Affinage

SHMT2

Serine hydroxymethyltransferase, mitochondrial · UniProt P34897

Length
504 aa
Mass
56.0 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHMT2 is a mitochondrial pyridoxal-5'-phosphate (PLP)-dependent serine hydroxymethyltransferase that catalyzes the reversible interconversion of serine and glycine coupled to tetrahydrofolate one-carbon unit transfer, serving as the primary entry point for mitochondrial one-carbon metabolism with critical roles in nucleotide biosynthesis, mitochondrial translation, epigenetic regulation, and systemic amino acid homeostasis. SHMT2 generates 10-formyl-THF required by MTFMT for formylmethionyl-tRNA production, which is essential for mitochondrial translation initiation and oxidative phosphorylation; Shmt2 knockout is embryonic lethal, with mitochondrial respiration defects causing fetal liver anemia (PMID:29452640, PMID:29323231, PMID:31690790). Beyond its metabolic function, SHMT2 serves as the targeting subunit of the BRISC deubiquitinase complex, directing K63-linked deubiquitination of IFNAR1 to sustain type I interferon signaling—a role modulated by HDAC11-mediated defatty-acylation and extended to protection of HIV-1 Tat from autophagic degradation (PMID:24075985, PMID:30819897, PMID:29791506). SHMT2 additionally channels one-carbon units into S-adenosylmethionine production to drive DNA and histone methylation-based epigenetic programs, operates predominantly in the glycine-to-serine direction in the liver to maintain circulating glycine homeostasis, and moonlights as an RNA-binding protein that enhances ADAM10 translation via 5'UTR GAGGG-motif recognition (PMID:33569544, PMID:38171330, PMID:38183387).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2009 High

    The SHMT2 locus was shown to produce an alternative transcript (SHMT2α) encoding a cytoplasmic/nuclear isoform that participates in S-phase nuclear thymidylate biosynthesis, establishing that SHMT2 contributes to folate metabolism in both mitochondrial and nuclear compartments.

    Evidence Thymidylate synthesis assays in purified mouse liver nuclei from Shmt1-/- mice, subcellular fractionation, S-phase localization

    PMID:19513116

    Open questions at the time
    • Nuclear isoform regulation and relative contribution versus SHMT1 in different tissues not defined
    • Direct structural basis for dual localization not established
  2. 2013 High

    SHMT2 was discovered to function as the targeting/adaptor subunit of the BRISC deubiquitinase complex, resolving how BRISC is directed to K63-ubiquitinated IFNAR1 to limit receptor internalization and sustain interferon signaling—revealing a non-metabolic scaffolding role.

    Evidence Reciprocal co-immunoprecipitation, proteomics, ubiquitination and IFNAR1 internalization assays, BRISC-deficient mouse models

    PMID:24075985

    Open questions at the time
    • Whether enzymatic activity and BRISC adaptor function are mutually exclusive or concurrent was unclear
    • Structural basis of SHMT2-BRISC assembly not resolved
  3. 2015 High

    SHMT2 was established as a metabolic vulnerability in glioma by linking its activity to PKM2 inhibition and reduced oxygen consumption, while also revealing that glycine toxicity from uncleared SHMT2 products creates a dependency on glycine decarboxylase—framing SHMT2 as a metabolic switch in tumor microenvironments.

    Evidence shRNA knockdown, isotope tracing, metabolic flux analysis, and xenograft studies in glioma cells

    PMID:25855294

    Open questions at the time
    • PKM2 regulation mechanism not biochemically defined
    • Generalizability to non-glioma tumors not established in this study
  4. 2017 High

    SIRT5 was identified as a direct post-translational regulator of SHMT2, with desuccinylation at K280 activating enzymatic function, establishing succinylation as a metabolic rheostat for one-carbon flux.

    Evidence Site-directed mutagenesis of K280, in vitro desuccinylation assay, enzymatic activity measurement, tumor xenograft

    PMID:29180469

    Open questions at the time
    • Physiological signals controlling SIRT5-SHMT2 axis not defined
    • Whether other acylation sites co-regulate activity unknown
  5. 2018 High

    The essential role of SHMT2 in mitochondrial translation was established: SHMT2 supplies 10-formyl-THF to MTFMT for formylmethionyl-tRNA production, and SHMT2 knockout causes embryonic lethality with mitochondrial respiration defects and fetal liver anemia due to impaired erythropoiesis.

    Evidence SHMT2 knockout cell lines and Shmt2-/- mouse embryos, fMet-tRNA quantification, Seahorse respirometry, metabolomic profiling of E13.5 embryonic livers

    PMID:29323231 PMID:29452640 PMID:31690790

    Open questions at the time
    • Whether tissue-specific rescue (e.g., glycine or formate supplementation) can bypass SHMT2 loss in vivo not tested
    • Contribution to mtDNA integrity versus translation initiation not fully disentangled
  6. 2018 High

    The BRISC adaptor role of SHMT2 was extended beyond IFNAR1: SHMT2-BRISC deubiquitinates HIV-1 Tat K63-ubiquitin chains, protecting Tat from autophagic degradation and establishing SHMT2-BRISC as a general K63-deubiquitination platform for diverse substrates.

