS and fatty acid β-oxidation. Chemical proteomics (target identification), in vitro and in vivo SHMT2 activity assays, X-ray crystallography of GA-SHMT2 complexes, SHMT2 knockout functional assays iScience High 35602963
2024 MAPK1 phosphorylates SHMT2 at Ser90, stabilizing SHMT2 by reducing STUB1-mediated ubiquitination and degradation; SHMT2-Ser90 dephosphorylation decreases S-adenosylmethionine levels, reducing m6A modification of global RNAs and accelerating degradation of oncogenic gene mRNAs. Compound library screen, phospho-proteomics, site-directed mutagenesis (Ser90), ubiquitination assays, STUB1 interaction studies, MeRIP-Seq, RNA-Seq Advanced science High 38460155
2024 SHMT2 acts as an RNA-binding protein that directly binds GAGGG motifs in the 5'UTR of ADAM10 mRNA, enhancing eIF2-dependent translation initiation; this function is independent of its canonical enzymatic role and mediates kenpaullone-induced ADAM10 upregulation. RNA pulldown/RIP, in vitro translation assays, SHMT2 overexpression/KD with 5'UTR reporter assays, in vivo APP/PS1 mouse model Advanced science Medium 38183387
2021 Reduced Shmt2 expression impairs mitochondrial folate accumulation by 25% and causes >20-fold increase in uracil content in liver mtDNA, impairing mitochondrial thymidylate (dTMP) synthesis and mitochondrial function (membrane potential, oxygen consumption rate). Shmt2+/- mouse model, mitochondrial folate quantification, uracil content measurement in mtDNA, mitochondrial respiration assays in mouse embryonic fibroblasts The Journal of nutrition High 34383924
2020 Loss of PYCR2 upregulates SHMT2, which is responsible for excess glycine synthesis in the brain; SHMT2 knockdown partially reverses the elevated cerebral glycine levels and rescues axonal beading and neurite length defects in Pycr2 knockout neurons. In situ neurotransmitter quantification, Pycr2 knockout mouse model, SHMT2 knockdown rescue experiments, crystal structure of PYCR2 Neuron High 32330411
2025 The oncoprotein SET physically interacts with mitochondrial SHMT2 and facilitates its enzymatic activity; loss of SET suppresses serine-derived one-carbon metabolic flux, and SET loss reduces intratumoral SHMT2 enzymatic activity in a Kras/Lkb1 lung tumor mouse model. Untargeted metabolomics, co-immunoprecipitation (SET-SHMT2 interaction), isotope tracing, SET knockout/overexpression, Kras/Lkb1 in vivo lung tumor model, SHMT2 enzymatic activity assays Proceedings of the National Academy of Sciences of the United States of America High 40339130
2022 SHMT2 deficiency impairs one-carbon unit production, reduces NADPH/NADP+, NADPH/NADP+, and GSH/GSSG ratios, leading to ROS accumulation, loss of mitochondrial membrane potential, cytochrome c release, Bcl-2 family protein translocation, and caspase-3 activation via the intrinsic apoptosis pathway; formate supplementation rescues the proliferation defect. SHMT2 knockout (CRISPR), ROS measurement, mitochondrial membrane potential assay, cytochrome c release, caspase-3 activation, formate/NAC rescue experiments, SHIN1 inhibitor treatment Cancer gene therapy Medium 35422087
2019 SHMT2 promotes liver regeneration by producing glycine, which activates the Akt/mTOR signaling pathway; SHMT2 knockdown reduces regenerative ability and glycine levels after partial hepatectomy, while SHMT2 overexpression enhances Akt/mTOR pathway activity in primary hepatocytes. In vivo partial hepatectomy mouse model with SHMT2 knockdown, SHMT2 overexpression in primary hepatocytes, glycine measurement, Akt inhibitor (LY294002) rescue Transplantation Medium 30964837
2022 SHMT2 knockdown reduces lipid accumulation in hepatocytes via the glycine-mediated mTOR/PPARγ pathway; decreased glycine production by SHMT2 KD downregulates mTOR/PPARγ signaling and lipogenesis genes, and pharmacological mTOR activation or PPARγ overexpression rescues the lipid accumulation defect. siRNA knockdown in primary mouse hepatocytes, glycine measurement, mTOR/PPARγ pathway analysis, pharmacological rescue (mTOR activator, PPARγ overexpression) Amino acids Medium 35212811
2024 SHMT2 catalyzes serine metabolism to produce SAM, which drives CpG island methylation at the PTEN promoter, suppressing PTEN expression and activating AKT signaling to promote papillary thyroid cancer metastasis; blocking AKT activation eliminates SHMT2's pro-metastatic effects. SHMT2 overexpression/knockdown, proteomic enrichment, AKT inhibitor rescue, methylation analysis of PTEN promoter CpG islands, in vitro and in vivo metastasis assays Cell death & disease Medium 38272883
