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Last update 08 May 2025

MTHFD

Last update 08 May 2025

Basic Info

Synonyms

C-1-tetrahydrofolate synthase, cytoplasmic, C-1-tetrahydrofolate synthase, cytoplasmic, N-terminally processed, C1-THF synthase

+ [8]

Introduction

Trifunctional enzyme that catalyzes the interconversion of three forms of one-carbon-substituted tetrahydrofolate: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate, 5,10-methenyltetrahydrofolate and (6S)-10-formyltetrahydrofolate (PubMed:10828945, PubMed:18767138, PubMed:1881876). These derivatives of tetrahydrofolate are differentially required in nucleotide and amino acid biosynthesis, (6S)-10-formyltetrahydrofolate being required for purine biosynthesis while (6R)-5,10-methylene-5,6,7,8-tetrahydrofolate is used for serine and methionine biosynthesis for instance (PubMed:18767138, PubMed:25633902).

Drugs associated with MTHFD

LY345899

Target

MTHFD x MTHFD2

Mechanism

MTHFD inhibitors [+1]

Active Org.-

Originator Org.

University of Stockholm

Active Indication-

Inactive Indication

Neoplasms

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with MTHFD

100 Translational Medicine associated with MTHFD

0 Patents (Medical) associated with MTHFD

372

Literatures (Medical) associated with MTHFD

01 Jun 2025·Toxicology Reports

Xenobiotic metabolizing gene variants and the risk of male infertility - A systematic review, meta-analysis and in silico analysis

Review

Author: Kapoor, Harmanpreet Singh ; Kaur, Mandeep ; Khetarpal, Preeti ; Kaur, Rajinder ; Rahman T K, Shahil ; Goyal, Lajya Devi ; Dolma, Sangay

Many studies have been performed to explore the role of xenobiotic metabolizing gene variants and male infertility risk. However, the results remain inconclusive and contradictory. Therefore, the objective of the present study was to investigate the association among 16 genes and its 24 variants (CAT rs1001179, rs7943316, SOD2 rs4880, GPX1 rs1050450, CYP1A1 rs1048943, rs4646903, GSTP1 rs1695, MTHFR rs1801133, rs1801131, rs2274976, rs2066472, MTHFD1 rs2236225, MTRR rs1801394, CYP2D6 rs3892097, PON1 rs854560, rs662, PON2 rs7493, NAT2 rs1799930, NRF2 rs6721961, AHR rs2066853, rs1476080, rs6960165, null GSTM1, null GSTT1) involved in xenobiotic metabolism and their correlation with male infertility. A literature search was done using PubMed, Google Scholar, and Science Direct. Meta-analysis was conducted using Review Manager 5.3 software. Genotype-tissue expression (GTEx) portal and RegulomDB were used to determine genotype and tissue expression. Pathogenicity of significant gene variants was determined using I-Mutant 2.0, PolyPhen 2, SNP & GO, SIFT, and CADD tools. A total of 106 studies were selected for the present study to analyze 16 genes and their variants. SOD2 rs4880, CYP1A1 rs4646903, MTHFR rs1801133, rs1801131, rs2274976, PON1 rs854560, NRF2 rs6721961, and null GSTM1 gene variants are associated with increased risk of male infertility. SOD2 rs4880 and MTHFR rs1801133, rs1801131, rs2274976 are found to decrease the stability of the protein. However, no significant association was observed between CAT rs1001179, rs7943316, GPX1 rs1050450, CYP1A1 rs1048943,GSTP1 rs1695,MTHFR rs2066472, MTHFD1 rs2236225, MTRR rs1801394, CYP2D6 rs3892097, PON1 rs662, PON2 rs7493, NAT2 rs1799930, AHR rs2066853, rs1476080, rs6960165, null GSTT1 gene polymorphisms and the risk of male infertility.