    Evidence DiffPOP mass spectrometry, shRNA knockdown of SHMT1/2 and BRCC36, K63-Ub immunoprecipitation, autophagy assays

    PMID:29791506

    Open questions at the time
    • Full substrate repertoire of SHMT2-BRISC beyond IFNAR1 and Tat not mapped
    • Whether SHMT2 enzymatic activity is required for BRISC targeting unclear
  7. 2019 High

    HDAC11 was shown to act as a lysine defatty-acylase on SHMT2, with defatty-acylation modulating SHMT2's BRISC-related interferon signaling function without affecting its catalytic activity—separating the metabolic and scaffolding roles at the PTM level.

    Evidence Biochemical defatty-acylation assays, HDAC11 depletion in cells and mice, IFNAR1 ubiquitination and surface level measurements

    PMID:30819897

    Open questions at the time
    • Specific fatty-acylation sites on SHMT2 not mapped
    • Writer enzyme for SHMT2 fatty acylation not identified
  8. 2019 High

    Crystal structures of SHMT2 with antifolate inhibitors (lometrexol, pemetrexed) defined the active-site architecture and hydrogen-bonding networks for inhibitor binding, providing a structural framework for rational drug design targeting this enzyme.

    Evidence X-ray crystallography of SHMT2–antifolate complexes, biochemical inhibition assays

    PMID:31127856

    Open questions at the time
    • No structure of SHMT2 in complex with BRISC subunits
    • Allosteric regulation and oligomerization dynamics not structurally resolved
  9. 2021 High

    SHMT2-derived one-carbon units were shown to fuel SAM production that drives DNA and histone hypermethylation, silencing tumor suppressors (SASH1, PTPRM) and cooperating with BCL2 in lymphomagenesis—establishing SHMT2 as an epigenetic driver through metabolite channeling.

    Evidence CRISPR knockout, isotope tracing, bisulfite sequencing, histone methylation analysis, mouse lymphoma models, pharmacological SHMT2 inhibition

    PMID:33569544

    Open questions at the time
    • Whether SAM-mediated epigenetic effects are cell-type specific not resolved
    • Direct demonstration that SHMT2-derived SAM (versus other SAM sources) is the limiting factor is correlative
  10. 2021 High

    Metformin was identified as a direct PLP-competitive inhibitor of SHMT2 that destabilizes catalytically active oligomers, providing a pharmacological mechanism for metformin's metabolic effects through one-carbon pathway suppression.

    Evidence In vitro competitive binding assays with recombinant SHMT2, DSF, molecular dynamics, CRISPR SHMT2 KO abolishing metformin's effect on SHMT activity

    PMID:34439169

    Open questions at the time
    • Whether metformin reaches sufficient concentrations in mitochondria for physiologically relevant SHMT2 inhibition is debated
    • Contribution of SHMT2 inhibition versus AMPK activation to metformin's clinical effects not delineated
  11. 2021 High

    Reduced SHMT2 expression was linked to mitochondrial folate depletion and uracil misincorporation into mtDNA, establishing SHMT2 as a guardian of mitochondrial genome integrity through folate pool maintenance.

    Evidence Shmt2+/- mouse model with dietary folate restriction, mtDNA uracil quantification, mitochondrial folate measurement, Seahorse respirometry

    PMID:34383924

    Open questions at the time
    • Whether uracil-containing mtDNA directly causes respiration defects or is a marker of broader folate insufficiency not resolved
    • mtDNA repair mechanisms for uracil in SHMT2-deficient context not characterized
  12. 2022 High

    In Burkitt lymphoma, SHMT2 inhibition depletes glycine and formate, suppressing mTOR signaling and triggering autophagic degradation of TCF3—collapsing the tonic BCR signaling essential for BL survival and revealing a targetable metabolic-signaling dependency.

    Evidence Genome-scale CRISPR screen, shRNA knockdown, pharmacological SHMT2 inhibition in vitro and in vivo, metabolomics, TCF3 stability assays

    PMID:34624079

    Open questions at the time
    • Whether mTOR inhibition is the sole mediator of TCF3 degradation or other pathways contribute
    • Biomarkers predicting SHMT2 inhibitor sensitivity in lymphoma subtypes not defined
  13. 2024 High

    Tissue-specific directionality of SHMT2 was established: in the liver, SHMT2 predominantly runs in reverse (glycine→serine), consuming circulating glycine; liver-specific knockout raised serum glycine up to eight-fold, redefining SHMT2 as a systemic glycine homeostasis regulator.

    Evidence Liver-specific Shmt2 knockout mice, whole-body SHMT inhibition, in vivo stable isotope tracing, serum glycine quantification

    PMID:38171330

    Open questions at the time
    • How hepatic SHMT2 directionality is regulated (substrate availability vs. allosteric control) not defined
    • Consequences of chronic hyperglycemia for extrahepatic organs not explored
  14. 2024 Medium

    MAPK1 was identified as a kinase that phosphorylates SHMT2 at Ser90, preventing STUB1-mediated ubiquitination and stabilizing the protein; phospho-SHMT2 sustains SAM levels driving m6A RNA methylation of oncogenic transcripts, linking growth factor signaling to epitranscriptomic control via one-carbon metabolism.

