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MTHFD2 methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase [ Homo sapiens (human) ]

Gene ID: 10797, updated on 3-Nov-2024

Summary

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Official Symbol
MTHFD2provided by HGNC
Official Full Name
methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolaseprovided by HGNC
Primary source
HGNC:HGNC:7434
See related
Ensembl:ENSG00000065911 MIM:604887; AllianceGenome:HGNC:7434
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
NMDMC
Summary
This gene encodes a nuclear-encoded mitochondrial bifunctional enzyme with methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase activities. The enzyme functions as a homodimer and is unique in its absolute requirement for magnesium and inorganic phosphate. Formation of the enzyme-magnesium complex allows binding of NAD. Alternative splicing results in two different transcripts, one protein-coding and the other not protein-coding. This gene has a pseudogene on chromosome 7. [provided by RefSeq, Mar 2009]
Expression
Ubiquitous expression in appendix (RPKM 27.6), lymph node (RPKM 27.0) and 25 other tissues See more
Orthologs
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Genomic context

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See MTHFD2 in Genome Data Viewer
Location:
2p13.1
Exon count:
9
Annotation release Status Assembly Chr Location
RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 2 NC_000002.12 (74198615..74217565)
RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 2 NC_060926.1 (74207390..74226316)
RS_2024_09 previous assembly GRCh37.p13 (GCF_000001405.25) 2 NC_000002.11 (74425742..74444692)

Chromosome 2 - NC_000002.12Genomic Context describing neighboring genes Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:74374793-74375452 Neighboring gene BOLA3 divergent transcript Neighboring gene MOB kinase activator 1A Neighboring gene ReSE screen-validated silencer GRCh37_chr2:74403666-74403858 Neighboring gene H3K27ac hESC enhancer GRCh37_chr2:74405031-74405714 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16046 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16047 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:74414816-74415489 Neighboring gene OCT4-NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:74415490-74416162 Neighboring gene NANOG-H3K27ac hESC enhancer GRCh37_chr2:74419240-74419966 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:74419967-74420694 Neighboring gene NANOG-H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:74425404-74425962 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11655 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 11656 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr2:74433385-74433964 Neighboring gene Sharpr-MPRA regulatory region 13618 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:74455229-74455729 Neighboring gene solute carrier family 4 member 5 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16049 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16050 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 16051 Neighboring gene ReSE screen-validated silencer GRCh37_chr2:74513902-74514036 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:74516904-74517404 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr2:74517405-74517905 Neighboring gene keratin 18 pseudogene 26 Neighboring gene RNA, U6 small nuclear 542, pseudogene

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma. Zhu Z, et al. Cancer Lett, 2022 Nov 28. PMID 36089117
  2. MTHFD2 promotes ovarian cancer growth and metastasis via activation of the STAT3 signaling pathway. Li Q, et al. FEBS Open Bio, 2021 Oct. PMID 34231329, Free PMC Article
  3. MTHFD2 promotes tumorigenesis and metastasis in lung adenocarcinoma by regulating AKT/GSK-3β/β-catenin signalling. Shi Y, et al. J Cell Mol Med, 2021 Jul. PMID 34121323, Free PMC Article
  4. Glioma cells require one-carbon metabolism to survive glutamine starvation. Tanaka K, et al. Acta Neuropathol Commun, 2021 Jan 19. PMID 33468252, Free PMC Article
  5. Clinical significance of circ-MTHFD2 in diagnosis, pathological staging and prognosis of NSCLC. Geng QQ, et al. Eur Rev Med Pharmacol Sci, 2020 Sep. PMID 33015789

See all (133) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.
    Title: MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions.
  2. Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.
    Title: Implications of MTHFD2 expression in renal cell carcinoma aggressiveness.
  3. Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.
    Title: Downregulation of MTHFD2 Inhibits Proliferation and Enhances Chemosensitivity in Hepatocellular Carcinoma via PI3K/AKT Pathway.
  4. SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression.
    Title: SNHG3/hsa-miR-455-5p Axis-mediated High Expression of MTHFD2 Correlates with Tumor Immune Infiltration and Endometrial Carcinoma Progression.
  5. MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.
    Title: MTHFD2 suppresses glioblastoma progression via the inhibition of ERK1/2 phosphorylation.
  6. Upregulation of MTHFD2 is associated with PDL1 activation in bladder cancer via the PI3K/AKT pathway.
    Title: Upregulation of MTHFD2 is associated with PD‑L1 activation in bladder cancer via the PI3K/AKT pathway.
  7. Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
    Title: Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
  8. Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
    Title: Metabolic collateral lethal target identification reveals MTHFD2 paralogue dependency in ovarian cancer.
  9. ATF4/MYC Regulates MTHFD2 to Promote NSCLC Progression by Mediating Redox Homeostasis.
    Title: ATF4/MYC Regulates MTHFD2 to Promote NSCLC Progression by Mediating Redox Homeostasis.
  10. Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
    Title: Deacetylation of MTHFD2 by SIRT4 senses stress signal to inhibit cancer cell growth by remodeling folate metabolism.
Submit: New GeneRIF Correction See all GeneRIFs (42)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

