Affinage

MTHFD1

C-1-tetrahydrofolate synthase, cytoplasmic · UniProt P11586

Length
935 aa
Mass
101.5 kDa
Annotated
2026-04-28
94 papers in source corpus 21 papers cited in narrative 22 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MTHFD1 is a cytoplasmic trifunctional enzyme that catalyzes the interconversion of tetrahydrofolate one-carbon derivatives—functioning as 5,10-methyleneTHF dehydrogenase, 5,10-methenylTHF cyclohydrolase, and 10-formylTHF synthetase—and thereby serves as the central hub for folate-mediated one-carbon metabolism supporting de novo purine synthesis, thymidylate biosynthesis, and homocysteine remethylation (PMID:1887335, PMID:15611115). During S-phase, a regulated fraction of MTHFD1 translocates to the nucleus, where it supplies 5,10-methyleneTHF for de novo thymidylate synthesis and interacts with the chromatin reader BRD4 at specific genomic loci to influence gene expression and nuclear metabolite composition (PMID:25213861, PMID:31133746). MTHFD1 activity is modulated by PRMT5-mediated Arg173 symmetric dimethylation (enhancing NADPH generation and anoikis resistance), TRIM21-mediated ubiquitination at K504 (accelerated by the common R653Q variant, impairing purine synthesis), SUMOylation-triggered degradation, and transcriptional control by MYCN and METTL3-dependent m6A modification of its mRNA (PMID:35798877, PMID:36913067, PMID:28265077, PMID:38336749, PMID:41805631). Biallelic loss-of-function mutations in MTHFD1 cause a severe inborn error of folate metabolism presenting with megaloblastic anemia, hemolytic uremic syndrome, and combined immunodeficiency (PMID:21813566, PMID:32414565).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1991 High

    Establishing that MTHFD1 encodes a single trifunctional polypeptide with dehydrogenase, cyclohydrolase, and synthetase activities resolved how three sequential folate interconversion steps are coordinated in the cytoplasm.

    Evidence Enzymatic assays and immunoblotting of CHO Ade-E mutant cells lacking MTHFD1 protein despite normal mRNA

    PMID:1887335

    Open questions at the time
    • Post-transcriptional regulation mechanism in the mutant not defined
    • No structural information on how three domains are organized
  2. 2004 High

    Genetic disruption in mouse cells proved MTHFD1 is the sole cytoplasmic source of these enzymatic activities and is essential for de novo purine synthesis, answering whether redundant cytoplasmic enzymes could compensate.

    Evidence Gene disruption in ES cells and fibroblasts with enzymatic activity assays and subcellular fractionation

    PMID:15611115

    Open questions at the time
    • Whether any compensatory pathway operates under specific metabolic stress conditions
    • Mitochondrial 10-formylTHF synthetase identity not resolved
  3. 2008 High

    Demonstrating embryonic lethality in homozygous gene-trap mice and altered SAM/uracil levels in heterozygotes established that MTHFD1 synthetase activity is essential for development and governs the partitioning of one-carbon units between methylation and thymidylate pathways.

    Evidence Mthfd1 gene-trap mouse model with hepatic AdoMet and uracil-in-DNA quantification

    PMID:19033438

    Open questions at the time
    • Tissue-specific requirements not dissected
    • Whether partitioning is regulated dynamically in vivo
  4. 2009 High

    Biochemical characterization of the common R653Q variant revealed reduced protein thermostability and impaired purine synthesis, providing a molecular mechanism for the epidemiological associations of this polymorphism.

    Evidence Purified enzyme thermostability assay and formate incorporation in transfected knockout cells

    PMID:18767138

    Open questions at the time
    • E3 ligase and degradation pathway for destabilized variant not yet identified at this time
    • In vivo metabolic consequences of the variant not assessed
  5. 2011 High

    Identification of biallelic MTHFD1 mutations in patients with megaloblastic anemia, atypical HUS, and SCID established MTHFD1 deficiency as a Mendelian inborn error of folate metabolism, revealing the enzyme's non-redundant role in human nucleotide synthesis and immune function.