2019 Proximity biotinylation (BioID) identifies ~48 mostly mitochondrial proteins associated with SHMT2, including ACOT2, GLUD1, and >20 proteins from mitochondrial respiratory complexes I and III; abundance of complex I and III proteins is inversely correlated with SHMT2 levels. BioID proximity biotinylation in vivo, mass spectrometry, HeLa inducible overexpression/knockdown, proteome and metabolite profiling PloS one Medium 32903271
2024 Samm50 interacts with Shmt2 (identified by Co-IP/mass spectrometry); Shmt2 acts as a crucial element in Samm50-mediated cardiac protection by hindering Bax transfer from cytoplasm to mitochondria and preventing caspase-3 activation; Shmt2 inhibition diminishes the protective effect of Samm50 overexpression against cardiac injury. Co-immunoprecipitation/mass spectrometry, Shmt2 overexpression/inhibition, Bax localization assay, caspase-3 activation, in vivo MI mouse model Cellular signalling Medium 38723737
2025 SUCLA2 negatively regulates lysine succinylation of SHMT2; SIRT5-mediated desuccinylation of SHMT2 inhibits Ang II-induced ferroptosis in renal cells, and the inhibitory effect of SUCLA2 overexpression on ferroptosis is reversed by SHMT2 silencing. SUCLA2 overexpression, lysine succinylation measurement, SIRT5 desuccinylation assays, SHMT2 silencing rescue experiments, Ang II-induced ferroptosis model FASEB journal Medium 41359112
2025 SHMT2 inhibition in preimplantation embryos causes insufficient dTTP supply and replication stress during the first mitotic cleavage, leading to failure of pronuclear fusion and developmental arrest at the pronuclear stage. SHMT2-IN-2 pharmacological inhibitor, low-input LC-MS/MS dNTP quantification in embryos, developmental arrest phenotyping Molecular therapy. Nucleic acids Medium 40171278
2024 SHMT2 deficiency leads to cytosolic mtDNA leakage (>2-fold increase); in MEF cells, decreased SHMT2 activates apoptosis (caspase-3 cleavage), while in HAP1 cells lacking SHMT2, the cGAS/STING pathway is activated. Shmt2+/- MEF cells, SHMT2 KO HAP1 cells, cytosolic mtDNA quantification, caspase-3 cleavage assay, cGAS/STING pathway analysis bioRxivpreprint Medium
2024 BRISC molecular glues (BLUEs) stabilize a 16-subunit BRISC dimer in an autoinhibited conformation that blocks BRCC36 active sites and interactions with the targeting subunit SHMT2, selectively inhibiting BRISC deubiquitylase activity and reducing interferon-stimulated gene expression. Biochemical characterization of BRISC complex, structural analysis of inhibitor-bound dimer, structure-guided mutagenesis of inhibitor-resistant BRISC, IFNAR1 ubiquitylation and surface level assays bioRxivpreprint Medium
2022 SHMT2-driven mitochondrial serine catabolism supports purine biosynthesis and potentiates the DNA damage response in 5-FU-resistant colorectal cancer cells; blocking mitochondrial serine metabolism (SHMT2 inhibition) or serine availability reverses 5-FU resistance. 5-FU resistant CRC in vitro and in vivo models, stable isotope tracing of serine, SHMT2 knockdown, purine biosynthesis measurement, DNA damage response assays Cell reports Medium 35977477
2023 SHMT2 enhances m6A modification of c-myc mRNA by increasing SAM production through one-carbon metabolism; this m6A modification (in a METTL3/FTO/ALKBH5/IGF2BP2-dependent manner) stabilizes c-myc mRNA, promoting esophageal cancer progression and immune escape. MeRIP (methylated RNA immunoprecipitation), SHMT2 silencing, SAM measurement, m6A writer/eraser/reader knockdown, in vivo xenograft model Cell & bioscience Medium 37932821
2022 SHMT2 enhances m6A modification of PPAT mRNA via endogenous SAM production, increasing PPAT expression in an m6A-IGF2BP2-dependent manner to promote renal cell carcinoma proliferation. SHMT2 knockdown/overexpression, m6A modification assay, SAM measurement, IGF2BP2 interaction studies, cell cycle analysis Genomics Medium 35798250
