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Protein

Dihydrofolate reductase

Gene

DHFR

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

Functioni

Key enzyme in folate metabolism. Contributes to the de novo mitochondrial thymidylate biosynthesis pathway. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis. Binds its own mRNA and that of DHFRL1.2 Publications

Catalytic activityi

5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.PROSITE-ProRule annotation7 Publications

Kineticsi

  1. KM=2.7 µM for dihydrofolate3 Publications
  2. KM=4.0 µM for NADPH3 Publications

    Pathway: tetrahydrofolate biosynthesis

    This protein is involved in step 1 of the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate.
    Proteins known to be involved in this subpathway in this organism are:
    1. Dihydrofolate reductase, mitochondrial (DHFRL1), Dihydrofolate reductase (DHFR)
    This subpathway is part of the pathway tetrahydrofolate biosynthesis, which is itself part of Cofactor biosynthesis.
    View all proteins of this organism that are known to be involved in the subpathway that synthesizes 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate, the pathway tetrahydrofolate biosynthesis and in Cofactor biosynthesis.

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei10 – 101NADP; via amide nitrogen and carbonyl oxygen3 Publications
    Binding sitei65 – 651Substrate
    Binding sitei71 – 711Substrate

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi16 – 227NADP3 Publications
    Nucleotide bindingi55 – 573NADP3 Publications
    Nucleotide bindingi77 – 793NADP3 Publications
    Nucleotide bindingi117 – 1248NADP3 Publications

    GO - Molecular functioni

    • dihydrofolate reductase activity Source: UniProtKB
    • drug binding Source: UniProtKB
    • mRNA binding Source: UniProtKB
    • NADP binding Source: InterPro

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    Methotrexate resistance, One-carbon metabolism

    Keywords - Ligandi

    NADP, RNA-binding

    Enzyme and pathway databases

    BRENDAi1.5.1.3. 2681.
    ReactomeiREACT_111176. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
    REACT_11167. Metabolism of folate and pterines.
    REACT_471. E2F mediated regulation of DNA replication.
    REACT_683. G1/S-Specific Transcription.
    SABIO-RKP00374.
    UniPathwayiUPA00077; UER00158.

    Protein family/group databases

    MoonProtiP00374.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dihydrofolate reductase (EC:1.5.1.3)
    Gene namesi
    Name:DHFR
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640 Componenti: Chromosome 5

    Organism-specific databases

    HGNCiHGNC:2861. DHFR.

    Subcellular locationi

    GO - Cellular componenti

    Complete GO annotation...

    Pathology & Biotechi

    Involvement in diseasei

    Megaloblastic anemia due to dihydrofolate reductase deficiency (DHFRD)2 Publications

    The disease is caused by mutations affecting the gene represented in this entry.

    Disease descriptionAn inborn error of metabolism, characterized by megaloblastic anemia and/or pancytopenia, severe cerebral folate deficiency, and cerebral tetrahydrobiopterin deficiency. Clinical features include variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy, to childhood absence epilepsy with learning difficulties, to lack of symptoms.

    See also OMIM:613839
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti80 – 801L → F in DHFRD. 1 Publication
    VAR_065818
    Natural varianti153 – 1531D → V in DHFRD. 1 Publication
    VAR_065819

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi23 – 231L → F, W or Y: Decreases affinity for NADP and dihydrofolate over 10-fold. 2 Publications
    Mutagenesisi23 – 231L → R: Strongly decreased affinity for methotrexate. Decreases catalytic rate constant 200-fold. Decreases affinity for NADP and dihydrofolate over 10-fold. 2 Publications
    Mutagenesisi32 – 321F → R: Reduces catalytic rate 5-fold. Reduces affinity for dihydrofolate 9-fold; when associated with E-36. 1 Publication
    Mutagenesisi36 – 361Q → E: Reduces catalytic rate 2-fold. Reduces affinity for dihydrofolate 9-fold; when associated with R-32. 3 Publications
    Mutagenesisi36 – 361Q → K: Increases affinity for dihydrofolate about 3-fold. Reduces affinity for NADPH about 3-fold. 3 Publications
    Mutagenesisi36 – 361Q → S: Increases affinity for dihydrofolate about 2-fold. No effect on affinity for NADPH. 3 Publications
    Mutagenesisi65 – 651N → F: Increases affinity for dihydrofolate about 3-fold. No effect on affinity for NADPH. 2 Publications
    Mutagenesisi65 – 651N → S: Increases affinity for dihydrofolate about 15-fold. No effect on affinity for NADPH. 2 Publications

    Keywords - Diseasei

    Disease mutation

    Organism-specific databases

    MIMi613839. phenotype.
    Orphaneti319651. Constitutional megaloblastic anemia with severe neurologic disease.
    PharmGKBiPA143.

