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 result... See more...

Aliases for MTHFD2 Gene

Aliases for MTHFD2 Gene

  • Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2, Methenyltetrahydrofolate Cyclohydrolase 2 3 5
  • Bifunctional Methylenetetrahydrofolate Dehydrogenase/Cyclohydrolase, Mitochondrial 3 4
  • NMDMC 3 4
  • NAD-Dependent Methylene Tetrahydrofolate Dehydrogenase Cyclohydrolase 3
  • MTHFD2 5

External Ids for MTHFD2 Gene

Previous GeneCards Identifiers for MTHFD2 Gene

  • GC02P074563
  • GC02P074638
  • GC02P074383
  • GC02P074400
  • GC02P074337
  • GC02P074095
  • GC02P074425
  • GC02P074161
  • GC02P074198

Summaries for MTHFD2 Gene

Entrez Gene Summary for MTHFD2 Gene

  • 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]

GeneCards Summary for MTHFD2 Gene

MTHFD2 (Methylenetetrahydrofolate Dehydrogenase (NADP+ Dependent) 2, Methenyltetrahydrofolate Cyclohydrolase) is a Protein Coding gene. Diseases associated with MTHFD2 include Cutis Laxa, Autosomal Dominant 3 and Cutis Laxa, Autosomal Dominant 1. Among its related pathways are One carbon pool by folate and Nucleotide Metabolism. Gene Ontology (GO) annotations related to this gene include magnesium ion binding and formate-tetrahydrofolate ligase activity. An important paralog of this gene is MTHFD2L.

UniProtKB/Swiss-Prot Summary for MTHFD2 Gene

  • Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.

Gene Wiki entry for MTHFD2 Gene

No data available for CIViC Summary , Tocris Summary , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for MTHFD2 Gene

Genomics for MTHFD2 Gene

GeneHancer (GH) Regulatory Elements Pubs

Promoters and enhancers for MTHFD2 Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around MTHFD2 on the GeneHancer Hub at the UCSC Golden Path

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for MTHFD2

Top Transcription factor binding sites by QIAGEN in the MTHFD2 gene promoter:
  • C/EBPbeta
  • CBF(2)
  • CBF-A
  • CBF-B
  • CP1A
  • NF-Y
  • NF-YA
  • NF-YB
  • p53
  • YY1

Genomic Locations for MTHFD2 Gene

Latest Assembly
chr2:74,186,172-74,217,565
(GRCh38/hg38)
Size:
31,394 bases
Orientation:
Plus strand

Previous Assembly
chr2:74,425,742-74,444,692
(GRCh37/hg19 by Entrez Gene)
Size:
18,951 bases
Orientation:
Plus strand

chr2:74,425,689-74,444,692
(GRCh37/hg19 by Ensembl)
Size:
19,004 bases
Orientation:
Plus strand

Genomic View for MTHFD2 Gene

Genes around MTHFD2 on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
MTHFD2 Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for MTHFD2 Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for MTHFD2 Gene

Proteins for MTHFD2 Gene

  • Protein details for MTHFD2 Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    P13995-MTDC_HUMAN
    Recommended name:
    Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
    Protein Accession:
    P13995
    Secondary Accessions:
    • Q53G90
    • Q53GV5
    • Q53S36
    • Q7Z650

    Protein attributes for MTHFD2 Gene

    Size:
    350 amino acids
    Molecular mass:
    37895 Da
    Cofactor:
    Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
    Quaternary structure:
    • Homodimer.
    SequenceCaution:
    • Sequence=AAX93061.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAD96546.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=BAD96761.1; Type=Erroneous initiation; Evidence={ECO:0000305}; Sequence=CAA34431.1; Type=Erroneous initiation; Evidence={ECO:0000305};
    Miscellaneous:
    • This NAD-dependent bifunctional enzyme has very different kinetic properties than the larger NADP-dependent trifunctional enzyme and is unique in that it requires formation of an enzyme-magnesium complex to allow binding of NAD.