2025 SHMT2 deficiency accumulates homocysteine, which interacts with AARS1 and suppresses histone lactylation, thereby perturbing transcriptional regulation and contributing to neurodegeneration in Huntington's disease models; SHMT2 overexpression attenuates MSN degeneration and improves motor function in YAC128 mice. RNA-seq and metabolomics in HD iPSC-derived human striatal organoids and YAC128 mice, SHMT2 overexpression/pharmacological inhibition, homocysteine measurement, AARS1 interaction assay, histone lactylation measurement, motor function testing The Journal of clinical investigation Medium 41805887
2025 SLC25A26 accelerates SHMT2 degradation via the ubiquitin-proteasome pathway, acting as a ubiquitin adapter; MTHFR directly binds and stabilizes SLC25A26, and this axis suppresses NSCLC by coordinated disruption of serine/one-carbon metabolism. Transcriptomic-metabolomic profiling, molecular interaction mapping, SLC25A26 overexpression/KD, ubiquitination assays, patient-derived xenograft models Cell death & disease Low 42225644
2019 STAT3 binding to the SHMT2 gene promoter upregulates SHMT2 expression via the JAK2/STAT3 canonical pathway upon IL-6 stimulation in prostate cancer cells; activated SHMT2 decreases serine levels, promoting PKM2 nuclear translocation where it activates STAT3 in a non-canonical fashion, creating a STAT3/SHMT2/PKM2 regulatory loop. IL-6 stimulation, STAT3/JAK2 inhibitors, SHMT2 expression measurement, serine level measurement, PKM2 nuclear localization assay, prostate cancer cell line experiments Cells Medium 31500219
2022 SHMT2 promotes oral squamous cell carcinoma progression by binding to ILF2 (interleukin enhancer-binding factor 2); SHMT2 silencing decreases ILF2 expression, and ILF2 overexpression rescues the suppressive effects of SHMT2 knockdown. Co-immunoprecipitation, database interaction prediction (MINT, BioGRID), siRNA knockdown, ILF2 overexpression rescue, cell proliferation/migration/invasion assays Bioengineered Low 35333683
2025 SHMT2 overexpression stabilizes PINK1 expression by enhancing PINK1 phosphorylation, thereby promoting mitophagy in retinal ganglion cells and protecting against glaucoma-associated cell death. Co-immunoprecipitation, immunofluorescence, SHMT2 overexpression, PINK1 phosphorylation measurement, mitophagy assays, in vivo AOH mouse model Diagnostic pathology Low 40604870
2025 RNA-based inhibition of SHMT2 (delivered with a mitochondrial import signal) effectively inhibits SHMT2's serine-to-glycine conversion in vitro (IC50 = 4.4 nM) and reduces cancer cell viability and tumor growth in vivo in a xenograft model. In vitro enzymatic inhibition assay with RNA inhibitor, mitochondrial delivery of inhibitory RNA, xenograft tumor model Cell death discovery Medium 40770176

Source papers

Stage 0 corpus · 81 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 SHMT2 drives glioma cell survival in ischaemia but imposes a dependence on glycine clearance. Nature 313 25855294
2017 SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation. Cancer research 190 29180469
2018 Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs. Molecular cell 171 29452640
2009 SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PloS one 161 19513116
2019 HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2. Proceedings of the National Academy of Sciences of the United States of America 151 30819897
2014 Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer research 137 24755469
2022 SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis. Cell reports 85 35977477
2016 Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget 66 27391339
2015 Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Scientific reports 66 26000717
2021 Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation. Theranostics 63 33456583
2020 The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing. Nature cancer 55 33569544
2021 Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis. Journal of Cancer 52 34476002
2018 Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal. Scientific reports 51 29323231
2024 Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells. Molecular and cellular biochemistry 49 38175377
2021 A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight. ACS pharmacology & translational science 46 33860190
2021 The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy. Oncogene 45 33990700
2019 Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs. FEBS letters 44 31127856