    Evidence Site-directed mutagenesis of S90, MAPK1 kinase assays, STUB1 ubiquitination assays, MeRIP-seq

    PMID:38460155

    Open questions at the time
    • Phosphatase that reverses S90 phosphorylation not identified
    • Whether S90 phosphorylation affects BRISC function not tested
    • Single-lab finding awaits independent replication
  15. 2024 Medium

    A non-canonical moonlighting function was discovered: SHMT2 acts as an RNA-binding protein that binds GAGGG motifs in the 5'UTR of ADAM10 mRNA to enhance translation initiation via eIF2-dependent ribosomal scanning, linking one-carbon metabolism to translational regulation independent of catalytic activity.

    Evidence Chemical biology target identification, 5'UTR reporter assays, RBP-RNA binding assays, in vivo APP/PS1 mouse validation of ADAM10 translation and cognitive function

    PMID:38183387

    Open questions at the time
    • Full spectrum of SHMT2 RNA targets beyond ADAM10 not defined
    • Structural basis for RNA binding not determined
    • Single-lab discovery requires independent confirmation
  16. 2025 High

    The oncoprotein SET was identified as a physical interactor that facilitates SHMT2 enzymatic activity, promoting one-carbon flux in KRAS/LKB1-mutant lung tumors and expanding the regulatory network controlling SHMT2 function.

    Evidence Reciprocal co-immunoprecipitation, isotope tracing, SET knockout cells, in vivo Kras/Lkb1 mouse lung tumor model

    PMID:40339130

    Open questions at the time
    • Mechanism by which SET enhances SHMT2 catalysis (allosteric, stabilizing, or cofactor-related) not defined
    • Whether SET-SHMT2 interaction occurs in non-tumor contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions include: how SHMT2 partitions between its metabolic enzyme and BRISC adaptor roles in the same cell, what the full RNA-binding target repertoire is, whether tissue-specific reaction directionality is allosterically or substrate-driven, and how the multiple PTMs (succinylation, phosphorylation, fatty acylation, lactylation) are integrated to coordinate SHMT2 outputs.
  • No structural model of SHMT2-BRISC holocomplex
  • Integrative PTM code not mapped
  • Full RBP target landscape unknown
  • Tissue-specific directionality mechanism unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 7 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 1
Localization
GO:0005739 mitochondrion 7 GO:0005829 cytosol 3 GO:0005634 nucleus 1
Pathway
R-HSA-1430728 Metabolism 9 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-5357801 Programmed Cell Death 2
Partners
BRCC36HDAC11IFNAR1MTFMTSAMM50SETSIRT5STUB1
Complex memberships
BRISC deubiquitinase complex

