Affinage

MTHFD1

C-1-tetrahydrofolate synthase, cytoplasmic · UniProt P11586

Length
935 aa
Mass
101.5 kDa
Annotated
2026-06-10
93 papers in source corpus 19 papers cited in narrative 21 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

MTHFD1 encodes a single cytoplasmic trifunctional polypeptide carrying N5,N10-methylenetetrahydrofolate dehydrogenase, N5,N10-methenyltetrahydrofolate cyclohydrolase, and N10-formyltetrahydrofolate synthetase activities that interconvert tetrahydrofolate-activated one-carbon units for de novo purine, thymidylate, and methionine synthesis (PMID:1887335, PMID:15611115). Genetic disruption causes purine auxotrophy in stem cells and embryonic lethality in mice, with heterozygotes showing competition between formate-derived and serine-derived one-carbon units for THF cofactors used in thymidylate synthesis versus homocysteine remethylation (PMID:15611115, PMID:19033438). A fraction of MTHFD1 translocates to the nucleus during S-phase—an enrichment intensified under folate deficiency—where it assembles with SHMT1, TYMS, and DHFR at the replication machinery to support de novo thymidylate biosynthesis and limit uracil misincorporation, and is also recruited to specific genomic loci through direct interaction with BRD4 to couple folate metabolism to transcriptional output (PMID:25213861, PMID:28265077, PMID:31133746). The enzyme is governed by multiple post-translational controls: PRMT5-mediated symmetric dimethylation at R173 augments NADPH output and anoikis resistance (PMID:35798877), and TRIM21-dependent ubiquitination at K504—accelerated by the common R653Q variant—drives proteasomal degradation and reduces serine-derived methyl flux into purines (PMID:36913067). MTHFD1 sustains NADPH/NADP+ and GSH/GSSG redox balance and is a direct transcriptional target of MYCN in neuroblastoma (PMID:38336749), while its mRNA is stabilized by METTL3-dependent m6A modification to maintain nucleotide supply in erythroid progenitors (PMID:41805631). Compound heterozygous MTHFD1 mutations that abolish enzyme protein and dehydrogenase activity cause a human inborn error of folate metabolism with defective methionine formation from formate (PMID:32414565, PMID:25633902). MTHFD1 enzymatic activity is also exploited to support replication of multiple RNA viruses and is inhibited at its active site by the natural product carolacton (PMID:29142318, PMID:34544865).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    Established that the three sequential folate-interconverting activities reside on a single polypeptide rather than separate proteins, defining MTHFD1 as a trifunctional enzyme and hinting at post-transcriptional control.

    Evidence Enzymatic assays, immunoblotting and Northern blot in a CHO Ade-E mutant showing co-loss of all three activities with normal mRNA

    PMID:1887335

    Open questions at the time
    • Did not resolve domain architecture or how the three active sites are spatially organized
    • Mechanism of the inferred post-transcriptional regulation not defined
  2. 2004 High

    Genetic ablation confirmed MTHFD1 carries all three cytoplasmic activities and caused purine auxotrophy, while distinguishing it from a separate monofunctional mitochondrial formyltetrahydrofolate synthetase.

    Evidence Mthfd1 knockout in murine embryonic stem cells with enzymatic assays and subcellular fractionation

    PMID:15611115

    Open questions at the time
    • Did not address tissue-specific or developmental requirements
    • Compartmental division of labor between cytosol and mitochondria left to later work
  3. 2008 High

    Demonstrated at the organismal level that MTHFD1-generated one-carbon units are partitioned between thymidylate synthesis and methylation, with formate-derived carbons competing with serine-derived carbons for THF cofactors.

    Evidence Gene-trap Mthfd1 mouse model with hepatic AdoMet and nuclear DNA uracil measurements

    PMID:19033438

    Open questions at the time
    • Did not identify the molecular determinants of flux partitioning
    • Mechanism of homozygous embryonic lethality not dissected
  4. 2014 High

    Revealed that MTHFD1 is not constitutively cytosolic but translocates to the nucleus during S-phase and is further enriched there under folate deficiency, prioritizing thymidylate synthesis over homocysteine remethylation.

    Evidence Subcellular fractionation and cell-cycle synchronization in MCF-7/HeLa plus a folate-depletion mouse liver model

    PMID:25213861

    Open questions at the time
    • Nuclear import signal and translocation machinery not identified
    • How nuclear folate cofactor pools are maintained unresolved
  5. 2017 High

    Defined the nuclear thymidylate synthesis complex and showed it is a regulated, degradable node, with arsenic trioxide driving MTHFD1 SUMOylation and ubiquitin-dependent degradation that destabilizes the genome.