    Chemistry

    DrugBankiDB00563. Methotrexate.
    DB00642. Pemetrexed.
    DB06813. Pralatrexate.
    DB01131. Proguanil.
    DB00205. Pyrimethamine.
    DB00440. Trimethoprim.
    DB01157. Trimetrexate.

    Polymorphism and mutation databases

    BioMutaiDHFR.
    DMDMi118992.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 187186Dihydrofolate reductasePRO_0000186362Add
    BLAST

    Proteomic databases

    MaxQBiP00374.
    PaxDbiP00374.
    PRIDEiP00374.

    2D gel databases

    UCD-2DPAGEP00374.

    PTM databases

    PhosphoSiteiP00374.

    Expressioni

    Tissue specificityi

    Widely expressed in fetal and adult tissues, including throughout the fetal and adult brains and whole blood. Expression is higher in the adult brain than in the fetal brain.1 Publication

    Gene expression databases

    BgeeiP00374.
    CleanExiHS_DHFR.
    ExpressionAtlasiP00374. baseline and differential.
    GenevisibleiP00374. HS.

    Organism-specific databases

    HPAiCAB037129.
    HPA051465.

    Interactioni

    Subunit structurei

    Homodimer.7 Publications

    Protein-protein interaction databases

    BioGridi108065. 11 interactions.
    IntActiP00374. 1 interaction.
    MINTiMINT-5002355.
    STRINGi9606.ENSP00000396308.

    Structurei

    Secondary structure

    1
    187
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi5 – 117Combined sources
    Beta strandi16 – 194Combined sources
    Beta strandi24 – 263Combined sources
    Helixi29 – 4012Combined sources
    Beta strandi43 – 464Combined sources
    Beta strandi48 – 547Combined sources
    Helixi55 – 606Combined sources
    Helixi63 – 653Combined sources
    Beta strandi71 – 766Combined sources
    Beta strandi88 – 936Combined sources
    Helixi94 – 1018Combined sources
    Turni104 – 1096Combined sources
    Beta strandi110 – 1156Combined sources
    Helixi119 – 1268Combined sources
    Beta strandi128 – 1303Combined sources
    Beta strandi132 – 14110Combined sources
    Beta strandi146 – 1483Combined sources
    Turni154 – 1563Combined sources
    Beta strandi157 – 1593Combined sources
    Beta strandi161 – 1633Combined sources
    Beta strandi171 – 1733Combined sources
    Beta strandi176 – 18510Combined sources

