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Protein

Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial

Gene

MTHFD2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Although its dehydrogenase activity is NAD-specific, it can also utilize NADP at a reduced efficiency.1 Publication

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.

Catalytic activityi

5,10-methylenetetrahydrofolate + NAD+ = 5,10-methenyltetrahydrofolate + NADH.1 Publication
5,10-methenyltetrahydrofolate + H2O = 10-formyltetrahydrofolate.

Cofactori

Kineticsi

  1. KM=202 µM for NAD1 Publication
  2. KM=352 µM for NADP1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei233NAD2 Publications1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi200 – 202NAD2 Publications3

    GO - Molecular functioni

    • magnesium ion binding Source: UniProtKB
    • methenyltetrahydrofolate cyclohydrolase activity Source: UniProtKB
    • methylenetetrahydrofolate dehydrogenase (NAD+) activity Source: UniProtKB
    • methylenetetrahydrofolate dehydrogenase (NADP+) activity Source: UniProtKB
    • phosphate ion binding Source: UniProtKB

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase, Oxidoreductase
    Biological processOne-carbon metabolism
    LigandMagnesium, NAD, NADP

    Enzyme and pathway databases

    BRENDAi1.5.1.15. 2681.
    ReactomeiR-HSA-196757. Metabolism of folate and pterines.
    SABIO-RKiP13995.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrial
    Including the following 2 domains:
    NAD-dependent methylenetetrahydrofolate dehydrogenase1 Publication (EC:1.5.1.15)
    Methenyltetrahydrofolate cyclohydrolase (EC:3.5.4.9)
    Gene namesi
    Name:MTHFD2
    Synonyms:NMDMC
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 2

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000065911.11.
    HGNCiHGNC:7434. MTHFD2.

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi168D → A: Significant loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication1
    Mutagenesisi168D → E: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication1
    Mutagenesisi168D → N: 80% decrease in NAD-dependent dehydrogenase specific activity. 18% decrease in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication1
    Mutagenesisi168D → S: 82% decrease in NAD-dependent dehydrogenase specific activity. 65% decrease in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication1
    Mutagenesisi201R → A, S or K: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication1
    Mutagenesisi225D → A, S or E: Complete loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication1
    Mutagenesisi225D → N: 84% decrease in NAD-dependent dehydrogenase specific activity. 36% increase in NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication1
    Mutagenesisi233R → A: Significant loss of NAD and NADP-dependent dehydrogenase specific activity. 1 Publication1
    Mutagenesisi233R → K: 50% decrease in NAD and NADP-dependent dehydrogenase specific activity. Reduced affinity for magnesium. 1 Publication1
    Mutagenesisi233R → S: Almost complete loss of NAD-dependent dehydrogenase specific activity. 50% decrease in NADP-dependent dehydrogenase specific activity. 1 Publication1

    Organism-specific databases

    DisGeNETi10797.
    OpenTargetsiENSG00000065911.
    PharmGKBiPA31238.

    Chemistry databases

    ChEMBLiCHEMBL3621036.
    DrugBankiDB00157. NADH.
    DB00116. Tetrahydrofolic acid.

    Polymorphism and mutation databases

    BioMutaiMTHFD2.
    DMDMi115311607.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 35MitochondrionCombined sourcesAdd BLAST35
    ChainiPRO_000003404936 – 350Bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase, mitochondrialAdd BLAST315

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei50N6-acetyllysine; alternateCombined sources1
    Cross-linki50Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources

    Keywords - PTMi

    Acetylation, Isopeptide bond, Ubl conjugation

    Proteomic databases

    EPDiP13995.
    MaxQBiP13995.
    PaxDbiP13995.
    PeptideAtlasiP13995.
    PRIDEiP13995.

    PTM databases

    iPTMnetiP13995.
    PhosphoSitePlusiP13995.

    Expressioni

    Developmental stagei

    Expressed only in developing normal tissues.

    Gene expression databases

    BgeeiENSG00000065911.
    CleanExiHS_MTHFD2.
    ExpressionAtlasiP13995. baseline and differential.
    GenevisibleiP13995. HS.

    Organism-specific databases

    HPAiCAB003684.
    HPA049657.

    Interactioni

    Subunit structurei

    Homodimer.1 Publication

    Protein-protein interaction databases

    BioGridi116011. 27 interactors.
    IntActiP13995. 11 interactors.
    MINTiMINT-4656441.
    STRINGi9606.ENSP00000377617.

    Chemistry databases

    BindingDBiP13995.

    Structurei

    Secondary structure

    1350
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi42 – 62Combined sources21
    Beta strandi69 – 76Combined sources8
    Helixi79 – 95Combined sources17
    Beta strandi98 – 104Combined sources7
    Helixi110 – 122Combined sources13
    Beta strandi128 – 131Combined sources4
    Helixi141 – 147Combined sources7
    Helixi150 – 152Combined sources3
    Helixi159 – 166Combined sources8
    Helixi175 – 187Combined sources13
    Beta strandi195 – 199Combined sources5
    Turni203 – 205Combined sources3
    Helixi206 – 214Combined sources9
    Beta strandi219 – 221Combined sources3
    Beta strandi227 – 231Combined sources5
    Helixi237 – 244Combined sources8
    Beta strandi248 – 252Combined sources5
    Helixi262 – 264Combined sources3
    Beta strandi270 – 273Combined sources4
    Beta strandi277 – 279Combined sources3
    Beta strandi288 – 290Combined sources3
    Helixi295 – 298Combined sources4
    Turni299 – 301Combined sources3
    Beta strandi303 – 305Combined sources3
    Beta strandi308 – 311Combined sources4
    Helixi312 – 329Combined sources18