    Evidence In vitro SUMOylation, Co-IP for the MTHFD1/SHMT1/TYMS/DHFR complex, ubiquitination and uracil-in-DNA assays in cultured cells

    PMID:28265077

    Open questions at the time
    • SUMO/ubiquitin sites and responsible E3 ligase not pinpointed in this study
    • Stoichiometry and architecture of the nuclear multienzyme complex undefined
  6. 2017 High

    Provided direct structural and biochemical evidence that MTHFD1's dehydrogenase/cyclohydrolase active site is druggable, via low-nanomolar inhibition by carolacton.

    Evidence X-ray crystallography of a bacterial FolD-carolacton complex with in vitro enzymatic inhibition of human MTHFD1 and MTHFD2

    PMID:29142318

    Open questions at the time
    • No crystal structure of human MTHFD1 with the inhibitor
    • Selectivity between MTHFD1 and MTHFD2 not resolved
  7. 2019 High

    Connected MTHFD1's nuclear pool to transcriptional control by identifying a direct BRD4 interaction that recruits the enzyme to chromatin and couples folate metabolism to gene expression.

    Evidence Converging genetic and physical interaction screens, Co-IP, nuclear metabolomics and in vivo synergy of BRD4/MTHFD1 inhibitors

    PMID:31133746

    Open questions at the time
    • Interaction interface and chromatin-recruitment mechanism not mapped
    • Whether enzymatic activity or scaffolding drives transcriptional effects unclear
  8. 2022 High

    Showed MTHFD1 is functionally tuned by arginine methylation, with PRMT5-mediated R173 symmetric dimethylation boosting NADPH output to confer anoikis resistance and metastasis.

    Evidence CRISPR screen, Co-IP, in vitro methylation, R173 mutagenesis, NADPH ratio measurement and metastasis xenografts

    PMID:35798877

    Open questions at the time
    • How R173 methylation structurally alters catalytic output not defined
    • Demethylase counter-regulation unknown
  9. 2023 Medium

    Identified TRIM21 as the E3 ligase ubiquitinating MTHFD1 at K504 and explained how the common R653Q variant destabilizes the protein and reduces purine biosynthetic flux.

    Evidence Co-IP, mass spectrometry site mapping, serine isotope flux analysis and xenograft growth assays

    PMID:36913067

    Open questions at the time
    • Single-lab finding without reciprocal validation of the TRIM21 interaction
    • Signals controlling TRIM21-MTHFD1 engagement not defined
  10. 2023 Medium

    Established a noncanonical role for MTHFD1 in repressing RARγ transcriptional activity, linking folate enzyme loss to neural tube defect pathology.

    Evidence IP-mass spectrometry, Co-IP, luciferase reporter and ChIP-qPCR with a retinoic acid-induced NTD mouse model

    PMID:36928982

    Open questions at the time
    • In vivo link is correlative rather than rescue-based
    • Whether repression depends on enzymatic activity or physical binding unresolved
  11. 2023 High

    Demonstrated that pharmacological MTHFD1/MTHFD2 dehydrogenase inhibition creates a nuclear '10-formyl-THF folate trap' that selectively kills MTHFD2-expressing cancer cells through thymidylate depletion.

    Evidence Metabolomics, isotope tracing and compartment-specific inhibitor (TH9619) studies

    PMID:37012496

    Open questions at the time
    • Determinants of nuclear versus mitochondrial inhibitor selectivity incompletely defined
    • Generality across tumor types not established
  12. 2024 Medium

    Placed MTHFD1 in redox homeostasis and oncogenic transcriptional circuitry, showing MYCN directly drives MTHFD1 expression to maintain NADPH and GSH pools and prevent apoptosis.

    Evidence ChIP-qPCR, dual-luciferase reporter, knockdown with NADPH/GSH/ROS measurements and xenografts

    PMID:38336749

    Open questions at the time
    • Direct biochemical link between MTHFD1 catalysis and the measured redox ratios not isolated
    • Single-lab finding
  13. 2024 Medium

    Showed MTHFD1 abundance is set post-transcriptionally by METTL3-dependent m6A modification, gating nucleotide supply and genome stability in erythroid progenitors.

    Evidence m6A-seq/RNA-seq integration, erythroid-specific Mettl3 knockout mouse, nucleotide measurements and rescue

    PMID:41805631

    Open questions at the time
    • m6A reader mediating MTHFD1 mRNA stabilization not identified
    • Tissue specificity of this regulation untested
  14. 2020 Medium

    Confirmed in patient-derived cells that disease-causing MTHFD1 mutations abolish protein and dehydrogenase activity, establishing MTHFD1 deficiency as a human inborn error of folate metabolism.

    Evidence Western blot and dehydrogenase activity assays in fibroblasts from compound heterozygous patients; complemented by [14C]-formate methionine-formation flux assays

    PMID:25633902 PMID:32414565

    Open questions at the time
    • Genotype-phenotype relationships across mutation classes incomplete
    • Tissue-level pathophysiology beyond fibroblasts not addressed
  15. 2021 Medium

    Defined MTHFD1 as a host dependency factor whose enzymatic activity supports replication of multiple RNA viruses, nominating it as an antiviral target.