2018 SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy. PLoS pathogens 43 29791506
2022 SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. Blood 41 34624079
2015 miR-615-5p prevents proliferation and migration through negatively regulating serine hydromethyltransferase 2 (SHMT2) in hepatocellular carcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 41 26662310
2022 SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells. Cancer gene therapy 40 35422087
2015 miR-370 and miR-373 regulate the pathogenesis of osteoarthritis by modulating one-carbon metabolism via SHMT-2 and MECP-2, respectively. Aging cell 40 26103880
2020 Circ_0072995 Promotes Cell Carcinogenesis via Up-Regulating miR-149-5p-Mediated SHMT2 in Breast Cancer. Cancer management and research 38 33173349
2019 Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism. Cells 36 31500219
2023 SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells Infiltration, and a Novel Therapeutic Target in Four Different Human Cancers. Current molecular medicine 30 35023455
2023 SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc. Cell & bioscience 30 37932821
2020 ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption. Bioscience reports 30 31894856
2020 Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. Neuron 30 32330411
2022 Exosome-mediated transfer of circ_0063526 enhances cisplatin resistance in gastric cancer cells via regulating miR-449a/SHMT2 axis. Anti-cancer drugs 27 36206102
2023 SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling. International journal of molecular sciences 25 37108312
2022 SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer. American journal of cancer research 25 35968337
2021 Metformin Is a Pyridoxal-5'-phosphate (PLP)-Competitive Inhibitor of SHMT2. Cancers 25 34439169
2022 SHMT2 Drives the Progression of Colorectal Cancer by Regulating UHRF1 Expression. Canadian journal of gastroenterology & hepatology 24 35211429
2019 Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning. Journal of chemical information and modeling 23 31442042
2022 Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2. iScience 22 35602963
2024 SHMT2 promotes papillary thyroid cancer metastasis through epigenetic activation of AKT signaling. Cell death & disease 21 38272883
2019 SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway. Transplantation 21 30964837
2022 Upregulation of Endothelial DKK1 (Dickkopf 1) Promotes the Development of Pulmonary Hypertension Through the Sp1 (Specificity Protein 1)/SHMT2 (Serine Hydroxymethyltransferase 2) Pathway. Hypertension (Dallas, Tex. : 1979) 20 35249365
2021 Silencing SHMT2 inhibits the progression of tongue squamous cell carcinoma through cell cycle regulation. Cancer cell international 20 33863325
2021 Reduced Shmt2 Expression Impairs Mitochondrial Folate Accumulation and Respiration, and Leads to Uracil Accumulation in Mouse Mitochondrial DNA. The Journal of nutrition 19 34383924
2024 Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 18 38460155
2022 Serine hydroxymethyltransferase 2 (SHMT2) potentiates the aggressive process of oral squamous cell carcinoma by binding to interleukin enhancer-binding factor 2 (ILF2). Bioengineered 18 35333683
2020 Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer. Biological research 18 33066813
2020 Cancer proteome and metabolite changes linked to SHMT2. PloS one 17 32903271
2022 SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the m6A modification of PPAT. Genomics 16 35798250
2022 Downregulation of SHMT2 promotes the prostate cancer proliferation and metastasis by inducing epithelial-mesenchymal transition. Experimental cell research 15 35398308
2022 SHMT2 Induces Stemness and Progression of Head and Neck Cancer. International journal of molecular sciences 14 36077112
2019 Disruption of the mouse Shmt2 gene confers embryonic anaemia via foetal liver-specific metabolomic disorders. Scientific reports 12 31690790
2024 SHMT2 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 11 38183387
2024 Uncovering SIRT3 and SHMT2-dependent pathways as novel targets for apigenin in modulating colorectal cancer: In vitro and in vivo studies. Experimental cell research 11 38971519
2022 The role of SHMT2 in modulating lipid metabolism in hepatocytes via glycine-mediated mTOR activation. Amino acids 11 35212811