    Evidence Exome sequencing with enzymatic assays in patient fibroblasts

    PMID:21813566

    Open questions at the time
    • Mechanism by which MTHFD1 deficiency specifically causes immune deficiency not elucidated
    • Whether residual protein supports partial activity in patients
  6. 2014 High

    Discovery of S-phase-dependent nuclear translocation of MTHFD1 resolved how thymidylate synthesis is compartmentalized and explained how folate one-carbon partitioning adapts to folate deficiency by prioritizing nuclear dTMP synthesis.

    Evidence Subcellular fractionation and immunofluorescence/cell cycle analysis in MCF-7, HeLa, and mouse liver

    PMID:25213861

    Open questions at the time
    • Nuclear import signal and transport mechanism not identified
    • Whether nuclear translocation is regulated by specific kinases or signals unknown
  7. 2015 Medium

    Haploinsufficiency of the synthetase domain alone caused ventricular septal defects in mouse embryos, dissecting the domain-specific contribution of MTHFD1 to cardiac development through purine supply.

    Evidence Mthfd1S+/- synthetase-specific mouse model with histological analysis of E14.5 hearts

    PMID:26408344

    Open questions at the time
    • Whether dehydrogenase/cyclohydrolase domain deficiency causes distinct developmental phenotypes not tested
    • Downstream purine-dependent signaling in cardiogenesis not defined
  8. 2017 High

    Two independent advances revealed MTHFD1 as a target of post-translational regulation (SUMOylation-triggered degradation by arsenic) and pharmacological inhibition (carolacton), establishing tools and regulatory mechanisms for modulating one-carbon flux.

    Evidence In vitro SUMOylation assays and cellular degradation experiments for arsenic; crystal structure of FolD-carolacton complex with biochemical inhibition of human MTHFD1

    PMID:28265077 PMID:29142318

    Open questions at the time
    • SUMO sites on MTHFD1 not mapped
    • Carolacton selectivity for MTHFD1 versus MTHFD2 in cells not fully resolved
  9. 2019 High

    Identification of the BRD4–MTHFD1 nuclear interaction linked folate one-carbon metabolism to chromatin-dependent gene regulation, revealing a non-metabolic nuclear function for MTHFD1.

    Evidence Complementary genetic and physical interaction screens, Co-IP, ChIP, nuclear metabolite profiling, and pharmacological synergy in vitro and in vivo

    PMID:31133746

    Open questions at the time
    • Whether MTHFD1 enzymatic activity or a scaffolding role mediates gene expression changes not distinguished
    • Specific genomic loci regulated by MTHFD1-BRD4 not comprehensively mapped
  10. 2021 High

    Genome-wide RNAi and CRISPR screens in bat and human cells identified MTHFD1 as a host factor required for RNA virus replication, expanding its functional relevance beyond endogenous metabolism.

    Evidence Orthogonal RNAi and CRISPR screens with carolacton validation against mumps virus, influenza A, and SARS-CoV-2

    PMID:34544865

    Open questions at the time
    • Whether purine supply, thymidylate supply, or another metabolic output is the rate-limiting factor for viral replication unknown
    • In vivo antiviral efficacy of MTHFD1 inhibition not demonstrated
  11. 2022 High

    Discovery that PRMT5-mediated symmetric dimethylation at Arg173 enhances MTHFD1 NADPH-generating activity linked one-carbon metabolism to redox homeostasis and anoikis resistance in metastatic cancer cells.

    Evidence CRISPR screen, Co-IP, mass spectrometry, NADPH/ROS measurements, and in vivo metastasis models

    PMID:35798877

    Open questions at the time
    • Whether Arg173 methylation affects nuclear translocation unknown
    • Stoichiometry of methylation in normal versus cancer cells not quantified
  12. 2023 High

    Three studies deepened the mechanistic picture: TH9619 revealed a 'folate trap' mechanism when MTHFD1 is inhibited; TRIM21-mediated ubiquitination at K504 explained accelerated degradation of the R653Q variant; and a physical interaction with RARγ linked MTHFD1 to retinoic acid signaling and neural tube closure.