    Evidence Genome-wide CRISPR and RNAi screens in bat cells with carolacton inhibition across mumps, influenza A and SARS-CoV-2

    PMID:34544865

    Open questions at the time
    • Which one-carbon outputs the viruses require not dissected
    • Direct dependence on individual MTHFD1 activities not separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MTHFD1's enzymatic and scaffolding functions are integrated with its partner enzymes and signaling inputs—including direct substrate channeling to MTHFR and the regulatory consequences of RIPK4 phosphorylation—remains unresolved.
  • No direct experimental demonstration of methylenetetrahydrofolate channeling between MTHFD1 and MTHFR
  • RIPK4 phosphorylation site and mechanism in MTHFD1 not mapped (preprint)
  • Integration of nuclear scaffolding, redox, and metabolic roles into a unified regulatory logic absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0016874 ligase activity 3 GO:0016787 hydrolase activity 1 GO:0016829 lyase activity 1
Localization
GO:0005634 nucleus 3 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-8953854 Metabolism of RNA 1
Partners
BRD4DHFRMTHFRPRMT5RARGSHMT1TRIM21TYMS
Complex memberships
nuclear thymidylate synthesis complex (MTHFD1-SHMT1-TYMS-DHFR)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 MTHFD1 (MTHFD) encodes a single trifunctional polypeptide with three sequential catalytic activities: N5,N10-methylenetetrahydrofolate dehydrogenase, N5,N10-methenyltetrahydrofolate cyclohydrolase, and N10-formyltetrahydrofolate synthetase, all required for interconversion of tetrahydrofolate derivatives for purine, thymidylate, and methionine synthesis. In a CHO Ade-E mutant, all three activities were lost together with reduced/absent protein despite normal mRNA, demonstrating the activities reside on a single polypeptide and suggesting a post-transcriptional regulatory mechanism. Enzymatic activity assays, immunoblotting, immunoprecipitation, Northern blot analysis in CHO Ade-E mutant cells Somatic cell and molecular genetics High 1887335
2004 Knockout of the Mthfd1 gene in murine embryonic stem cells eliminates all three cytoplasmic MTHFD1 activities (dehydrogenase, cyclohydrolase, synthetase), causes purine auxotrophy, and reveals a separate mitochondrial monofunctional 10-formyltetrahydrofolate synthetase (encoded by a recently identified mitochondrial transcript). Absence of NADP-dependent dehydrogenase activity in these null cells confirmed the mitochondrial enzyme lacks dehydrogenase/cyclohydrolase activities. Gene knockout in embryonic stem cells, enzymatic activity assays, subcellular fractionation/localization, Northern blot The Journal of biological chemistry High 15611115
2008 Disruption of the Mthfd1 gene (gene-trap insertion inactivating formyl-THF synthetase/FTHFS activity) causes embryonic lethality in homozygous mice. Heterozygous Mthfd1gt/+ mice show lower hepatic S-adenosylmethionine (indicating formate-derived one carbons contribute to methylation reactions), decreased uracil in nuclear DNA (indicating enhanced thymidylate synthesis when FTHFS is reduced), demonstrating that formate-derived carbons compete with serine-derived carbons for THF cofactors used in thymidylate vs. homocysteine remethylation. Gene-trap mouse model, metabolite measurements (AdoMet, uracil in DNA), genetic analysis The Journal of biological chemistry High 19033438
2009 The common MTHFD1 p.Arg653Gln (R653Q) variant reduces enzyme thermostability (36% reduction in half-life at 42°C) without altering substrate affinity. Thermolability is rescued by folate pentaglutamate and Mg-ATP. In murine Mthfd1 knockout cells transfected with the Arg653Gln variant, formate incorporation into DNA (a proxy for de novo purine synthesis) is reduced by 26% compared to wild-type, indicating impaired de novo purine synthesis. In vitro enzyme activity and stability assays (purified recombinant protein), mammalian cell transfection with formate incorporation into DNA measurement Human mutation High 18767138
2014 MTHFD1 translocates to the nucleus during S-phase in MCF-7 and HeLa cells. During folate deficiency, MTHFD1 is enriched >2-fold in the nucleus at the expense of cytosolic levels in mouse liver, and nuclear folate cofactors are maintained when total cellular folate is reduced by >50%. This nuclear enrichment supports de novo thymidylate biosynthesis preferentially over cytosolic homocysteine remethylation during folate deficiency. Subcellular fractionation, Western blot, cell cycle synchronization (S-phase), mouse dietary folate depletion model The Journal of biological chemistry High 25213861
