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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
    mouse all
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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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    Find tests for this gene in the NIH Genetic Testing Registry (GTR)

    Review eQTL and phenotype association data in this region using PheGenI

    Variation

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    See variants in ClinVar

    See studies and variants in dbVar

    See Variation Viewer (GRCh37.p13)

    See Variation Viewer (GRCh38)

    Genotypes

    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

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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