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    1ZN4model-A/B37-350[»]
    5TC4X-ray1.89A36-350[»]
    ProteinModelPortaliP13995.
    SMRiP13995.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni84 – 88Substrate binding1 Publication5
    Regioni131 – 133Substrate binding1 Publication3
    Regioni309 – 313Substrate binding1 Publication5

    Sequence similaritiesi

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG0089. Eukaryota.
    COG0190. LUCA.
    GeneTreeiENSGT00880000137956.
    HOGENOMiHOG000218242.
    HOVERGENiHBG006411.
    InParanoidiP13995.
    KOiK13403.
    OMAiAGKLCGD.
    OrthoDBiEOG091G0VB7.
    PhylomeDBiP13995.
    TreeFamiTF323998.

    Family and domain databases

    HAMAPiMF_01576. THF_DHG_CYH. 1 hit.
    InterProiView protein in InterPro
    IPR016040. NAD(P)-bd_dom.
    IPR000672. THF_DH/CycHdrlase.
    IPR020630. THF_DH/CycHdrlase_cat_dom.
    IPR020867. THF_DH/CycHdrlase_CS.
    IPR020631. THF_DH/CycHdrlase_NAD-bd_dom.
    PANTHERiPTHR10025. PTHR10025. 1 hit.
    PfamiView protein in Pfam
    PF00763. THF_DHG_CYH. 1 hit.
    PF02882. THF_DHG_CYH_C. 1 hit.
    PRINTSiPR00085. THFDHDRGNASE.
    SUPFAMiSSF51735. SSF51735. 1 hit.
    PROSITEiView protein in PROSITE
    PS00766. THF_DHG_CYH_1. 1 hit.
    PS00767. THF_DHG_CYH_2. 1 hit.

    Sequences (2)i

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

    Isoform 1 (identifier: P13995-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

            10         20         30         40         50
    MAATSLMSAL AARLLQPAHS CSLRLRPFHL AAVRNEAVVI SGRKLAQQIK
    60 70 80 90 100
    QEVRQEVEEW VASGNKRPHL SVILVGENPA SHSYVLNKTR AAAVVGINSE
    110 120 130 140 150
    TIMKPASISE EELLNLINKL NNDDNVDGLL VQLPLPEHID ERRICNAVSP
    160 170 180 190 200
    DKDVDGFHVI NVGRMCLDQY SMLPATPWGV WEIIKRTGIP TLGKNVVVAG
    210 220 230 240 250
    RSKNVGMPIA MLLHTDGAHE RPGGDATVTI SHRYTPKEQL KKHTILADIV
    260 270 280 290 300
    ISAAGIPNLI TADMIKEGAA VIDVGINRVH DPVTAKPKLV GDVDFEGVRQ
    310 320 330 340 350
    KAGYITPVPG GVGPMTVAML MKNTIIAAKK VLRLEEREVL KSKELGVATN
    Length:350
    Mass (Da):37,895
    Last modified:September 19, 2006 - v2
    Checksum:i4DBD263CF7BE28F4
    GO
    Isoform 2 (identifier: P13995-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-102: Missing.

    Show »
    Length:248
    Mass (Da):26,849
    Checksum:iB879A764146114F6
    GO

    Sequence cautioni

    The sequence AAX93061 differs from that shown. Reason: Erroneous initiation.Curated
    The sequence BAD96546 differs from that shown. Reason: Erroneous initiation.Curated
    The sequence BAD96761 differs from that shown. Reason: Erroneous initiation.Curated
    The sequence CAA34431 differs from that shown. Reason: Erroneous initiation.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti75V → A in BAD96546 (Ref. 3) Curated1
    Sequence conflicti95V → A in BAD96761 (Ref. 3) Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0561881 – 102Missing in isoform 2. 2 PublicationsAdd BLAST102

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    X16396 mRNA. Translation: CAA34431.1. Different initiation.
    AK300035 mRNA. Translation: BAG61846.1.
    AK222826 mRNA. Translation: BAD96546.1. Different initiation.
    AK223041 mRNA. Translation: BAD96761.1. Different initiation.
    AC073263 Genomic DNA. Translation: AAX93061.1. Different initiation.
    CH471053 Genomic DNA. Translation: EAW99671.1.
    CH471053 Genomic DNA. Translation: EAW99672.1.
    BC001548 mRNA. Translation: AAH01548.2.
    BC015062 mRNA. Translation: AAH15062.1.
    BC017054 mRNA. Translation: AAH17054.2.
    CCDSiCCDS1935.2. [P13995-1]
    PIRiS14902. DEHUMT.
    RefSeqiNP_006627.2. NM_006636.3. [P13995-1]
    XP_006711987.1. XM_006711924.2. [P13995-2]
    UniGeneiHs.469030.

    Genome annotation databases

    EnsembliENST00000394053; ENSP00000377617; ENSG00000065911. [P13995-1]
    GeneIDi10797.
    KEGGihsa:10797.
    UCSCiuc002skk.4. human. [P13995-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiMTDC_HUMAN
    AccessioniPrimary (citable) accession number: P13995
    Secondary accession number(s): Q53G90
    , Q53GV5, Q53S36, Q7Z650
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: January 1, 1990
    Last sequence update: September 19, 2006
    Last modified: September 27, 2017
    This is version 188 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Multifunctional enzyme, Reference proteome

    Documents

    1. Human chromosome 2
      Human chromosome 2: entries, gene names and cross-references to MIM
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families