2017 Arsenic trioxide (As2O3) increases MTHFD1 SUMOylation (confirmed in cultured cells and in vitro SUMOylation reactions) and promotes MTHFD1 ubiquitination and proteolytic degradation (along with SHMT1). This leads to inhibition of de novo thymidylate biosynthesis, increased uracil misincorporation into nuclear DNA, and genome instability. MTHFD1 and SHMT1 form a multienzyme complex with TYMS and DHFR at the nuclear DNA replication machinery during S-phase. In vitro SUMOylation assay, immunoprecipitation (Co-IP), Western blot for ubiquitination and protein levels, uracil-in-DNA measurement, genome instability assays in cultured cells Proceedings of the National Academy of Sciences of the United States of America High 28265077
2017 The natural product carolacton inhibits both bacterial FolD and the human orthologs MTHFD1 and MTHFD2 in the low nanomolar range. Crystal structure of the bacterial FolD-carolacton complex reveals the binding mode; carolacton occupies the active site and inhibits the dehydrogenase/cyclohydrolase activities. Biophysical binding assay, X-ray crystallography of FolD-carolacton complex, in vitro enzymatic inhibition assays for MTHFD1 and MTHFD2 Nature communications High 29142318
2019 A fraction of MTHFD1 resides in the nucleus where it is recruited to specific genomic loci by direct physical interaction with BRD4 (bromodomain-containing protein 4). Genetic and pharmacological screens identified this MTHFD1-BRD4 interaction. Inhibition of either BRD4 or MTHFD1 produces similar changes in nuclear metabolite composition and gene expression, and the two inhibitors synergize to impair cancer cell viability in vitro and in vivo. Complementary genetic interaction screen and physical interaction screen (converging on MTHFD1-BRD4), nuclear localization by fractionation, co-immunoprecipitation, metabolomics, in vitro and in vivo pharmacological studies Nature genetics High 31133746
2022 PRMT5 directly binds MTHFD1 and symmetrically dimethylates it at arginine R173. Under suspension conditions (anoikis stress), the MTHFD1-PRMT5 interaction is strengthened, elevating R173 symmetric dimethylation, which augments MTHFD1 metabolic activity (NADPH generation), promoting anoikis resistance and distant organ metastasis. Genetic depletion or pharmacological inhibition of PRMT5 reduced tumor metastasis. CRISPR-Cas9 metabolic enzyme screen, Co-immunoprecipitation, in vitro methylation assay, site-directed mutagenesis (R173), NADPH/NADP+ ratio measurement, xenograft/metastasis models Oncogene High 35798877
2023 TH9619, a dual inhibitor of MTHFD1 and MTHFD2 dehydrogenase/cyclohydrolase activities, selectively targets nuclear MTHFD2 but not mitochondrial MTHFD2. Continued mitochondrial formate overflow accumulates 10-formyl-THF downstream of MTHFD1 inhibition, creating a 'folate trap.' This results in thymidylate depletion and selective death of MTHFD2-expressing cancer cells. The trapping is exacerbated by physiological hypoxanthine which blocks de novo purine synthesis and prevents 10-formyl-THF consumption. Metabolomics (10-formyl-THF accumulation), isotope tracing, selective MTHFD2 nuclear vs. mitochondrial inhibition analysis, cellular viability assays, genetic and pharmacological perturbations Nature metabolism High 37012496
2023 MTHFD1 negatively regulates retinoic acid receptor γ (RARγ) transcription factor activity. IP-mass spectrometry identified MTHFD1 as a specific RARγ-interacting protein; co-immunoprecipitation and immunofluorescence confirmed the interaction. MTHFD1 knockdown de-repressed RARγ signaling; low MTHFD1 expression and activated RAR signaling were observed in human anencephaly and a retinoic acid-induced NTD mouse model. Immunoprecipitation-mass spectrometry, co-immunoprecipitation, immunofluorescence confocal microscopy, luciferase reporter assay, ChIP-qPCR, mouse NTD model Brain : a journal of neurology Medium 36928982
2023 The MTHFD1 G1958A (R653Q) SNP reduces protein stability through ubiquitination-mediated proteasomal degradation. The R653Q variant shows enhanced binding to the E3 ubiquitin ligase TRIM21 compared to wild-type; lysine K504 is the primary ubiquitination site. R653Q expression results in reduced serine-derived methyl flux into purine synthesis precursors (confirmed by metabolic flux analysis) and impaired tumor growth in xenograft models. Immunoprecipitation for ubiquitination, mass spectrometry identification of ubiquitination site and interacting proteins, metabolic flux analysis with serine isotope, xenograft tumor growth assay Cellular oncology (Dordrecht, Netherlands) Medium 36913067