Evidence

Reading pass · 32 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 in glioma cells, eliciting a metabolic state that confers survival advantage in poorly vascularized tumor regions; excess glycine not cleared by GLDC (glycine decarboxylase) can be converted to toxic aminoacetone and methylglyoxal, rendering high-SHMT2 cells dependent on glycine clearance. Genetic loss-of-function (shRNA knockdown), metabolic flux analysis, tumor xenograft studies, and isotope tracing in glioma cell lines and patient tissue Nature High 25855294
2018 SHMT2 catalyzes the first step in mitochondrial one-carbon metabolism to produce 10-formyl-THF, which is used by MTFMT to generate formylmethionyl-tRNAs required for proper initiation of mitochondrial translation; SHMT2 null cells fail to maintain formylmethionyl-tRNA pools and mitochondrially encoded proteins, impairing oxidative phosphorylation under low-glucose conditions. Genetic screens, SHMT2 knockout cell lines, isotope tracing, mitochondrial tRNA analysis, and comparison to MTFMT-deficient patient phenotypes Molecular cell High 29452640
2017 SIRT5 desuccinylates SHMT2 at lysine 280, which activates its enzymatic activity; hypersuccinylation of SHMT2-K280 inhibits enzymatic activity and suppresses tumor cell growth in vitro and in vivo. Co-immunoprecipitation, site-directed mutagenesis (K280), enzymatic activity assays, in vitro desuccinylation assay, tumor xenograft model Cancer research High 29180469
2013 SHMT2 serves as a targeting/adaptor subunit of the BRISC deubiquitinase complex, directing its K63-linked deubiquitinase activity to IFNAR1 (type I interferon receptor chain 1); BRISC-SHMT2 complexes localize to and deubiquitinate actively engaged IFNAR1, limiting its K63-Ub-mediated internalization and lysosomal degradation, thereby sustaining interferon signaling. Co-immunoprecipitation, proteomics, shRNA knockdown, ubiquitination assays, IFNAR1 internalization assays, BRISC-deficient mouse models Cell reports High 24075985
2019 HDAC11 acts as a lysine defatty-acylase (>10,000-fold more efficient than its deacetylase activity) and removes fatty acyl modifications from SHMT2; defatty-acylation of SHMT2 by HDAC11 does not affect SHMT2 enzymatic activity but regulates SHMT2's ability to control type I IFN receptor ubiquitination and cell surface levels, thus modulating type I IFN signaling. Proteomics, biochemical validation of defatty-acylation, HDAC11 depletion in cells and mice, IFNAR1 ubiquitination and cell surface assays Proceedings of the National Academy of Sciences of the United States of America High 30819897
2009 SHMT2 encodes two transcripts: one encoding a mitochondria-exclusive protein (SHMT2) and one lacking exon 1 (SHMT2α) that encodes a protein localizing to the cytoplasm and nucleus during S-phase; SHMT2α participates in nuclear de novo thymidylate biosynthesis and is functionally redundant with SHMT1 in this process. Purified intact mouse liver nuclei thymidylate synthesis assays, Shmt1-/- mouse nuclei (retaining 25% activity attributed to SHMT2α), subcellular fractionation, S-phase localization studies PloS one High 19513116
2018 SHMT2-deficient mouse embryos are embryonic lethal after E13.5, and fibroblasts from Shmt2-/- embryos exhibit mitochondrial respiration defects and growth retardation, confirming that SHMT2 substantially controls fMet-tRNA production in mitochondria, which is required for mitochondrial translation and respiration. Shmt2 knockout mouse generation, embryonic fibroblast isolation, mitochondrial respiration measurement (Seahorse), growth assays Scientific reports High 29323231
2024 In the liver, SHMT2 operates predominantly in the reverse direction (glycine→serine) to consume circulating glycine rather than produce it; liver-specific SHMT2 knockout raised circulating glycine levels up to eight-fold, and isotope tracing showed liver converts glycine to serine via SHMT2, which is then converted by serine dehydratase to pyruvate for TCA cycle oxidation. Liver-specific Shmt2 knockout mice, pharmacological whole-body SHMT1/2 inhibition, stable isotope tracing (in vivo), serum glycine measurement Cell metabolism High 38171330
2018 SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation; knockdown of SHMT1/2 or BRCC36 or inhibition of SHMT2 by JIB-04 increased Tat K63-Ub-dependent destruction via autophagy, demonstrating that SHMT2 (as part of the BRISC complex) protects Tat from autophagic degradation by deubiquitinating K63-Ub chains on Tat. Proteomics (DiffPOP mass spectrometry), shRNA knockdown of SHMT1/2 and BRCC36, K63-Ub immunoprecipitation, autophagy assays, Tat point mutations PLoS pathogens High 29791506
2019 Crystal structures of SHMT2 in complex with antifolates (lometrexol, pemetrexed) were solved, revealing the active site architecture and distinct hydrogen bond networks for each antifolate; lometrexol was identified as the best hSHMT1/2 inhibitor from the panel. X-ray crystallography (SHMT2-antifolate co-crystal structures), biochemical inhibition assays FEBS letters High 31127856