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1BOZX-ray2.10A2-187[»]
    1DHFX-ray2.30A/B2-187[»]
    1DLRX-ray2.30A2-187[»]
    1DLSX-ray2.30A2-187[»]
    1DRFX-ray2.00A2-187[»]
    1HFPX-ray2.10A2-187[»]
    1HFQX-ray2.10A2-187[»]
    1HFRX-ray2.10A2-187[»]
    1KMSX-ray1.09A2-187[»]
    1KMVX-ray1.05A2-187[»]
    1MVSX-ray1.90A1-187[»]
    1MVTX-ray1.80A1-187[»]
    1OHJX-ray2.50A2-187[»]
    1OHKX-ray2.50A2-187[»]
    1PD8X-ray2.10A2-187[»]
    1PD9X-ray2.20A2-187[»]
    1PDBX-ray2.20A2-187[»]
    1S3UX-ray2.50A2-187[»]
    1S3VX-ray1.80A2-187[»]
    1S3WX-ray1.90A2-187[»]
    1U71X-ray2.20A2-187[»]
    1U72X-ray1.90A2-187[»]
    1YHONMR-A2-187[»]
    2C2SX-ray1.40A/B2-187[»]
    2C2TX-ray1.50A/B2-187[»]
    2DHFX-ray2.30A/B2-187[»]
    2W3AX-ray1.50A/B1-187[»]
    2W3BX-ray1.27A/B1-187[»]
    2W3MX-ray1.60A/B1-187[»]
    3EIGX-ray1.70A2-187[»]
    3F8YX-ray1.45A1-187[»]
    3F8ZX-ray2.01A1-187[»]
    3F91X-ray1.90A1-187[»]
    3FS6X-ray1.23A1-187[»]
    3GHCX-ray1.30A2-187[»]
    3GHVX-ray1.30A2-187[»]
    3GHWX-ray1.24A2-187[»]
    3GI2X-ray1.53A1-187[»]
    3GYFX-ray1.70A1-187[»]
    3L3RX-ray2.00A2-187[»]
    3N0HX-ray1.92A2-187[»]
    3NTZX-ray1.35A2-187[»]
    3NU0X-ray1.35A2-187[»]
    3NXOX-ray1.35A2-187[»]
    3NXRX-ray1.35A2-187[»]
    3NXTX-ray1.70A2-187[»]
    3NXVX-ray1.90A2-187[»]
    3NXXX-ray1.35A2-187[»]
    3NXYX-ray1.90A2-187[»]
    3NZDX-ray1.80A2-187[»]
    3OAFX-ray1.70A2-187[»]
    3S3VX-ray1.53A2-187[»]
    3S7AX-ray1.80A2-187[»]
    4DDRX-ray2.05A2-187[»]
    4G95X-ray1.35A2-187[»]
    4KAKX-ray1.80A/B2-187[»]
    4KBNX-ray1.84A/B2-187[»]
    4KD7X-ray2.72A/B2-187[»]
    4KEBX-ray1.45A/B2-187[»]
    4KFJX-ray1.76A/B2-187[»]
    4M6JX-ray1.20A1-187[»]
    4M6KX-ray1.40A1-187[»]
    4M6LX-ray1.70A1-187[»]
    ProteinModelPortaliP00374.
    SMRiP00374. Positions 2-186.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP00374.

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini4 – 185182DHFRPROSITE-ProRule annotationAdd
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni31 – 366Substrate binding

    Sequence similaritiesi

    Belongs to the dihydrofolate reductase family.Curated
    Contains 1 DHFR (dihydrofolate reductase) domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiCOG0262.
    GeneTreeiENSGT00390000010283.
    HOGENOMiHOG000040235.
    HOVERGENiHBG000773.
    InParanoidiP00374.
    KOiK00287.
    OMAiDQVWVIG.
    OrthoDBiEOG7V1FS3.
    PhylomeDBiP00374.
    TreeFamiTF317636.

    Family and domain databases

    Gene3Di3.40.430.10. 1 hit.
    InterProiIPR012259. DHFR.
    IPR024072. DHFR-like_dom.
    IPR017925. DHFR_CS.
    IPR001796. DHFR_dom.
    [Graphical view]
    PfamiPF00186. DHFR_1. 1 hit.
    [Graphical view]
    PRINTSiPR00070. DHFR.
    SUPFAMiSSF53597. SSF53597. 1 hit.
    PROSITEiPS00075. DHFR_1. 1 hit.
    PS51330. DHFR_2. 1 hit.
    [Graphical view]

    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: P00374-1) [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
    MVGSLNCIVA VSQNMGIGKN GDLPWPPLRN EFRYFQRMTT TSSVEGKQNL
    60 70 80 90 100
    VIMGKKTWFS IPEKNRPLKG RINLVLSREL KEPPQGAHFL SRSLDDALKL
    110 120 130 140 150
    TEQPELANKV DMVWIVGGSS VYKEAMNHPG HLKLFVTRIM QDFESDTFFP
    160 170 180
    EIDLEKYKLL PEYPGVLSDV QEEKGIKYKF EVYEKND
    Length:187
    Mass (Da):21,453
    Last modified:January 23, 2007 - v2
    Checksum:iEBDF3D1EC73E1566
    GO
    Isoform 2 (identifier: P00374-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-52: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:135
    Mass (Da):15,672
    Checksum:i92704AAABEE1EF40
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti113 – 1131V → L in AAH70280 (PubMed:15489334).Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti80 – 801L → F in DHFRD. 1 Publication
    VAR_065818
    Natural varianti153 – 1531D → V in DHFRD. 1 Publication
    VAR_065819