2021 Genome-wide CRISPR and RNAi screens in bat cells identified MTHFD1 as required for viral replication (mumps virus, influenza A, SARS-CoV-2). The MTHFD1 inhibitor carolacton potently blocked replication of several RNA viruses including SARS-CoV-2, demonstrating that MTHFD1 enzymatic activity supports viral replication in both bat and human cells. Genome-wide CRISPR and RNAi library screens, carolacton pharmacological inhibition, viral replication assays Proceedings of the National Academy of Sciences of the United States of America Medium 34544865
2020 MTHFD1 protein expression is markedly reduced (to 4.8–14.3% of control values) and methylenetetrahydrofolate dehydrogenase specific activity is undetectable in fibroblasts from MTHFD1-deficient patients bearing compound heterozygous MTHFD1 mutations, confirming that patient mutations abolish enzymatic function. Western blot for MTHFD1 protein expression in patient fibroblasts, enzymatic activity assay for dehydrogenase activity Molecular genetics and metabolism Medium 32414565
2015 Patient fibroblasts with MTHFD1 deficiency show severely reduced methionine formation from [14C]-formate (a direct measure of formyl-THF synthetase activity feeding homocysteine remethylation), which did not improve with cobalamin supplementation but was responsive to folic and folinic acid treatment, indicating that MTHFD1 is required for formate entry into folate metabolism for methionine synthesis. Radiolabeled formate ([14C]-formate) metabolic flux assay in patient fibroblasts, supplementation experiments Journal of inherited metabolic disease Medium 25633902
2024 MTHFD1 maintains NADPH/NADP+ and GSH/GSSG redox homeostasis in MYCN-amplified neuroblastoma. MYCN directly activates MTHFD1 transcription (confirmed by ChIP-qPCR and dual-luciferase reporter assay). Knockdown of MTHFD1 reduces NADPH/NADP+ and GSH/GSSG ratios, increases ROS, and triggers apoptosis. ChIP-qPCR, dual-luciferase reporter assay, MTHFD1 knockdown, NADPH/NADP+ and GSH/GSSG ratio measurements, ROS measurement, mouse xenograft model Cell death & disease Medium 38336749
2024 MTHFD1 regulates autophagy via the PI3K-AKT-mTOR signaling pathway in colorectal cancer cells. MTHFD1 overexpression suppresses autophagy and activates PI3K-AKT-mTOR, promoting proliferation and metastasis, while MTHFD1 knockdown increases autophagy and suppresses these phenotypes. Validated in xenograft models. Western blot for PI3K-AKT-mTOR pathway and autophagy markers, Transwell invasion assay, xenograft tumor models Cancer medicine Low 39571599
2024 METTL3-mediated m6A modification controls MTHFD1 mRNA stability in erythroid cells. Mettl3 deletion reduces Mthfd1 expression, causing nucleotide (dTMP and IMP) shortage, DNA damage, and apoptosis in erythroid progenitors. Re-introduction or rescue of MTHFD1 activity reverses the genome instability phenotype. m6A-seq and RNA-seq integration, Western blot, nucleotide measurement (dTMP and IMP), DNA damage assays, erythroid-specific Mettl3 knockout mouse (EpoR-Cre) The Journal of clinical investigation Medium 41805631
2024 MTHFD1 protein interacts with MTHFR (methylenetetrahydrofolate reductase) as identified by affinity purification-mass spectrometry and confirmed by immunoprecipitation-immunoblotting. An AlphaFold3 model places the MTHFD1 dehydrogenase/cyclohydrolase domain in direct contact with the MTHFR catalytic domain, suggesting substrate (methylenetetrahydrofolate) channeling between the two enzymes. Affinity purification-mass spectrometry (AP-MS), immunoprecipitation-immunoblotting, AlphaFold3 structural modeling Biochimie Low 39571719
2025 Genetic knockout and chemical degradation of NUDT5 revealed that NUDT5 interacts with PPAT (the rate-limiting enzyme of de novo purine synthesis) to repress the pathway in response to elevated purine levels. This NUDT5-PPAT scaffolding role (non-enzymatic) mediates sensitivity to adenosine in MTHFD1 deficiency, placing NUDT5 downstream of MTHFD1 in regulating purine de novo synthesis. CRISPR knockout, selective NUDT5 chemical degrader (PROTAC-type), genetic epistasis in MTHFD1 mutant background, interaction studies (NUDT5-PPAT) bioRxivpreprint Low
2024 RIPK4 (driven by TP53 mutations) phosphorylates MTHFD1, boosting NADPH production, reducing ROS, and promoting resistance to PANoptosis and metastasis in colorectal cancer. Phosphorylation assay (RIPK4-MTHFD1), NADPH measurement, ROS measurement, metastasis models in CRC bioRxivpreprint Low