    Evidence Pharmacological inhibition with metabolomics (TH9619); IP-MS with mutagenesis and metabolic flux (TRIM21/R653Q); IP-MS, Co-IP, and retinoic acid NTD mouse model (RARγ)

    PMID:36913067 PMID:36928982 PMID:37012496

    Open questions at the time
    • Whether the RARγ interaction is enzymatic or scaffolding-dependent not resolved
    • Folate trap mechanism not validated in vivo
    • Whether TRIM21-mediated degradation of R653Q contributes to neural tube defect risk unknown
  13. 2024 High

    MTHFD1 was identified as a direct MYCN transcriptional target essential for NADPH homeostasis in neuroblastoma, and an MTHFD1–MTHFR physical interaction was shown by AP-MS, suggesting direct metabolite channeling of methyleneTHF.

    Evidence ChIP-qPCR and reporter assays for MYCN regulation; AP-MS and Co-IP with AlphaFold3 modeling for MTHFR interaction

    PMID:38336749 PMID:39571719

    Open questions at the time
    • Whether MTHFD1-MTHFR channeling occurs in vivo and affects methylation flux not demonstrated
    • MTHFR interaction structural model is computational, awaiting experimental validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the nuclear import mechanism and signal controlling S-phase translocation, the relative contribution of enzymatic versus scaffolding roles in BRD4-dependent gene regulation, and whether the MTHFD1-MTHFR metabolite channeling complex operates under physiological conditions.
  • Nuclear localization signal or chaperone for translocation not identified
  • Structural basis for BRD4 interaction unknown
  • In vivo relevance of MTHFR channeling not tested

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 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 4 GO:0005829 cytosol 3
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-1643685 Disease 3 R-HSA-69306 DNA Replication 3
Partners
BRD4MTHFRPRMT5RARGRIPK4TRIM21