    Three dimensional structures from OCA and Proteopedia for MTHFD2 Gene

    Alternative splice isoforms for MTHFD2 Gene

    UniProtKB/Swiss-Prot:

neXtProt entry for MTHFD2 Gene

Post-translational modifications for MTHFD2 Gene

  • Modification sites at PhosphoSitePlus
  • Modification sites at neXtProt

No data available for DME Specific Peptides for MTHFD2 Gene

Domains & Families for MTHFD2 Gene

Gene Families for MTHFD2 Gene

Human Protein Atlas (HPA):
  • Enzymes
  • Predicted intracellular proteins

Protein Domains for MTHFD2 Gene

Suggested Antigen Peptide Sequences for MTHFD2 Gene

GenScript: Design optimal peptide antigens:
  • cDNA FLJ55007, highly similar to Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (B4DY35_HUMAN)
  • Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial (MTDC_HUMAN)
  • cDNA FLJ52745, highly similar to Bifunctional methylenetetrahydrofolatedehydrogenase/cyclohydrolase, mitochondrial (Q7Z650_HUMAN)

Graphical View of Domain Structure for InterPro Entry

P13995

UniProtKB/Swiss-Prot:

MTDC_HUMAN :
  • Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
Family:
  • Belongs to the tetrahydrofolate dehydrogenase/cyclohydrolase family.
genes like me logo Genes that share domains with MTHFD2: view

Function for MTHFD2 Gene

Molecular function for MTHFD2 Gene

UniProtKB/Swiss-Prot Function:
Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.
UniProtKB/Swiss-Prot CatalyticActivity:
Reaction=(6R)-5,10-methylene-5,6,7,8-tetrahydrofolate + NAD(+) = 5,10-methenyltetrahydrofolate + NADH; Xref=Rhea:RHEA:22892, ChEBI:CHEBI:15636, ChEBI:CHEBI:57455, ChEBI:CHEBI:57540, ChEBI:CHEBI:57945; EC=1.5.1.15; Evidence={ECO:0000269|PubMed:16100107};.
UniProtKB/Swiss-Prot CatalyticActivity:
Reaction=5,10-methenyltetrahydrofolate + H2O = (6S)-10-formyltetrahydrofolate + H(+); Xref=Rhea:RHEA:23700, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57454, ChEBI:CHEBI:57455; EC=3.5.4.9;.
UniProtKB/Swiss-Prot BiophysicochemicalProperties:
Kinetic parameters: KM=202 uM for NAD {ECO:0000269|PubMed:16100107}; KM=352 uM for NADP {ECO:0000269|PubMed:16100107};

Gene Ontology (GO) - Molecular Function for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000287 magnesium ion binding IMP 16100107
GO:0003824 catalytic activity IEA --
GO:0004477 methenyltetrahydrofolate cyclohydrolase activity IEA,ISS 8218174
GO:0004487 methylenetetrahydrofolate dehydrogenase (NAD+) activity IBA,IMP 16100107
GO:0004488 methylenetetrahydrofolate dehydrogenase (NADP+) activity IEA,IMP 16100107
genes like me logo Genes that share ontologies with MTHFD2: view
genes like me logo Genes that share phenotypes with MTHFD2: view

Animal Models for MTHFD2 Gene

MGI Knock Outs for MTHFD2:

miRNA for MTHFD2 Gene

miRTarBase miRNAs that target MTHFD2

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MTHFD2

No data available for Enzyme Numbers (IUBMB) , Phenotypes From GWAS Catalog , Human Phenotype Ontology , Transcription Factor Targets and HOMER Transcription for MTHFD2 Gene

Localization for MTHFD2 Gene

Subcellular locations from UniProtKB/Swiss-Prot for MTHFD2 Gene

Mitochondrion.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for MTHFD2 gene
Compartment Confidence
mitochondrion 5
extracellular 4
cytosol 3
nucleus 2
plasma membrane 1
cytoskeleton 1
peroxisome 1
endoplasmic reticulum 1
endosome 1
lysosome 1