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. The pharmacogenomics journal 136 14647408
1998 Molecular genetic analysis of the gene encoding the trifunctional enzyme MTHFD (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase) in patients with neural tube defects. Clinical genetics 124 9611072
2009 The MTHFD1 p.Arg653Gln variant alters enzyme function and increases risk for congenital heart defects. Human mutation 88 18767138
2008 Mthfd1 is an essential gene in mice and alters biomarkers of impaired one-carbon metabolism. The Journal of biological chemistry 74 19033438
2019 MTHFD1 interaction with BRD4 links folate metabolism to transcriptional regulation. Nature genetics 71 31133746
2017 The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. Nature communications 67 29142318
2014 Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. The Journal of biological chemistry 59 25213861
2003 Genotype frequencies and linkage disequilibrium in the CEPH human diversity panel for variants in folate pathway genes MTHFR, MTHFD, MTRR, RFC1, and GCP2. Birth defects research. Part A, Clinical and molecular teratology 56 14632302
2007 Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. Acta neurobiologiae experimentalis 55 17691219
2011 Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband. Journal of medical genetics 51 21813566
2007 Polymorphisms of MTHFD, plasma homocysteine levels, and risk of gastric cancer in a high-risk Chinese population. Clinical cancer research : an official journal of the American Association for Cancer Research 47 17438114
2023 Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature metabolism 46 37012496
2005 A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss. Molecular human reproduction 46 16123074
2004 Disruption of the mthfd1 gene reveals a monofunctional 10-formyltetrahydrofolate synthetase in mammalian mitochondria. The Journal of biological chemistry 44 15611115
2013 Severe combined immunodeficiency resulting from mutations in MTHFD1. Pediatrics 42 23296427
2013 Homocysteine Level and Mechanisms of Injury in Parkinson's Disease as Related to MTHFR, MTR, and MTHFD1 Genes Polymorphisms and L-Dopa Treatment. Current genomics 35 24532985
2015 Characterization and review of MTHFD1 deficiency: four new patients, cellular delineation and response to folic and folinic acid treatment. Journal of inherited metabolic disease 33 25633902
2021 Orthogonal genome-wide screens of bat cells identify MTHFD1 as a target of broad antiviral therapy. Proceedings of the National Academy of Sciences of the United States of America 32 34544865
2017 Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis. Proceedings of the National Academy of Sciences of the United States of America 32 28265077
2022 Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis. Oncogene 31 35798877
2016 MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability. Biochimie 31 26853819
2013 Polymorphisms in MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among North Indian women. Archives of gynecology and obstetrics 30 23685927
2012 Maternal Mthfd1 disruption impairs fetal growth but does not cause neural tube defects in mice. The American journal of clinical nutrition 27 22378735
2010 Mthfd1 is a modifier of chemically induced intestinal carcinogenesis. Carcinogenesis 26 21156972
2009 Analysis of the MTHFD1 promoter and risk of neural tube defects. Human genetics 26 19130090
2011 MTHFR, MTR, and MTHFD1 gene polymorphisms compared to homocysteine and asymmetric dimethylarginine concentrations and their metabolites in epileptic patients treated with antiepileptic drugs. Seizure 25 21543238
2019 Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer. Gene 24 31377316
2007 MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatric genetics 24 17417062
2016 Moderate folic acid supplementation and MTHFD1-synthetase deficiency in mice, a model for the R653Q variant, result in embryonic defects and abnormal placental development. The American journal of clinical nutrition 23 27707701
2014 Association between MTHFD1 G1958A polymorphism and neural tube defects susceptibility: a meta-analysis. PloS one 20 24977710
2012 Reduced MTHFD1 activity in male mice perturbs folate- and choline-dependent one-carbon metabolism as well as transsulfuration. The Journal of nutrition 19 23190757
2017 One-carbon genetic variants and the role of MTHFD1 1958G>A in liver and colon cancer risk according to global DNA methylation. PloS one 18 28968444
2016 Precision Molecular Diagnosis Defines Specific Therapy in Combined Immunodeficiency with Megaloblastic Anemia Secondary to MTHFD1 Deficiency. The journal of allergy and clinical immunology. In practice 16 27707659
2011 MTHFD1 G1958A, BHMT G742A, TC2 C776G and TC2 A67G polymorphisms and head and neck squamous cell carcinoma risk. Molecular biology reports 16 21630102