01 Apr 2025·Gene

Identification of genetic variants in MTHFD1 associated with risk of hypertension

Article

Author: Wang, Zhenbo ; Lin, Qi ; Li, Xiaobo ; Yang, Yixiu ; Xie, Pingdong ; Li, Quanni ; Du, Shuli ; Zhong, Yi ; Jin, Tianbo ; Zhou, Xiaoli ; Ding, Yipeng ; He, Chanyi ; Zhang, Yunjun

BACKGROUNDMTHFD1, involved in folate metabolism, has been associated with various health outcomes, including cardiovascular diseases. This study aimed to investigate the association between four single nucleotide polymorphisms (SNPs) in MTHFD1 and the risk of hypertension.METHODSWe conducted a case-control study involving 838 hypertensive patients and 438 controls. Genotyping for four MTHFD1 SNPs was performed using the Agena MassARRAY platform. The association between these SNPs and hypertension risk was evaluated using logistic regression, adjusting for age and sex. Stratified analysis was conducted and visualized using Sangerbox software. The Multifactor Dimensionality Reduction (MDR) method was applied to assess SNP-SNP interactions.RESULTSOur results analysis revealed a significant correlation between the rs1950902 SNP and an increased risk of hypertension in overall, males and individuals aged 69 years or younger; rs8016556 was associated with a decreased risk of hypertension, particularly in females; and rs11849530 was also linked to a reduced risk of hypertension, especially in older individuals. SNP-SNP interaction analysis revealed significant interactions between the four SNPs, suggesting a joint effect on hypertension risk.CONCLUSIONSOur findings suggest that certain MTHFD1 polymorphisms (rs1950902, rs8016556, and rs11849530) are associated with the risk of hypertension, and these associations may be influenced by gender and age.

01 Mar 2025·Biochimie

Evidence for interaction of 5,10-methylenetetrahydrofolate reductase (MTHFR) with methylenetetrahydrofolate dehydrogenase (MTHFD1) and general control nonderepressible 1 (GCN1)

Article

Author: Zanotelli, Vito R T ; Froese, D. Sean ; Büchler, Linda R ; Froese, D Sean ; Büchler, Linda R. ; Bürer, Céline ; Blomgren, Linnea K M ; Blomgren, Linnea K.M. ; Zanotelli, Vito R.T.

5,10-Methylenetetrahydrofolate reductase (MTHFR) is a folate cycle enzyme required for the intracellular synthesis of methionine. MTHFR was previously shown to be partially phosphorylated at 16 residues, which was abrogated by conversion of threonine 34 to alanine (T34A) or truncation of the first 37 amino acids (i.e. expression of amino acids 38-656), and promoted by methionine supplementation. Here, we over-expressed wild-type MTHFR (MTFHR_WT), as well as the variants MTHFR_T34A and MTHFR_38-656 in 293T cells to provide further insights into these mechanisms. We demonstrate that following incubation in high methionine conditions (100-1000 μM) MTHFR_WT is almost completely phosphorylated, but in methionine restricted conditions (0-10 μM) phosphorylation is reduced, while MTHFR_T34A always remains unphosphorylated. Following affinity purification coupled mass spectrometry of an empty vector, MTHFR_WT, MTHFR_T34A and MTHFR_38-656 in three separate experiments, we identified 134 proteins consistently pulled-down by all three MTHFR protein variants, of which 5 were indicated to be likely true interactors (SAINT prediction threshold of 0.95 and 2 fold-change). Amongst these were the folate cycle enzyme methylenetetrahydrofolate dehydrogenase (MTHFD1) and the amino acid starvation sensor general control nonderepressible 1 (GCN1). Immunoprecipitation-immunoblotting of MTHFR_WT replicated interaction with both proteins. An AlphaFold 3 generated model of the MTHFR-MTHFD1 interaction places the MTHFD1 dehydrogenase/cyclohydrolase domain in direct contact with the MTHFR catalytic domain, suggesting their interaction may facilitate direct delivery of methylenetetrahydrofolate. Overall, we confirm methionine availability increases MTHFR phosphorylation, and identified potential interaction of MTHFR with MTHFD1 and GCN1.

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MTHFD

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