2021 Metformin directly and specifically inhibits SHMT2 enzymatic activity by acting as a PLP-competitive inhibitor; metformin occupies the cofactor pyridoxal-5'-phosphate (PLP) cavity and destabilizes the formation of catalytically active SHMT2 oligomers, as confirmed by competitive binding assays, computational docking, molecular dynamics, and differential scanning fluorimetry. In vitro competitive binding assays with human recombinant SHMT1 and SHMT2, computational docking, molecular dynamics simulation, differential scanning fluorimetry, CRISPR/Cas9 SHMT2 KO, isotope tracing Cancers High 34439169
2022 Glycyrrhetinic acid (GA) binds directly to the folate-binding pocket of SHMT2 and inhibits its activity; crystal structures of GA derivatives bound to SHMT2 were solved, and SHMT2 inhibition by GA restricts mitochondrial OXPHOS and fatty acid β-oxidation, suppressing cancer cell proliferation. Chemical proteomics, in vitro binding and activity assays, SHMT2 knockout, X-ray crystallography of SHMT2-GA derivative complexes, Seahorse respirometry iScience High 35602963
2021 SHMT2 interacts with cytosolic β-catenin via its lysine 64 residue (SHMT2-K64), inhibiting ubiquitylation-mediated degradation of β-catenin and thereby promoting β-catenin target gene expression, CRC cell proliferation, and metastasis; TCF4/β-catenin in turn increases SHMT2 expression, forming a positive feedback loop. Co-immunoprecipitation, site-directed mutagenesis (K64), immunofluorescence, mRNA-seq, ChIP-qPCR, xenograft experiments Theranostics Medium 33456583
2021 SHMT2 (at cytoplasmic localization) inhibits autophagy by binding cytosolic p53, preventing p53 degradation by inhibiting p53-HDM2 interaction; SHMT2 depletion promotes autophagy and inhibits apoptosis under 5-FU treatment. Co-immunoprecipitation (SHMT2-p53, p53-HDM2), autophagy assays, apoptosis assays, in vitro and in vivo rescue experiments with autophagy inhibitors Oncogene Medium 33990700
2020 SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma; elevated SHMT2 catalyzes serine-to-glycine conversion producing one-carbon units that support S-adenosylmethionine synthesis, inducing DNA and histone methylation changes that silence tumor suppressor genes (e.g., SASH1, PTPRM), cooperating with BCL2 to initiate lymphomagenesis. CRISPR/Cas9 loss-of-function, isotope tracing, bisulfite sequencing (DNA methylation), histone methylation analysis, mouse lymphoma models, pharmacological SHMT2 inhibition Nature cancer High 33569544
2022 SHMT2 inhibition in Burkitt lymphoma reduces intracellular glycine and formate, inhibiting the mTOR pathway and triggering autophagic degradation of the oncogenic transcription factor TCF3, leading to collapse of tonic BCR signaling essential for BL cell survival. CRISPR-Cas9 genome-scale screens, shRNA knockdown, pharmacological SHMT2 inhibition (in vitro and in vivo), metabolomics, mTOR pathway analysis, TCF3 protein stability assays Blood High 34624079
2019 IL-6 stimulation activates the JAK2/STAT3 canonical pathway, which upregulates SHMT2 expression in LNCaP prostate cancer cells; increased SHMT2 activity reduces serine levels, driving PKM2 into the nuclear compartment where it activates STAT3 non-canonically, creating a STAT3/SHMT2/PKM2 feedback loop that promotes a shift toward anaerobic metabolism. IL-6 stimulation, JAK2 inhibition, SHMT2 overexpression/knockdown, PKM2 nuclear localization assay, STAT3 transcriptional activity assays, FFPE tissue validation Cells Medium 31500219
2015 Epigenetic downregulation of SHMT2 in fibroblasts from elderly humans is responsible for age-associated mitochondrial respiration defects; reprogramming elderly fibroblasts to iPSCs restored mitochondrial respiration, and these aging phenotypes are controlled by epigenetic regulation rather than mtDNA mutations. iPSC reprogramming of elderly fibroblasts, microarray screening, mitochondrial respiration measurement, glycine supplementation rescue experiments Scientific reports Medium 26000717
2021 Loss of PYCR2 upregulates SHMT2 expression, increasing cerebral glycine synthesis and causing encephalopathy; SHMT2 knockdown in Pycr2 knockout neurons partially reversed hyperglycemia and rescued axonal beading and neurite lengths, placing SHMT2 downstream of PYCR2 in the glycine metabolic pathway. Pycr2 knockout mice, SHMT2 knockdown (siRNA), in situ neurotransmitter quantification in mouse brains and patient tissue, neuronal morphology assays Neuron High 32330411
2019 SHMT2 promotes liver regeneration after partial hepatectomy by producing glycine, which activates the Akt/mTOR signaling pathway in hepatocytes; LY294002 (Akt inhibitor) blocked the SHMT2-mediated proliferative effect, placing SHMT2-derived glycine upstream of Akt/mTOR in liver regeneration. Shmt2 knockdown in vivo (partial hepatectomy mouse model), SHMT2 overexpression in primary hepatocytes, glycine measurement, Akt inhibitor rescue, mTOR pathway analysis Transplantation Medium 30964837
2024 MAPK1 phosphorylates SHMT2 at Ser90, stabilizing SHMT2 by reducing STUB1-mediated ubiquitination and proteasomal degradation; phospho-SHMT2 maintains higher S-adenosylmethionine levels to support global m6A RNA methylation of oncogenic transcripts in lung adenocarcinoma. Site-directed mutagenesis (Ser90), MAPK1 kinase assays, STUB1 ubiquitination assay, MeRIP-Seq, RNA-Seq, SHMT2-S90 dephosphorylation cell models Advanced science Medium 38460155