2017 Relationship of the MTHFD1 (rs2236225), eNOS (rs1799983), CBS (rs2850144) and ACE (rs4343) gene polymorphisms in a population of Iranian pediatric patients with congenital heart defects. The Kaohsiung journal of medical sciences 14 28865601
2015 MTHFD1 formyltetrahydrofolate synthetase deficiency, a model for the MTHFD1 R653Q variant, leads to congenital heart defects in mice. Birth defects research. Part A, Clinical and molecular teratology 14 26408344
2008 The MTHFD1 gene is not involved in cleft lip with or without palate onset among the Italian population. Annals of human genetics 14 18261183
2023 Association of Maternal Folate Intake and Offspring MTHFD1 and MTHFD2 Genes with Congenital Heart Disease. Nutrients 13 37630697
2022 The Emerging Role of MTHFD Family Genes in Regulating the Tumor Immunity of Oral Squamous Cell Carcinoma. Journal of oncology 13 35693982
2022 Association of MTHFD1 gene polymorphisms and maternal smoking with risk of congenital heart disease: a hospital-based case-control study. BMC pregnancy and childbirth 12 35100977
2014 Association between MTHFD1 polymorphisms and neural tube defect susceptibility. Journal of the neurological sciences 12 25524527
2010 Methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study. Journal of medicine and life 12 21254748
2024 MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma. Cell death & disease 11 38336749
2018 Low Dietary Folate Interacts with MTHFD1 Synthetase Deficiency in Mice, a Model for the R653Q Variant, to Increase Incidence of Developmental Delays and Defects. The Journal of nutrition 11 29659962
2017 Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene. Computational biology and chemistry 11 28734179
2020 CpG-SNP site methylation regulates allele-specific expression of MTHFD1 gene in type 2 diabetes. Laboratory investigation; a journal of technical methods and pathology 10 32238907
2020 Biochemical analysis of patients with mutations in MTHFD1 and a diagnosis of methylenetetrahydrofolate dehydrogenase 1 deficiency. Molecular genetics and metabolism 10 32414565
2014 Association study of MTHFD1 coding polymorphisms R134K and R653Q with migraine susceptibility. Headache 10 25039261
2010 Association analysis of CbetaS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer's disease in Chinese. Journal of neural transmission (Vienna, Austria : 1996) 10 20217437
2015 Paternal transmission of MTHFD1 G1958A variant predisposes to neural tube defects in the offspring. Developmental medicine and child neurology 9 26394717
2014 Combined folate gene MTHFD and TC polymorphisms as maternal risk factors for Down syndrome in China. Genetics and molecular research : GMR 9 24668664
2017 Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice. Behavioural brain research 8 28559181
2016 Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors. Molecular carcinogenesis 8 27597531
1991 A pseudogene on the X chromosome for the human trifunctional enzyme MTHFD (methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase-formyltetrahydrofolate synthetase). Genomics 8 1916813
2022 A Common Polymorphism in the MTHFD1 Gene Is a Modulator of Risk of Congenital Heart Disease. Journal of cardiovascular development and disease 7 35735795
2017 Evidence of gene-gene interactions between MTHFD1 and MTHFR in relation to anterior encephalocele susceptibility in Northeast India. Birth defects research 7 28398708
2014 Significant association of MTHFD1 1958G>A single nucleotide polymorphism with nonsyndromic cleft lip and palate in Indian population. Medicina oral, patologia oral y cirugia bucal 7 25129243
2013 The MTHFD1 1958G>A variant is associated with elevated C-reactive protein and body mass index in Canadian women from a premature birth cohort. Molecular genetics and metabolism 7 24368157
2009 Association between HIC1 and RASSF1A promoter hypermethylation with MTHFD1 G1958A polymorphism and clinicopathological features of breast cancer in Iranian patients. Iranian biomedical journal 7 19946345
2025 Identifying MTHFD1 and LGALS4 as Potential Therapeutic Targets in Prostate Cancer Through Multi-Omics Mendelian Randomization Analysis. Biomedicines 6 39857769
2024 MTHFD1 Regulates Autophagy to Promote Growth and Metastasis in Colorectal Cancer via the PI3K-AKT-mTOR Signaling Pathway. Cancer medicine 6 39571599
2023 MTHFD1 is critical for the negative regulation of retinoic acid receptor signalling in anencephaly. Brain : a journal of neurology 6 36928982
2021 A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma. Cell death discovery 6 33934113
2020 Independent and Interactive Influences of Environmental UVR, Vitamin D Levels, and Folate Variant MTHFD1-rs2236225 on Homocysteine Levels. Nutrients 6 32443475
2018 Methylenetetrahydrofolate Dehydrogenase 1 (MTHFD1) is Underexpressed in Clear Cell Renal Cell Carcinoma Tissue and Transfection and Overexpression in Caki-1 Cells Inhibits Cell Proliferation and Increases Apoptosis. Medical science monitor : international medical journal of experimental and clinical research 6 30459299