2022 SHMT2 regulates serine metabolism to promote the progression and immunosuppression of papillary renal cell carcinoma. Frontiers in oncology 11 36110969
2024 SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice. Communications biology 10 38347107
2022 Inhibition of SHMT2 mRNA translation increases embryonic mortality in sheep†. Biology of reproduction 10 35871545
2025 SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy. EBioMedicine 9 39808948
2023 Vital role of SHMT2 in diverse disease. Biochemical and biophysical research communications 7 37302290
2023 Multi-omics reveals that green pea (Pisum sativum L.) hull supplementation ameliorates non-alcoholic fatty liver disease via the SHMT2/glycine/mTOR/PPAR-γ signaling pathway. Food & function 7 37462466
2022 Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities. European journal of medical genetics 7 35398349
2023 Understanding The Regulatory Role of USP32 and SHMT2 in The Progression of Gastric Cancer. Cell journal 6 37210642
2025 TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells. Cell death & disease 5 40097394
2023 NFYB increases chemosensitivity in glioblastoma by promoting HDAC5-mediated transcriptional inhibition of SHMT2. Journal of neuropathology and experimental neurology 5 37742129
2022 Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway. Open life sciences 5 36213384
2025 The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity. Proceedings of the National Academy of Sciences of the United States of America 4 40339130
2025 Discovery of W478, a novel SHMT2 inhibitor for the treatment of esophageal carcinoma. Bioorganic chemistry 4 41014834
2012 Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma. Frontiers in genetics 4 22461784
2025 SHMT2 is essential for mammalian preimplantation embryonic development through de novo biosynthesis of nucleotide metabolites. Molecular therapy. Nucleic acids 3 40171278
2024 MiR-383-5p inhibits the proliferation and migration of lung adenocarcinoma cells by targeting SHMT2. Journal of Cancer 3 38577602
2025 The ALDH2-PKC delta-SHMT2 axis regulates cellular metabolic plasticity to promote leukemia stem cells self-renewal and evasion of chemotherapy in AML. Cancer letters 2 40752747
2025 SUCLA2 Inhibited Lysine Succinylation of SHMT2 to Suppress Ferroptosis and Renal Interstitial Fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2 41359112
2024 Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2. Cellular signalling 2 38723737
2025 RNA-mediated inhibition of mitochondrial SHMT2 impairs cancer cell proliferation. Cell death discovery 1 40770176
2023 Impairments in SHMT2 expression or cellular folate availability reduce oxidative phosphorylation and pyruvate kinase activity. Genes & nutrition 1 36959541
2021 Generation of SHMT2 knockout human embryonic stem cell line (WAe009-A-67) using CRISPR/Cas9 technique. Stem cell research 1 34688993
2026 SHMT2 deficiency disrupts transcriptional regulation through homocysteine-mediated suppression of histone lactylation in Huntington's disease models. The Journal of clinical investigation 0 41805887
2026 SHMT2 inhibition triggers mitochondrial apoptosis to suppress lung adenocarcinoma progression. Journal of translational medicine 0 41814419
2026 A metabolic-immune subtype of breast cancer defined by G6PD and SHMT2: From single‑cell dissection to dual-targeted therapy. The Journal of steroid biochemistry and molecular biology 0 41819344
2026 Novel Insights Into the Association Between Parkinson's Disease and Constipation: Role of SHMT2 as a Promising Biomarker. CNS neuroscience & therapeutics 0 42076895
2026 MTHFR functions as a metabolic checkpoint in NSCLC through SLC25A26-mediated SHMT2 inhibition. Cell death & disease 0 42225644
2025 SHMT2 overexpression improves glaucoma by enhancing mitophagy in retinal ganglion cells through promoting the phospho of PINK1. Diagnostic pathology 0 40604870
2025 SHMT2 modulates the transcriptome and metabolism profiles to promote the tumor phenotypes of bladder cancer HT-1376 cells. Frontiers in genetics 0 41347062
2025 N7-Methylguanine Modification of SHMT2 Mediated by GEMIN5 Inhibits Cell Ferroptosis of Colorectal Cancer Cells. Journal of biochemical and molecular toxicology 0 41416630

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