Subcellular locations from the

Human Protein Atlas (HPA)

Gene Ontology (GO) - Cellular Components for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005615 extracellular space HDA 22664934
GO:0005739 mitochondrion IBA,ISS 8218174
GO:0005759 mitochondrial matrix TAS --
genes like me logo Genes that share ontologies with MTHFD2: view

Pathways & Interactions for MTHFD2 Gene

genes like me logo Genes that share pathways with MTHFD2: view

Gene Ontology (GO) - Biological Process for MTHFD2 Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006730 one-carbon metabolic process IEA --
GO:0008152 metabolic process IEA --
GO:0035999 tetrahydrofolate interconversion IBA 21873635
GO:0046653 tetrahydrofolate metabolic process IDA 8218174
GO:0046655 folic acid metabolic process TAS --
genes like me logo Genes that share ontologies with MTHFD2: view

No data available for SIGNOR curated interactions for MTHFD2 Gene

Drugs & Compounds for MTHFD2 Gene

(9) Drugs for MTHFD2 Gene - From: DrugBank and HMDB

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
NADH Approved Nutra Target 0
Magnesium Approved, Experimental, Investigational Pharma 0
Water Approved Pharma 0
Formic acid Experimental, Investigational Pharma 0
NAD Experimental Pharma 0

(5) Additional Compounds for MTHFD2 Gene - From: HMDB

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
10-formyltetrahydrofolate
  • 10-Formyl-THF
  • 10-Formyltetrahydrofolic acid
  • 10-Formyl-(6Rs)-tetrahydrofolic acid
  • 10-Formyl-H4pteglu1
  • 10-Formyl-tetrahydrofolate
2800-34-2
5,10-Methenyltetrahydrofolic acid
  • 5,10-Methenyltetrahydrofolate
  • 5,10-Methenyl-THF
  • Anhydro-leucovorin
  • Anhydro-leucovorin a
  • Anhydroleucovorin
7444-29-3
5,10-Methylene-THF
  • (6R)-5,10-Methylenetetrahydrofolate
  • (6R)-5,10-Methylenetetrahydrofolic acid
  • 5,10-Methenyltetrahydropteroylglutamate
  • 5,10-Methylene-6-hydrofolate
  • 5,10-Methylene-6-hydrofolic acid
31690-11-6
ADP
  • 5'-Adenylphosphoric acid
  • Adenosine 5'-diphosphate
  • ADENOSINE-5'-diphosphATE
  • H3ADP
  • 5'-Adenylphosphate
58-64-0
Hydrogen Ion
  • H+
  • H(+)
  • Hydron
  • Hydrogen cation
  • Proton
genes like me logo Genes that share compounds with MTHFD2: view

Transcripts for MTHFD2 Gene

mRNA/cDNA for MTHFD2 Gene

2 REFSEQ mRNAs :
13 NCBI additional mRNA sequence :
21 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

Inhibitory RNAs for research

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MTHFD2

Alternative Splicing Database (ASD) splice patterns (SP) for MTHFD2 Gene

ExUns: 1a · 1b · 1c ^ 2 ^ 3a · 3b ^ 4a · 4b ^ 5 ^ 6 ^ 7a · 7b · 7c ^ 8a · 8b ^ 9a · 9b · 9c · 9d ^ 10 ^ 11a · 11b · 11c
SP1: - - - -
SP2: - - -
SP3: - - - - - -
SP4: - - - - - - -
SP5:
SP6: - - -
SP7: - - - - - - - - - - - -
SP8:

Relevant External Links for MTHFD2 Gene

GeneLoc Exon Structure for
MTHFD2

Expression for MTHFD2 Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for MTHFD2 Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

Protein differential expression in normal tissues from HIPED for MTHFD2 Gene

This gene is overexpressed in Liver (48.5) and Breast (6.1).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for MTHFD2 Gene



Transcriptomic regulation report from SPP (The Signaling Pathways Project) for MTHFD2

SOURCE GeneReport for Unigene cluster for MTHFD2 Gene:

Hs.469030

Evidence on tissue expression from TISSUES for MTHFD2 Gene

  • Nervous system(4.8)
  • Liver(4.6)
  • Intestine(4.6)
  • Thyroid gland(4.2)
  • Blood(3.9)
  • Eye(3)
  • Lung(2.7)
  • Lymph node(2.2)
  • Pancreas(2.1)
genes like me logo Genes that share expression patterns with MTHFD2: view

Primer products for research

No data available for mRNA differential expression in normal tissues , Protein tissue co-expression partners , mRNA Expression by UniProt/SwissProt and Phenotype-based relationships between genes and organs from Gene ORGANizer for MTHFD2 Gene

Orthologs for MTHFD2 Gene

This gene was present in the common ancestor of eukaryotes.

Orthologs for MTHFD2 Gene

Organism Taxonomy Gene Similarity Type Details
Chimpanzee
(Pan troglodytes)
Mammalia MTHFD2 29 30
  • 99.43 (n)
OneToOne
Dog
(Canis familiaris)
Mammalia MTHFD2 29 30
  • 89.81 (n)
OneToOne
Cow
(Bos Taurus)
Mammalia MTHFD2 29 30
  • 89.33 (n)
OneToOne
Mouse
(Mus musculus)
Mammalia Mthfd2 29 16 30
  • 85.62 (n)
OneToOne
Rat
(Rattus norvegicus)
Mammalia Mthfd2 29
  • 84.53 (n)
Oppossum
(Monodelphis domestica)
Mammalia -- 30
  • 83 (a)
ManyToMany
Platypus
(Ornithorhynchus anatinus)
Mammalia -- 30
  • 76 (a)
ManyToMany
Chicken
(Gallus gallus)
Aves MTHFD2 29 30
  • 77.53 (n)
ManyToMany
Lizard
(Anolis carolinensis)
Reptilia -- 30
  • 80 (a)
ManyToMany
Tropical Clawed Frog
(Silurana tropicalis)
Amphibia mthfd2 29
  • 74.45 (n)
Zebrafish
(Danio rerio)
Actinopterygii mthfd2 29 30
  • 70.23 (n)
ManyToMany
African malaria mosquito
(Anopheles gambiae)
Insecta AgaP_AGAP004677 29
  • 62.01 (n)
Fruit Fly
(Drosophila melanogaster)
Insecta Nmdmc 29 30 31
  • 57.21 (n)
OneToMany
Baker's yeast
(Saccharomyces cerevisiae)
Saccharomycetes ADE3 30
  • 13 (a)
OneToMany
Barley
(Hordeum vulgare)
Liliopsida Hv.8473 29
Rice
(Oryza sativa)
Liliopsida Os.7067 29
Wheat
(Triticum aestivum)
Liliopsida Ta.3377 29
Sea Vase
(Ciona intestinalis)
Ascidiacea Cin.890 29
Species where no ortholog for MTHFD2 was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Eremothecium gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • Alicante grape (Vitis vinifera)
  • Alpha proteobacteria (Wolbachia pipientis)
  • Amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • Beta proteobacteria (Neisseria meningitidis)
  • Bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • Common water flea (Daphnia pulex)
  • Corn (Zea mays)
  • E. coli (Escherichia coli)
  • Filamentous fungi (Aspergillus nidulans)
  • Firmicute Bacteria (Streptococcus pneumoniae)
  • Fission Yeast (Schizosaccharomyces pombe)
  • Green Algae (Chlamydomonas reinhardtii)
  • Honey Bee (Apis mellifera)
  • K. Lactis Yeast (Kluyveromyces lactis)
  • Loblloly Pine (Pinus taeda)
  • Malaria Parasite (Plasmodium falciparum)
  • Medicago Trunc (Medicago Truncatula)
  • Moss (Physcomitrella patens)
  • Orangutan (Pongo pygmaeus)
  • Pig (Sus scrofa)
  • Rainbow Trout (Oncorhynchus mykiss)
  • Rice Blast Fungus (Magnaporthe grisea)
  • Schistosome Parasite (Schistosoma mansoni)
  • Sea Anemone (Nematostella vectensis)
  • Sea Squirt (Ciona savignyi)
  • Sea Urchin (Strongylocentrotus purpuratus)
  • Sorghum (Sorghum bicolor)
  • Soybean (Glycine max)
  • Stem Rust Fungus (Puccinia graminis)
  • Sugarcane (Saccharum officinarum)
  • Thale Cress (Arabidopsis thaliana)
  • Tomato (Lycopersicon esculentum)
  • Toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • Worm (Caenorhabditis elegans)