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 5252Missing in isoform 2. 1 PublicationVSP_056352Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J00140 mRNA. Translation: AAA58485.1.
    V00507 mRNA. Translation: CAA23765.1.
    J00139
    , K01612, K01613, J00138, K01614 Genomic DNA. Translation: AAA58484.1.
    X00855
    , X00856, X00857, X00858, X00859 Genomic DNA. Translation: CAA25409.1.
    AK293146 mRNA. Translation: BAG56693.1.
    AC008434 Genomic DNA. No translation available.
    AC010270 Genomic DNA. No translation available.
    BC000192 mRNA. Translation: AAH00192.1.
    BC003584 mRNA. Translation: AAH03584.2.
    BC070280 mRNA. Translation: AAH70280.1.
    BC071996 mRNA. Translation: AAH71996.1.
    CCDSiCCDS47240.1. [P00374-1]
    PIRiA22551. RDHUD.
    RefSeqiNP_000782.1. NM_000791.3. [P00374-1]
    NP_001277283.1. NM_001290354.1. [P00374-2]
    UniGeneiHs.592364.
    Hs.648635.

    Genome annotation databases

    EnsembliENST00000439211; ENSP00000396308; ENSG00000228716. [P00374-1]
    ENST00000504396; ENSP00000421334; ENSG00000228716. [P00374-2]
    ENST00000505337; ENSP00000426474; ENSG00000228716. [P00374-1]
    GeneIDi1719.
    KEGGihsa:1719.
    UCSCiuc003kgy.1. human. [P00374-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Web resourcesi

    Wikipedia

    Dihydrofolate reductase entry

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    J00140 mRNA. Translation: AAA58485.1.
    V00507 mRNA. Translation: CAA23765.1.
    J00139
    , K01612, K01613, J00138, K01614 Genomic DNA. Translation: AAA58484.1.
    X00855
    , X00856, X00857, X00858, X00859 Genomic DNA. Translation: CAA25409.1.
    AK293146 mRNA. Translation: BAG56693.1.
    AC008434 Genomic DNA. No translation available.
    AC010270 Genomic DNA. No translation available.
    BC000192 mRNA. Translation: AAH00192.1.
    BC003584 mRNA. Translation: AAH03584.2.
    BC070280 mRNA. Translation: AAH70280.1.
    BC071996 mRNA. Translation: AAH71996.1.
    CCDSiCCDS47240.1. [P00374-1]
    PIRiA22551. RDHUD.
    RefSeqiNP_000782.1. NM_000791.3. [P00374-1]
    NP_001277283.1. NM_001290354.1. [P00374-2]
    UniGeneiHs.592364.
    Hs.648635.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1BOZX-ray2.10A2-187[»]
    1DHFX-ray2.30A/B2-187[»]
    1DLRX-ray2.30A2-187[»]
    1DLSX-ray2.30A2-187[»]
    1DRFX-ray2.00A2-187[»]
    1HFPX-ray2.10A2-187[»]
    1HFQX-ray2.10A2-187[»]
    1HFRX-ray2.10A2-187[»]
    1KMSX-ray1.09A2-187[»]
    1KMVX-ray1.05A2-187[»]
    1MVSX-ray1.90A1-187[»]
    1MVTX-ray1.80A1-187[»]
    1OHJX-ray2.50A2-187[»]
    1OHKX-ray2.50A2-187[»]
    1PD8X-ray2.10A2-187[»]
    1PD9X-ray2.20A2-187[»]
    1PDBX-ray2.20A2-187[»]
    1S3UX-ray2.50A2-187[»]
    1S3VX-ray1.80A2-187[»]
    1S3WX-ray1.90A2-187[»]
    1U71X-ray2.20A2-187[»]
    1U72X-ray1.90A2-187[»]
    1YHONMR-A2-187[»]
    2C2SX-ray1.40A/B2-187[»]
    2C2TX-ray1.50A/B2-187[»]
    2DHFX-ray2.30A/B2-187[»]
    2W3AX-ray1.50A/B1-187[»]
    2W3BX-ray1.27A/B1-187[»]
    2W3MX-ray1.60A/B1-187[»]
    3EIGX-ray1.70A2-187[»]
    3F8YX-ray1.45A1-187[»]
    3F8ZX-ray2.01A1-187[»]
    3F91X-ray1.90A1-187[»]
    3FS6X-ray1.23A1-187[»]
    3GHCX-ray1.30A2-187[»]
    3GHVX-ray1.30A2-187[»]
    3GHWX-ray1.24A2-187[»]
    3GI2X-ray1.53A1-187[»]
    3GYFX-ray1.70A1-187[»]
    3L3RX-ray2.00A2-187[»]
    3N0HX-ray1.92A2-187[»]
    3NTZX-ray1.35A2-187[»]
    3NU0X-ray1.35A2-187[»]
    3NXOX-ray1.35A2-187[»]
    3NXRX-ray1.35A2-187[»]
    3NXTX-ray1.70A2-187[»]
    3NXVX-ray1.90A2-187[»]
    3NXXX-ray1.35A2-187[»]
    3NXYX-ray1.90A2-187[»]
    3NZDX-ray1.80A2-187[»]
    3OAFX-ray1.70A2-187[»]
    3S3VX-ray1.53A2-187[»]
    3S7AX-ray1.80A2-187[»]
    4DDRX-ray2.05A2-187[»]
    4G95X-ray1.35A2-187[»]
    4KAKX-ray1.80A/B2-187[»]
    4KBNX-ray1.84A/B2-187[»]
    4KD7X-ray2.72A/B2-187[»]
    4KEBX-ray1.45A/B2-187[»]
    4KFJX-ray1.76A/B2-187[»]
    4M6JX-ray1.20A1-187[»]
    4M6KX-ray1.40A1-187[»]
    4M6LX-ray1.70A1-187[»]
    ProteinModelPortaliP00374.
    SMRiP00374. Positions 2-186.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi108065. 11 interactions.
    IntActiP00374. 1 interaction.
    MINTiMINT-5002355.
    STRINGi9606.ENSP00000396308.