2024 SHMT2 generates S-adenosylmethionine (SAM) via serine metabolism to epigenetically repress PTEN through CpG island methylation of its promoter, leading to AKT pathway activation and papillary thyroid cancer metastasis. SHMT2 overexpression/knockdown, proteomic enrichment analysis, bisulfite sequencing (PTEN promoter methylation), AKT pathway inhibition, xenograft experiments Cell death & disease Medium 38272883
2025 The oncoprotein SET physically interacts with mitochondrial SHMT2 and facilitates its enzymatic activity, promoting serine-derived one-carbon metabolic flux; loss of SET suppresses SHMT2 enzymatic activity and reduces one-carbon metabolite production in vitro and in vivo (Kras/Lkb1 mouse lung tumor model). Co-immunoprecipitation (SET-SHMT2 interaction), untargeted metabolomics, isotope tracing, SET knockout cell lines, in vivo Kras/Lkb1 mouse model, pharmacological SHMT inhibition Proceedings of the National Academy of Sciences of the United States of America High 40339130
2022 SHMT2 interacts with MTHFD1L in esophageal cancer cells under hypoxia; hypoxia-induced lactylation of SHMT2 protein stabilizes SHMT2 protein and enhances MTHFD1L expression, facilitating glycolysis and stemness of esophageal cancer cells. Immunoprecipitation/western blot for SHMT2 lactylation detection, bioinformatics interaction analysis, rescue experiments with MTHFD1L Molecular and cellular biochemistry Low 38175377
2021 Reduced Shmt2 expression impairs mitochondrial folate accumulation, increases uracil misincorporation into mitochondrial DNA, reduces mitochondrial membrane potential, and decreases oxygen consumption rate; dietary folate deficiency exacerbates uracil accumulation in liver mtDNA. Shmt2+/- mouse model, dietary folate restriction, mitochondrial folate measurement, uracil quantification in mtDNA, Seahorse respirometry in mouse embryonic fibroblasts The Journal of nutrition High 34383924
2024 SHMT2 acts as an RNA-binding protein (RBP) by binding GAGGG motifs in the 5'UTR of ADAM10 mRNA, enhancing 5'UTR-dependent ADAM10 translation initiation by affecting eIF2 ribosomal scanning; this non-canonical 'moonlighting' function links one-carbon metabolism to translational regulation. Chemical biology (kenpaullone as probe), SHMT2 identification as target, 5'UTR reporter assays, RBP-RNA binding assays (GAGGG motif), in vitro and in vivo (APP/PS1 mice) ADAM10 translation and cognitive function studies Advanced science Medium 38183387
2024 Mitochondrial outer membrane protein Samm50 interacts with Shmt2; this Samm50-Shmt2 interaction hinders the transfer of Bax from cytoplasm to mitochondria and prevents caspase-3 activation, protecting cardiomyocytes from hypoxia-induced apoptosis. Co-immunoprecipitation/mass spectrometry (Samm50 interactome), Samm50 overexpression/knockdown, Shmt2 inhibition, Bax translocation assay, caspase-3 activation, MI mouse model Cellular signalling Medium 38723737
2025 ALDH2 sustains mitochondrial homeostasis in leukemia stem cells by increasing expression of PKC delta and SHMT2; the ALDH2-PKC delta-SHMT2 axis mediates metabolic reprogramming that facilitates LSC adaptation to chemotherapy-induced stress. ALDH2 overexpression/knockdown, PKC delta and SHMT2 expression analysis, AML patient samples, synergy with chemotherapy, bone marrow microenvironment model Cancer letters Low 40752747
2024 In KRAS/LKB1-mutant NSCLC, LKB1 loss activates SHMT (including SHMT2) through inactivation of the SIK-NRF2 axis, fulfilling increased demand for one-carbon units for antioxidant defense; pharmacological SHMT suppression increases oxidative stress sensitivity and enhances efficacy of paclitaxel in vivo. RNA-seq and metabolomics from human NSCLC, genetic SHMT suppression, SIK-NRF2 pathway epistasis, SHMT inhibitor treatment in vivo (KL tumor models), oxidative stress assays Nature metabolism High 38877143
2024 SHMT2 in hepatocytes reduces lipid accumulation through glycine-mediated mTOR/PPARγ signaling; SHMT2 KO raises serine/glycine in circulation, decreases liver methylation potential (SAM), and increases susceptibility to fatty liver disease while paradoxically reducing hepatic inflammation and fibrosis in a diet-induced NASH model. Hepatocyte-specific Shmt2 KO mice, high-fat/fructose/cholesterol diet challenge, SAM measurement, serine/glycine metabolomics, liver histopathology Communications biology Medium 38347107
2019 Disruption of Shmt2 in mouse embryos induces liver-specific downregulation of one-carbon metabolic pathways, depleting taurine and nucleotides required for mitochondrial respiratory function and cell division; mitochondrial respiration defects in fetal livers inhibit erythroblast differentiation, causing embryonic anemia and lethality. Shmt2-knockout E13.5 embryos, metabolomic profiling (liver vs brain), mitochondrial respiration measurement, erythroblast differentiation analysis Scientific reports High 31690790
2022 SHMT2 promotes oral squamous cell carcinoma progression by binding to and upregulating ILF2 (interleukin enhancer-binding factor 2); ILF2 overexpression rescues the tumor-suppressive effects of SHMT2 silencing, placing ILF2 downstream of SHMT2 in OSCC progression. Co-immunoprecipitation (SHMT2-ILF2), bioinformatics prediction (MINT/BioGRID), ILF2 overexpression rescue, proliferation/migration/invasion assays Bioengineered Low 35333683