Variation

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See Variation Viewer (GRCh37.p13)

HIV-1 interactions

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Protein interactions

Protein Gene Interaction Pubs
Nef nef HIV-1 Nef is identified to have a physical interaction with methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 2 (MTHFD2) in human HEK293 and/or Jurkat cell lines by using affinity tagging and purification mass spectrometry analyses PubMed

Go to the HIV-1, Human Interaction Database

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables magnesium ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables magnesium ion binding IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables methenyltetrahydrofolate cyclohydrolase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables methenyltetrahydrofolate cyclohydrolase activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables methenyltetrahydrofolate cyclohydrolase activity ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 
enables methenyltetrahydrofolate cyclohydrolase activity TAS
Traceable Author Statement
more info
  
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables methylenetetrahydrofolate dehydrogenase (NAD+) activity TAS
Traceable Author Statement
more info
  
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity IDA
Inferred from Direct Assay
more info
 PubMed 
enables methylenetetrahydrofolate dehydrogenase (NADP+) activity IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables phosphate ion binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables phosphate ion binding IMP
Inferred from Mutant Phenotype
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
Process Evidence Code Pubs
involved_in folic acid metabolic process TAS
Traceable Author Statement
more info
  
involved_in tetrahydrofolate interconversion IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in tetrahydrofolate metabolic process IDA
Inferred from Direct Assay
more info
 PubMed 
Component Evidence Code Pubs
located_in extracellular space HDA PubMed 
located_in mitochondrial matrix TAS
Traceable Author Statement
more info
  
located_in mitochondrion HTP PubMed 
is_active_in mitochondrion IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in mitochondrion IDA
Inferred from Direct Assay
more info
  
located_in mitochondrion ISS
Inferred from Sequence or Structural Similarity
more info
 PubMed 

General protein information

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Preferred Names
bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
Names
NAD-dependent methylene tetrahydrofolate dehydrogenase cyclohydrolase
NP_001397121.1
NP_006627.2
XP_006711987.1
XP_054196197.1

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

  1. NG_029162.2 RefSeqGene

    Range
    5002..23952
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001410192.1 → NP_001397121.1  bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform B

    Status: REVIEWED

    Source sequence(s)
    AC073263
    Related
    ENSP00000503701.1, ENST00000679055.1

  2. NM_006636.4 → NP_006627.2  bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform A precursor

    See identical proteins and their annotated locations for NP_006627.2

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the shorter transcript and is the protein-coding transcript.
    Source sequence(s)
    AC073263, BC017054, BX475613, CB124593
    Consensus CDS
    CCDS1935.2
    UniProtKB/Swiss-Prot
    P13995, Q53G90, Q53GV5, Q53S36, Q7Z650
    UniProtKB/TrEMBL
    B2R7W0
    Related
    ENSP00000377617.2, ENST00000394053.7
    Conserved Domains (3) summary
    cd01080
    Location:150 → 329
    NAD_bind_m-THF_DH_Cyclohyd; NADP binding domain of methylene-tetrahydrofolate dehydrogenase/cyclohydrolase
    COG0190
    Location:39 → 334
    FolD; 5,10-methylene-tetrahydrofolate dehydrogenase/Methenyl tetrahydrofolate cyclohydrolase [Coenzyme transport and metabolism]
    pfam00763
    Location:39 → 155
    THF_DHG_CYH; Tetrahydrofolate dehydrogenase/cyclohydrolase, catalytic domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2024_08

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000002.12 Reference GRCh38.p14 Primary Assembly

    Range
    74198615..74217565
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_006711924.3 → XP_006711987.1  bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform X1

    See identical proteins and their annotated locations for XP_006711987.1

    UniProtKB/TrEMBL
    A0A7I2V482
    Related
    ENSP00000503927.1, ENST00000678731.1
    Conserved Domains (1) summary
    COG0190
    Location:3 → 232
    FolD; 5,10-methylene-tetrahydrofolate dehydrogenase/Methenyl tetrahydrofolate cyclohydrolase [Coenzyme transport and metabolism]

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060926.1 Alternate T2T-CHM13v2.0

    Range
    74207390..74226316
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054340222.1 → XP_054196197.1  bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial isoform X1

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P13995.2 GenPept UniProtKB/Swiss-Prot:P13995

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