2015 Polymorphisms in MTHFD1 Gene and Susceptibility to Neural Tube Defects: A Case-Control Study in a Chinese Han Population with Relatively Low Folate Levels. Medical science monitor : international medical journal of experimental and clinical research 6 26343515
2025 Association of MTHFD1 G1958A (rs2236225) gene polymorphism with the risk of congenital heart disease: a systematic review and meta-analysis. BMC medical genomics 4 39871280
2024 Betaine and B12 Intake, Glutathione Concentration, and MTHFR, PEMT, and MTHFD1 Genotypes Are Associated with Diabetes-Related Parameters in Polish Adults. The Journal of nutrition 4 39442756
2022 Association of Maternal Dietary Habits and MTHFD1 Gene Polymorphisms With Ventricular Septal Defects in Offspring: A Case-Control Study. Frontiers in pediatrics 4 35186819
2019 Detection of Polymorphisms in MTHFD1 G1958A and Its Possible Association with Idiopathic Male Infertility. Urology journal 4 30882176
2015 Is MTHFD1 polymorphism rs 2236225 (c.1958G>A) associated with the susceptibility of NSCL/P? A systematic review and meta-analysis. F1000Research 4 26834978
2010 The MTHFD1 c.1958 G>A polymorphism and recurrent spontaneous abortions. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 4 20334533
2024 Specific association of MTHFD1 expressions with small cell lung cancer development and chemoradiotherapy outcome. Saudi medical journal 3 39074897
2024 Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L. Scientific reports 3 39256448
2023 Common Variants in One-Carbon Metabolism Genes (MTHFR, MTR, MTHFD1) and Depression in Gynecologic Cancers. International journal of molecular sciences 3 37628752
2014 [G894T (NOS3) and G1958A (MTHFD1) gene polymorphisms and risk of ischemic heart disease in Yucatan, Mexico]. Clinica e investigacion en arteriosclerosis : publicacion oficial de la Sociedad Espanola de Arteriosclerosis 3 25304051
2024 Association of MTHFD1 G1958A Polymorphism with Gestational Diabetes Mellitus. Cureus 2 38435941
2024 Evidence for interaction of 5,10-methylenetetrahydrofolate reductase (MTHFR) with methylenetetrahydrofolate dehydrogenase (MTHFD1) and general control nonderepressible 1 (GCN1). Biochimie 2 39571719
2023 Doubly bi-allelic variants of MTHFR and MTHFD1 in a Chinese patient with hyperhomocysteinemia and failure of folic acid therapy. Frontiers in genetics 2 36685872
2023 The negative effect of G1958A polymorphism on MTHFD1 protein stability and HCC growth. Cellular oncology (Dordrecht, Netherlands) 2 36913067
2018 Impact of RFC1, MTHFR, and MTHFD1 polymorphism on unexplained pregnancy loss (UPL): comparative analysis of maternal and fetal components using mother-abortus paired samples. European journal of obstetrics, gynecology, and reproductive biology 2 30388610
2014 The role of 401a>G polymorphism of methylenetetrahydrofolate dehydrogenase gene (MTHFD1) in fetal hypotrophy. Ginekologia polska 2 25118499
2011 [Prediction of the efficacy of modified FOLFOX6 therapy according to the mRNA levels of thymidylate synthase (TS), excision repair cross-complementing-1 and -2( ERCC-1 and ERCC-2) and methylenetetrahydrofolate dehydrogenase( MTHFD) in the primary lesion of colorectal cancer]. Gan to kagaku ryoho. Cancer & chemotherapy 2 22202336
1991 Deficient synthesis of MTHFD, a trifunctional folate-dependent enzyme, in the CHO Ade E mutant. Somatic cell and molecular genetics 2 1887335
2026 CRISPR screen of human pancreatic cancer xenografts identifies a KLF5 proliferation vulnerability through epigenetic modifiers NCAPD2 and MTHFD1. Molecular cancer 1 41668133
2022 [Association of maternal MTHFD1 and MTHFD2 gene polymorphisms with congenital heart disease in offspring]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 1 35894196
2021 Triglyceride regulate ACE2 level through MTHFD1. Journal of biosciences 1 34168100
2021 Association Between MTHFD1 1958G > A Variant and non-Syndromic Cleft lip and Palate: An Updated Meta-Analysis. The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association 1 34904448
2017 MTHFR and MTHFD1 gene polymorphisms are not associated with pseudoexfoliation syndrome in South Indian population. International ophthalmology 1 28299500
2015 MTHFD1 gene polymorphisms as risk factors involved in orofacial cleft: an independent case-control study and a meta-analysis. International journal of clinical and experimental medicine 1 26221324
2026 Methyltransferase complex subunit METTL3 maintains genome stability of erythroid cells via MTHFD1-mediated nucleotide biosynthesis. The Journal of clinical investigation 0 41805631
2026 Discovery of 1,2,3,4-Tetrahydrochromeno[3,4-c]pyridin-5-one Derivatives as Novel MTHFD Inhibitors for the Treatment of Acute Myeloid Leukemia. Journal of medicinal chemistry 0 41859783
2025 Contrasting Effects of Phosphatidylcholine and Betaine Supplementation on Embryonic Development in a Mouse Model of the MTHFD1 R653Q Variant. The Journal of nutrition 0 40714174

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