Source papers

Stage 0 corpus · 100 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 306 25855294
2017 Human SHMT inhibitors reveal defective glycine import as a targetable metabolic vulnerability of diffuse large B-cell lymphoma. Proceedings of the National Academy of Sciences of the United States of America 204 29073064
2017 SHMT2 Desuccinylation by SIRT5 Drives Cancer Cell Proliferation. Cancer research 189 29180469
2018 Serine Catabolism by SHMT2 Is Required for Proper Mitochondrial Translation Initiation and Maintenance of Formylmethionyl-tRNAs. Molecular cell 166 29452640
2009 SHMT1 and SHMT2 are functionally redundant in nuclear de novo thymidylate biosynthesis. PloS one 157 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 148 30819897
2014 Comparative oncogenomics identifies PSMB4 and SHMT2 as potential cancer driver genes. Cancer research 136 24755469
2001 Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Molecular genetics and metabolism 118 11386852
2020 SHMT inhibition is effective and synergizes with methotrexate in T-cell acute lymphoblastic leukemia. Leukemia 108 32382081
2013 A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell reports 84 24075985
2022 SHMT2-mediated mitochondrial serine metabolism drives 5-FU resistance by fueling nucleotide biosynthesis. Cell reports 82 35977477
2015 Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Scientific reports 66 26000717
2016 Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget 64 27391339
2021 Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation. Theranostics 59 33456583
2020 Repurposing the Antidepressant Sertraline as SHMT Inhibitor to Suppress Serine/Glycine Synthesis-Addicted Breast Tumor Growth. Molecular cancer therapeutics 59 33203732
2020 The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing. Nature cancer 53 33569544
2021 Roles of Mitochondrial Serine Hydroxymethyltransferase 2 (SHMT2) in Human Carcinogenesis. Journal of Cancer 51 34476002
2018 Mice deficient in the Shmt2 gene have mitochondrial respiration defects and are embryonic lethal. Scientific reports 50 29323231
2015 Inhibitors of plasmodial serine hydroxymethyltransferase (SHMT): cocrystal structures of pyrazolopyrans with potent blood- and liver-stage activities. Journal of medicinal chemistry 48 25785478
2007 Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer causes & control : CCC 47 17206530
2024 Hypoxia-induced SHMT2 protein lactylation facilitates glycolysis and stemness of esophageal cancer cells. Molecular and cellular biochemistry 45 38175377
2021 A Review of Small-Molecule Inhibitors of One-Carbon Enzymes: SHMT2 and MTHFD2 in the Spotlight. ACS pharmacology & translational science 43 33860190
2021 The loss of SHMT2 mediates 5-fluorouracil chemoresistance in colorectal cancer by upregulating autophagy. Oncogene 43 33990700
2019 Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs. FEBS letters 43 31127856
2018 SHMT2 and the BRCC36/BRISC deubiquitinase regulate HIV-1 Tat K63-ubiquitylation and destruction by autophagy. PLoS pathogens 41 29791506
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
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 39 26103880
2024 Glycine homeostasis requires reverse SHMT flux. Cell metabolism 38 38171330
2022 SHMT2 inhibition disrupts the TCF3 transcriptional survival program in Burkitt lymphoma. Blood 38 34624079
1979 Regional assignment of human genes TPI1, GAPDH, LDHB, SHMT, and PEPB on chromosome 12. Cytogenetics and cell genetics 38 477403
2022 SHMT2 promotes cell viability and inhibits ROS-dependent, mitochondrial-mediated apoptosis via the intrinsic signaling pathway in bladder cancer cells. Cancer gene therapy 37 35422087
2020 Circ_0072995 Promotes Cell Carcinogenesis via Up-Regulating miR-149-5p-Mediated SHMT2 in Breast Cancer. Cancer management and research 37 33173349
2019 Shmt2: A Stat3 Signaling New Player in Prostate Cancer Energy Metabolism. Cells 36 31500219
2017 Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures. Journal of medicinal chemistry 34 28537728
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 29 35023455
2023 SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc. Cell & bioscience 29 37932821
2020 ERRα activates SHMT2 transcription to enhance the resistance of breast cancer to lapatinib via modulating the mitochondrial metabolic adaption. Bioscience reports 29 31894856
2020 Loss of PYCR2 Causes Neurodegeneration by Increasing Cerebral Glycine Levels via SHMT2. Neuron 28 32330411
2022 Exosome-mediated transfer of circ_0063526 enhances cisplatin resistance in gastric cancer cells via regulating miR-449a/SHMT2 axis. Anti-cancer drugs 25 36206102
1997 Photosynthesis and fluorescence quenching, and the mRNA levels of plastidic glutamine synthetase or of mitochondrial serine hydroxymethyltransferase (SHMT) in the leaves of the wild-type and of the SHMT-deficient stm mutant of Arabidopsis thaliana in relation to the rate of photorespiration. Planta 24 9232907
2023 SHMT2 Promotes Gastric Cancer Development through Regulation of HIF1α/VEGF/STAT3 Signaling. International journal of molecular sciences 23 37108312
2022 SHMT2 Drives the Progression of Colorectal Cancer by Regulating UHRF1 Expression. Canadian journal of gastroenterology & hepatology 23 35211429
2021 Metformin Is a Pyridoxal-5'-phosphate (PLP)-Competitive Inhibitor of SHMT2. Cancers 23 34439169
2019 Study of SHMT2 Inhibitors and Their Binding Mechanism by Computational Alanine Scanning. Journal of chemical information and modeling 23 31442042
2022 SHMT2 promotes tumor growth through VEGF and MAPK signaling pathway in breast cancer. American journal of cancer research 22 35968337
2017 Essential Function of the Serine Hydroxymethyl Transferase (SHMT) Gene During Rapid Syncytial Cell Cycles in Drosophila. G3 (Bethesda, Md.) 21 28515048
2021 Silencing SHMT2 inhibits the progression of tongue squamous cell carcinoma through cell cycle regulation. Cancer cell international 20 33863325
2019 SHMT2 Promotes Liver Regeneration Through Glycine-activated Akt/mTOR Pathway. Transplantation 20 30964837
2024 SHMT2 promotes papillary thyroid cancer metastasis through epigenetic activation of AKT signaling. Cell death & disease 19 38272883
2024 Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer. Nature metabolism 19 38877143