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 MTHFD1 encodes a trifunctional protein with three sequential enzymatic activities: N5,N10-methylenetetrahydrofolate dehydrogenase, N5,N10-methenyltetrahydrofolate cyclohydrolase, and N10-formyltetrahydrofolate synthetase. These activities catalyze interconversion of tetrahydrofolate derivatives required for purine, methionine, and thymidylate synthesis. Loss-of-function in the CHO Ade-E mutant showed reduced activities of all three enzymes with greatly reduced protein, despite normal mRNA levels, indicating post-transcriptional regulation. Enzymatic assays, immunoblotting, immunoprecipitation, Northern analysis in CHO mutant cell line Somatic cell and molecular genetics High 1887335
2004 Disruption of the cytoplasmic Mthfd1 gene in mouse embryonic stem cells and fibroblasts demonstrated purine auxotrophy, confirming the essential role of cytoplasmic MTHFD1 in de novo purine synthesis. Additionally, a residual low-level 10-formylTHF synthetase activity was identified in mitochondria (from a distinct gene), but no mitochondrial NADP-dependent dehydrogenase activity was detected, establishing that MTHFD1 is the sole cytoplasmic source of these activities. Gene disruption (null ES cells), enzymatic activity assays in fibroblast cell lines, Northern blot, subcellular fractionation The Journal of biological chemistry High 15611115
2008 Mthfd1 is an essential gene in mice: homozygous gene-trap disruption of the formyl-THF synthetase (FTHFS) activity causes embryonic lethality. Heterozygous Mthfd1gt/+ mice show lower hepatic S-adenosylmethionine (indicating reduced formate-derived one-carbon units for methylation) and decreased uracil in nuclear DNA (indicating enhanced thymidylate synthesis), demonstrating that FTHFS activity channels formate-derived one-carbons into both purine synthesis/homocysteine remethylation and competes with thymidylate synthesis for THF cofactors. Gene-trap mouse model, metabolite quantification (AdoMet, uracil in DNA), enzymatic assays The Journal of biological chemistry High 19033438
2009 The MTHFD1 p.Arg653Gln (R653Q) variant reduces enzyme stability (36% reduction in half-life at 42°C), which is rescued by folate pentaglutamate substrate analog but not by Mg-ATP, and reduces formate incorporation into DNA (de novo purine synthesis) by 26% in transfected knockout cells, demonstrating that this variant impairs MTHFD1 metabolic activity within cells. Purified enzyme thermostability assay, in vitro activity assay, formate incorporation into DNA in Mthfd1 knockout cells transfected with wild-type or variant protein Human mutation High 18767138
2014 MTHFD1 translocates to the nucleus during S-phase in MCF-7 and HeLa cells and is enriched in the nucleus >2-fold during folate deficiency in mouse liver. Nuclear MTHFD1 generates 5,10-methyleneTHF from formate, ATP, and NADPH to support de novo thymidylate biosynthesis, while cytosolic pools support homocysteine remethylation. This nuclear enrichment preserves thymidylate synthesis at the expense of homocysteine remethylation under folate-limiting conditions. Subcellular fractionation, immunofluorescence/cell cycle analysis, nuclear folate quantification in mouse liver, human cell lines The Journal of biological chemistry High 25213861
2017 Arsenic trioxide (As2O3) causes SUMOylation and subsequent ubiquitination of MTHFD1, leading to its proteolytic degradation. This is demonstrated in cultured cells and in vitro SUMOylation reactions. As2O3 inhibits de novo thymidylate biosynthesis in a dose-dependent manner and increases uracil incorporation into nuclear DNA and genome instability, identifying MTHFD1 as a direct molecular target of arsenic. In vitro SUMOylation assay, cellular SUMOylation and ubiquitination assays, uracil-in-DNA quantification, genome instability assay Proceedings of the National Academy of Sciences of the United States of America High 28265077
2017 MTHFD1 and its bacterial ortholog FolD are inhibited by the natural product carolacton in the low nanomolar range. Crystal structure of the bacterial FolD-carolacton complex reveals the binding mode, and the human MTHFD1 is inhibited similarly, demonstrating structural and biochemical conservation of the active site. Crystal structure of FolD-carolacton complex, biophysical binding assays, enzymatic inhibition assays with human 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 the chromatin reader BRD4. 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 and physical interaction screens, Co-IP, chromatin immunoprecipitation, nuclear metabolite profiling, pharmacological inhibition in vitro and in vivo Nature genetics High 31133746
2022 MTHFD1 undergoes symmetric dimethylation on Arg173 by PRMT5. Under suspension conditions, MTHFD1–PRMT5 interaction is strengthened, increasing dimethylation of MTHFD1 and augmenting its NADPH-generating metabolic activity, which promotes anoikis resistance and tumor metastasis. Co-IP, mass spectrometry, CRISPR-Cas9 genetic screen, metabolic assays (NADPH/NADP+, GSH/GSSG, ROS), in vivo metastasis models Oncogene High 35798877
2023 TH9619, a dual dehydrogenase/cyclohydrolase inhibitor, targets nuclear MTHFD2 and cytoplasmic/nuclear MTHFD1 but not mitochondrial MTHFD2. Inhibition of MTHFD1 downstream of mitochondrial formate release causes accumulation of 10-formyl-THF (a 'folate trap'), leading to thymidylate depletion and selective death of MTHFD2-expressing cancer cells. This folate trapping is exacerbated by physiological hypoxanthine levels that block de novo purine synthesis and prevent 10-formyl-THF consumption. Pharmacological inhibition with TH9619, metabolite profiling (formate, THF derivatives, thymidylate), cell viability assays, mechanistic dissection with nuclear vs. mitochondrial fractionation Nature metabolism High 37012496
