MTHFD

Last update 23 Jan 2025

Basic Info

Synonyms

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

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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:1881876, PubMed:10828945, PubMed:18767138). 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:25633902, PubMed:18767138).

100 Clinical Results associated with MTHFD

100 Translational Medicine associated with MTHFD

0 Patents (Medical) associated with MTHFD

422

Literatures (Medical) associated with MTHFD

01 Jan 2025·The Journal of Nutrition

Betaine and B12 Intake, Glutathione Concentration, and MTHFR, PEMT, and MTHFD1 Genotypes Are Associated with Diabetes-Related Parameters in Polish Adults

Article

Author: Mlodzik-Czyzewska, Monika A ; Szwengiel, Artur ; Mlodzik-Czyzewska, Monika A. ; Chmurzynska, Agata

BACKGROUNDThere is a growing body of evidence on associations between one-carbon metabolism (OCM) and diabetes-related parameters.OBJECTIVESFor this reason, we aimed to examine the associations of plasma choline, betaine, trimethylamine N-oxide (TMAO), glutathione (GSH), serum folate, vitamin B12, dihydrofolate reductase (rs70991108) genotype, methylenetetrahydrofolate reductase (MTHFR) (rs180113) genotype, methylenetetrahydrofolate dehydrogenase (MTHFD1) (rs2236225) genotype, and phosphatidylethanolamine N-methyltransferase (rs7946 and rs12325817) genotype with fasting glucose level, insulin level, and diabetes-related indices.METHODSThe study group consisted of 421 Polish adults aged 20-40 y. Food intake was assessed using a 3-d food diary. Plasma concentrations of choline, betaine, and TMAO were determined by ultra-high-performance liquid chromatography-electrospray ionization mass spectrometry. The total plasma GSH level was measured by high-performance liquid chromatography. Insulin, folate, and vitamin B12 concentrations were estimated by enzyme-linked immunosorbent assay method. Genotyping was performed with TaqMan probes.RESULTSGSH level was negatively associated with insulin (β = -0.11, P < 0.05) and gamma-glutamyl transferase (GGTP) (β = -0.12, P < 0.05), and positively associated with fasting glucose (β = 0.11, P < 0.05). Betaine intake was negatively associated with serum insulin concentration (β = -0.13, P < 0.05) and HOMA-IR (β = -0.12, P < 0.05). Choline intake was negatively associated with insulin (β = -0.17, P < 0.01). Serum folate level was negatively associated with GGTP (β = -0.11; P < 0.05). The methylenetetrahydrofolate reductase (MTHFR) CC genotype was associated with higher serum insulin levels (β = 0.15; P < 0.01) and higher HOMA-IR (β = 0.15, P < 0.01), whereas the MTHFD1 AA genotype was negatively associated with Quantitative Insulin Sensitivity Check Index (β = -0.11, P < 0.05).CONCLUSIONSOur findings suggest that higher GSH level and higher intake of betaine, B₁₂, and choline, as well as the TT genotype of MTHFR and the AA genotype of MTHFD1, are associated with lower diabetes-related parameters among adults.

31 Dec 2024·Redox Report

MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions

Article

Author: Li, Xin-Yu ; Tian, Tian ; Ma, Meng-Yao ; Han, Yi ; Mo, Hai-Yu ; Wang, Ruo-Bing ; Wen, Wang-Rong ; Zhang, Yi

OBJECTIVESCancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.METHODSROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.RESULTSWe found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.DISCUSSIONour study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

12 Dec 2024·Journal of Medicinal Chemistry

Development of Potent and Selective Inhibitors of Methylenetetrahydrofolate Dehydrogenase 2 for Targeting Acute Myeloid Leukemia: SAR, Structural Insights, and Biological Characterization

Article

Author: Lu, Cheng-Tai ; Lin, Li-Mei ; Peng, Yi-Hui ; Huang, Chih-Hsiang ; Chang, Ling ; Chang, Hsin-Huei ; Huang, Zih-Ting ; Hsu, Tsu ; Huang, Yu-Chen ; Hsueh, Ching-Cheng ; Yeh, Teng-Kuang ; Kung, Fang-Chun ; Tang, Ya-Chu ; Li, Li-Hsuan ; Kuo, Ching-Chuan ; Wang, Yi-Hsin ; Jiaang, Weir-Torn ; Hsieh, Chih-Chien ; Wu, Su-Ying ; Lee, Lung-Chun

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2), a pivotal mitochondrial enzyme in one-carbon metabolism, is significantly upregulated in various cancers but minimally expressed in normal proliferating cells. In contrast, MTHFD1, which performs similar functions, is predominantly expressed in normal cells. Therefore, targeting MTHFD2 with selective inhibitors holds promise for a broader therapeutic window with reduced toxicity and fewer side effects. This study identified selective 2,4-diamino-6-oxo-1,6-dihydropyrimidin-5-yl ureido-based derivatives through systematic chemical modifications and SAR studies. Structural biology investigations revealed substitutions in the phenyl ring and tail region modulate potency and selectivity toward MTHFD2. Additionally, a comprehensive cell screening platform revealed acute myeloid leukemia cells with FLT3 internal tandem duplication mutations are particularly sensitive to these inhibitors. Furthermore, synergistic effects were observed when combining potential compounds with Alimta. Compound 16e emerged as a leading candidate, demonstrating superior inhibition and selectivity for MTHFD2, favorable pharmacokinetics, and potent antitumor efficacy in MOLM-14 xenograft models.

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