2022 Glycyrrhetinic acid restricts mitochondrial energy metabolism by targeting SHMT2. iScience 18 35602963
2021 Reduced Shmt2 Expression Impairs Mitochondrial Folate Accumulation and Respiration, and Leads to Uracil Accumulation in Mouse Mitochondrial DNA. The Journal of nutrition 18 34383924
2024 Phosphorylated SHMT2 Regulates Oncogenesis Through m6A Modification in Lung Adenocarcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 38460155
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) 17 35249365
2020 Evaluating the clinical significance of SHMT2 and its co-expressed gene in human kidney cancer. Biological research 17 33066813
2018 Potent Inhibitors of Plasmodial Serine Hydroxymethyltransferase (SHMT) Featuring a Spirocyclic Scaffold. ChemMedChem 17 29655285
2022 Genome-wide identification and expression analysis of serine hydroxymethyltransferase (SHMT) gene family in tomato (Solanum lycopersicum). PeerJ 16 35186505
2022 Serine hydroxymethyltransferase 2 (SHMT2) potentiates the aggressive process of oral squamous cell carcinoma by binding to interleukin enhancer-binding factor 2 (ILF2). Bioengineered 16 35333683
2022 SHMT2 promotes the tumorigenesis of renal cell carcinoma by regulating the m6A modification of PPAT. Genomics 16 35798250
2020 Cancer proteome and metabolite changes linked to SHMT2. PloS one 16 32903271
2022 Downregulation of SHMT2 promotes the prostate cancer proliferation and metastasis by inducing epithelial-mesenchymal transition. Experimental cell research 15 35398308
2017 Conformational Aspects in the Design of Inhibitors for Serine Hydroxymethyltransferase (SHMT): Biphenyl, Aryl Sulfonamide, and Aryl Sulfone Motifs. Chemistry (Weinheim an der Bergstrasse, Germany) 15 28967982
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
2010 Dynamic subcellular localization of isoforms of the folate pathway enzyme serine hydroxymethyltransferase (SHMT) through the erythrocytic cycle of Plasmodium falciparum. Malaria journal 12 21129192
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 Mediates Small-Molecule-Induced Alleviation of Alzheimer Pathology Via the 5'UTR-dependent ADAM10 Translation Initiation. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 10 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 10 38971519
2022 Inhibition of SHMT2 mRNA translation increases embryonic mortality in sheep†. Biology of reproduction 10 35871545
2022 Genome-wide identification of SHMT family genes in cucumber (Cucumis sativus L.) and functional analyses of CsSHMTs in response to hormones and abiotic stresses. 3 Biotech 9 36276449
2019 Secretory expression, immunoaffinity purification and metal-binding ability of recombinant metallothionein (ShMT) from freshwater crab Sinopotamon henanense. Ecotoxicology and environmental safety 9 30472469
2024 SHMT2 reduces fatty liver but is necessary for liver inflammation and fibrosis in mice. Communications biology 8 38347107
2023 SHMT as a Potential Therapeutic Target for Renal Cell Carcinoma. Frontiers in bioscience (Landmark edition) 8 37796681
2025 SHMT2 regulates CD8+ T cell senescence via the reactive oxygen species axis in HIV-1 infected patients on antiretroviral therapy. EBioMedicine 7 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
1998 Serine hydroxymethyltransferase pseudogene, SHMT-ps1: a unique genetic marker of the order primates. The Journal of experimental zoology 7 9723172
2025 SHMT inhibitor synergizes with 5-Fu to suppress gastric cancer via cell cycle arrest and chemoresistance alleviation. NPJ precision oncology 6 40346149
2023 Understanding The Regulatory Role of USP32 and SHMT2 in The Progression of Gastric Cancer. Cell journal 6 37210642
2022 Second report of SHMT2 related neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities. European journal of medical genetics 6 35398349
2023 NFYB increases chemosensitivity in glioblastoma by promoting HDAC5-mediated transcriptional inhibition of SHMT2. Journal of neuropathology and experimental neurology 5 37742129
2013 DHFR 19-bp deletion and SHMT C1420T polymorphisms and metabolite concentrations of the folate pathway in individuals with Down syndrome. Genetic testing and molecular biomarkers 5 23421317
2025 TFE3 and HIF1α regulates the expression of SHMT2 isoforms via alternative promoter utilization in ovarian cancer cells. Cell death & disease 4 40097394
2025 SHMT proteins: An emerging set of serine hydroxymethyltransferase in cancer. Cellular signalling 4 40617370
2024 Genome-wide identification of SHMT family genes in alfalfa (Medicago sativa) and its functional analyses under various abiotic stresses. BMC genomics 4 39134931
2023 A gene-nutrient interaction between vitamin B6 and serine hydroxymethyltransferase (SHMT) affects genome integrity in Drosophila. Journal of cellular physiology 4 37183313
2022 Knockdown of SHMT2 enhances the sensitivity of gastric cancer cells to radiotherapy through the Wnt/β-catenin pathway. Open life sciences 4 36213384
2012 Regular Multivitamin Supplement Use, Single Nucleotide Polymorphisms in ATIC, SHMT2, and SLC46A1, and Risk of Ovarian Carcinoma. Frontiers in genetics 4 22461784
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 3 40339130
2024 MiR-383-5p inhibits the proliferation and migration of lung adenocarcinoma cells by targeting SHMT2. Journal of Cancer 3 38577602
2025 Discovery of W478, a novel SHMT2 inhibitor for the treatment of esophageal carcinoma. Bioorganic chemistry 2 41014834
2024 Mitochondrial outer membrane protein Samm50 protects against hypoxia-induced cardiac injury by interacting with Shmt2. Cellular signalling 2 38723737
2018 The folic acid metabolism gene mel-32/Shmt is required for normal cell cycle lengths in Caenorhabditis elegans. The International journal of developmental biology 2 30378389
2014 Arg-265: a critical residue of L.donovani cytosolic SHMT in maintaining the binding of THF and catalysis. Experimental parasitology 2 25499510
2025 SHMT, SHMTML and PRPS1 synergize to regulate blood digestion and nutrient metabolism in Aedes aegypti mosquitoes. International journal of biological macromolecules 1 40245636
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 1 40752747
2023 Glycine homeostasis requires reverse SHMT flux. bioRxiv : the preprint server for biology 1 36711816
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