2023 MTHFD1 negatively regulates retinoic acid receptor γ (RARγ) transcription factor activity. Identified by IP-MS as a specific RARγ interactor, MTHFD1 interaction was confirmed by Co-IP and immunofluorescence confocal microscopy. Low MTHFD1 expression leads to activation of RAR signaling in anencephaly human fetal tissue and in a retinoic acid-induced mouse NTD model. IP-mass spectrometry, co-immunoprecipitation, immunofluorescence laser confocal microscopy, luciferase reporter assay, ChIP-qPCR, retinoic acid-induced NTD mouse model Brain : a journal of neurology High 36928982
2023 The MTHFD1 R653Q (G1958A) variant protein shows enhanced binding to the E3 ubiquitin ligase TRIM21, which increases ubiquitination at K504 and accelerates proteasomal degradation of MTHFD1. This leads to repressed serine-derived methyl group flux into purine synthesis precursors, compromising purine synthesis and cell growth. Immunoprecipitation, mass spectrometry, metabolic flux analysis (serine isotope labeling), ubiquitination assay, site-directed mutagenesis (K504), xenograft analysis Cellular oncology (Dordrecht, Netherlands) High 36913067
2024 MTHFD1 is a direct transcriptional target of MYCN in neuroblastoma, demonstrated by ChIP-qPCR and dual-luciferase reporter assays. MTHFD1 maintains NADPH redox homeostasis; its knockdown reduces NADPH/NADP+ and GSH/GSSG ratios and increases ROS, triggering apoptosis in MYCN-amplified NB cells. ChIP-qPCR, dual-luciferase reporter assay, MTHFD1 knockdown, NADPH/NADP+ and GSH/GSSG ratio measurements, ROS assay, in vivo mouse xenograft model Cell death & disease High 38336749
2024 MTHFR physically interacts with MTHFD1 (identified by affinity purification-coupled mass spectrometry and confirmed by co-immunoprecipitation). An AlphaFold3 model places the MTHFD1 dehydrogenase/cyclohydrolase domain in direct contact with the MTHFR catalytic domain, suggesting their interaction may facilitate direct delivery of methyleneTHF between the two enzymes. Affinity purification coupled to mass spectrometry (AP-MS), immunoprecipitation-immunoblotting, AlphaFold3 structural modeling Biochimie Medium 39571719
2021 MTHFD1 is required for viral replication in bat and human cells: genome-wide RNAi and CRISPR screens independently identified MTHFD1 as a dependency for mumps virus and influenza A virus replication. The MTHFD1 inhibitor carolacton potently blocked replication of several RNA viruses including SARS-CoV-2. Genome-wide RNAi and CRISPR screens in bat and human cells, pharmacological inhibition with carolacton Proceedings of the National Academy of Sciences of the United States of America High 34544865
2011 Biallelic loss-of-function mutations in MTHFD1 (a splice-site mutation affecting intron 8 and a missense mutation p.R173C disrupting the NADP-binding site) cause an inborn error of folate metabolism presenting with megaloblastic anemia, atypical HUS, and SCID, establishing that MTHFD1 is essential for human nucleotide synthesis, homocysteine metabolism, and immune function. Exome sequencing, clinical fibroblast studies, enzymatic assays Journal of medical genetics High 21813566
2020 MTHFD1 protein expression was markedly decreased (4.8–14.3% of controls) in fibroblasts from MTHFD1-deficient patients, and no detectable methyleneTHF dehydrogenase specific activity was found in any patient, directly confirming MTHFD1 loss-of-function at the protein and enzymatic level. Western blotting, enzymatic activity assay in patient fibroblast extracts Molecular genetics and metabolism High 32414565
2015 Deficiency of the MTHFD1 10-formylTHF synthetase (synthetase) activity alone (Mthfd1S+/- mice) is sufficient to cause increased incidence of ventricular septal defects in embryos, demonstrating that the synthetase domain's role in purine synthesis is critical for cardiac development. Mouse genetic model (Mthfd1S+/- synthetase-specific deficiency), histological examination of embryonic hearts at E14.5 Birth defects research. Part A, Clinical and molecular teratology Medium 26408344
2015 Patient fibroblast studies revealed severely reduced methionine formation from [14C]-formate in MTHFD1-deficient cells, which was not improved by cobalamin supplementation but was responsive to folic and folinic acid, establishing the causal pathway from MTHFD1 enzyme deficiency to impaired homocysteine remethylation/methionine synthesis. Radiolabeled formate incorporation assay ([14C]-formate to methionine) in patient fibroblasts, supplementation experiments Journal of inherited metabolic disease High 25633902
2016 MTHFD1 determines partitioning of folate-activated one-carbon units between de novo thymidylate biosynthesis (nuclear pathway) and homocysteine remethylation (cytosolic pathway) through its regulated nuclear localization during S-phase, and MTHFD1 impairment compromises genome stability. Genetic mouse models (Mthfd1gt/+), cell fractionation, uracil-in-DNA assay, immunofluorescence Biochimie Medium 26853819
2026 METTL3-mediated m6A modification of Mthfd1 mRNA is required for Mthfd1 expression in erythroid cells. Deletion of Mettl3 decreases Mthfd1 expression, leading to nucleotide (dTMP and IMP) shortage, DNA damage, and apoptosis/cell cycle arrest during erythropoiesis, establishing a METTL3-m6A-MTHFD1 regulatory axis. EpoR-Cre conditional Mettl3 knockout mouse, m6A sequencing, RNA-seq, nucleotide quantification (LC-MS), Western blot, DNA damage assays The Journal of clinical investigation High 41805631
2024 RIPK4 phosphorylates MTHFD1 in colorectal cancer cells. TP53 mutations drive increased RIPK4 expression, which enhances MTHFD1 phosphorylation, boosting NADPH production, reducing ROS, and promoting resistance to PANoptosis and metastasis. Kinase-substrate assay, phosphorylation mapping, cell-based ROS and PANoptosis assays, in vivo metastasis models (preprint) bioRxivpreprint Medium