Evolution for MTHFD2 Gene

ENSEMBL:
Gene Tree for MTHFD2 (if available)
TreeFam:
Gene Tree for MTHFD2 (if available)
Aminode:
Evolutionary constrained regions (ECRs) for MTHFD2: view image
Alliance of Genome Resources:
Additional Orthologs for MTHFD2

Paralogs for MTHFD2 Gene

Paralogs for MTHFD2 Gene

(4) SIMAP similar genes for MTHFD2 Gene using alignment to 7 proteins:

  • MTDC_HUMAN
  • B4DY35_HUMAN
  • B8ZZU9_HUMAN
  • B9A062_HUMAN
  • F8WF06_HUMAN
  • F8WF89_HUMAN
  • Q7Z650_HUMAN
genes like me logo Genes that share paralogs with MTHFD2: view

Variants for MTHFD2 Gene

dbSNP identifiers (rs#s) for variants without ClinVar clinical significance for MTHFD2 Gene

All consequence types are included: molecular consequences (e.g. missense, synonymous), and location-based (e.g. intron, upstream).

Structural Variations from Database of Genomic Variants (DGV) for MTHFD2 Gene

Variant ID Type Subtype PubMed ID
nsv1117245 CNV tandem duplication 24896259
nsv834261 CNV loss 17160897
nsv961419 CNV duplication 23825009

Variation tolerance for MTHFD2 Gene

Residual Variation Intolerance Score: 33.8% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 1.14; 23.12% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for MTHFD2 Gene

SNPedia medical, phenotypic, and genealogical associations of SNPs for
MTHFD2
Leiden Open Variation Database (LOVD)
MTHFD2

SNP Genotyping and Copy Number Assays for research

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot and Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for MTHFD2 Gene

Disorders for MTHFD2 Gene

MalaCards: The human disease database

(5) MalaCards diseases for MTHFD2 Gene - From: COP

- elite association - COSMIC cancer census association via MalaCards

Additional Disease Information for MTHFD2

Human Genome Epidemiology Navigator
(HuGE)
Atlas
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
Open Targets Platform
Open Targets Platform
genes like me logo Genes that share disorders with MTHFD2: view

No data available for UniProtKB/Swiss-Prot and Genatlas for MTHFD2 Gene

Publications for MTHFD2 Gene

  1. Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase. (PMID: 16100107) Christensen KE … Mackenzie RE (The Journal of biological chemistry 2005) 3 4 22
  2. Nucleotide sequence of the human NAD-dependent methylene tetrahydrofolate dehydrogenase-cyclohydrolase. (PMID: 2587219) Peri KG … Mackenzie RE (Nucleic acids research 1989) 2 3 4
  3. Crystal Structure of the Emerging Cancer Target MTHFD2 in Complex with a Substrate-Based Inhibitor. (PMID: 27899380) Gustafsson R … Stenmark P (Cancer research 2017) 3 4
  4. Maternal genes and facial clefts in offspring: a comprehensive search for genetic associations in two population-based cleft studies from Scandinavia. (PMID: 20634891) Jugessur A … Murray JC (PloS one 2010) 3 40
  5. A Large-scale genetic association study of esophageal adenocarcinoma risk. (PMID: 20453000) Liu CY … Christiani DC (Carcinogenesis 2010) 3 40

Products for MTHFD2 Gene

Sources for MTHFD2 Gene