Source papers

Stage 0 corpus · 94 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 135 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 70 31133746
2017 The natural product carolacton inhibits folate-dependent C1 metabolism by targeting FolD/MTHFD. Nature communications 65 29142318
2016 MTHFD1 controls DNA methylation in Arabidopsis. Nature communications 64 27291711
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 54 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
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
2023 Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature metabolism 40 37012496
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 31 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 31 28265077
2016 MTHFD1 regulates nuclear de novo thymidylate biosynthesis and genome stability. Biochimie 31 26853819
2022 Arginine methylation of MTHFD1 by PRMT5 enhances anoikis resistance and cancer metastasis. Oncogene 30 35798877
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
2007 MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatric genetics 24 17417062
2019 Mitochondrial MTHFD isozymes display distinct expression, regulation, and association with cancer. Gene 23 31377316
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
2022 The Emerging Role of MTHFD Family Genes in Regulating the Tumor Immunity of Oral Squamous Cell Carcinoma. Journal of oncology 13 35693982
2023 Association of Maternal Folate Intake and Offspring MTHFD1 and MTHFD2 Genes with Congenital Heart Disease. Nutrients 12 37630697
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
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 11 35100977
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
2024 MTHFD1 regulates the NADPH redox homeostasis in MYCN-amplified neuroblastoma. Cell death & disease 9 38336749
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
2010 Association analysis of CbetaS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer's disease in Chinese. Journal of neural transmission (Vienna, Austria : 1996) 9 20217437
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
2017 Deletion of one allele of Mthfd1 (methylenetetrahydrofolate dehydrogenase 1) impairs learning in mice. Behavioural brain research 7 28559181
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
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
2024 MTHFD1 Regulates Autophagy to Promote Growth and Metastasis in Colorectal Cancer via the PI3K-AKT-mTOR Signaling Pathway. Cancer medicine 5 39571599
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
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 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 3 39442756
2023 Common Variants in One-Carbon Metabolism Genes (MTHFR, MTR, MTHFD1) and Depression in Gynecologic Cancers. International journal of molecular sciences 3 37628752
2024 Association of MTHFD1 G1958A Polymorphism with Gestational Diabetes Mellitus. Cureus 2 38435941
2024 Specific association of MTHFD1 expressions with small cell lung cancer development and chemoradiotherapy outcome. Saudi medical journal 2 39074897
2024 Selectivity analysis of diaminopyrimidine-based inhibitors of MTHFD1, MTHFD2 and MTHFD2L. Scientific reports 2 39256448
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
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 2 25304051
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