    Chemistry

    BindingDBiP00374.
    ChEMBLiCHEMBL202.
    DrugBankiDB00563. Methotrexate.
    DB00642. Pemetrexed.
    DB06813. Pralatrexate.
    DB01131. Proguanil.
    DB00205. Pyrimethamine.
    DB00440. Trimethoprim.
    DB01157. Trimetrexate.
    GuidetoPHARMACOLOGYi2603.

    Protein family/group databases

    MoonProtiP00374.

    PTM databases

    PhosphoSiteiP00374.

    Polymorphism and mutation databases

    BioMutaiDHFR.
    DMDMi118992.

    2D gel databases

    UCD-2DPAGEP00374.

    Proteomic databases

    MaxQBiP00374.
    PaxDbiP00374.
    PRIDEiP00374.

    Protocols and materials databases

    DNASUi1719.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000439211; ENSP00000396308; ENSG00000228716. [P00374-1]
    ENST00000504396; ENSP00000421334; ENSG00000228716. [P00374-2]
    ENST00000505337; ENSP00000426474; ENSG00000228716. [P00374-1]
    GeneIDi1719.
    KEGGihsa:1719.
    UCSCiuc003kgy.1. human. [P00374-1]

    Organism-specific databases

    CTDi1719.
    GeneCardsiGC05M079922.
    HGNCiHGNC:2861. DHFR.
    HPAiCAB037129.
    HPA051465.
    MIMi126060. gene.
    613839. phenotype.
    neXtProtiNX_P00374.
    Orphaneti319651. Constitutional megaloblastic anemia with severe neurologic disease.
    PharmGKBiPA143.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiCOG0262.
    GeneTreeiENSGT00390000010283.
    HOGENOMiHOG000040235.
    HOVERGENiHBG000773.
    InParanoidiP00374.
    KOiK00287.
    OMAiDQVWVIG.
    OrthoDBiEOG7V1FS3.
    PhylomeDBiP00374.
    TreeFamiTF317636.

    Enzyme and pathway databases

    UniPathwayiUPA00077; UER00158.
    BRENDAi1.5.1.3. 2681.
    ReactomeiREACT_111176. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
    REACT_11167. Metabolism of folate and pterines.
    REACT_471. E2F mediated regulation of DNA replication.
    REACT_683. G1/S-Specific Transcription.
    SABIO-RKP00374.

    Miscellaneous databases

    ChiTaRSiDHFR. human.
    EvolutionaryTraceiP00374.
    GeneWikiiDihydrofolate_reductase.
    GenomeRNAii1719.
    NextBioi35470906.
    PROiP00374.
    SOURCEiSearch...

    Gene expression databases

    BgeeiP00374.
    CleanExiHS_DHFR.
    ExpressionAtlasiP00374. baseline and differential.
    GenevisibleiP00374. HS.

    Family and domain databases

    Gene3Di3.40.430.10. 1 hit.
    InterProiIPR012259. DHFR.
    IPR024072. DHFR-like_dom.
    IPR017925. DHFR_CS.
    IPR001796. DHFR_dom.
    [Graphical view]
    PfamiPF00186. DHFR_1. 1 hit.
    [Graphical view]
    PRINTSiPR00070. DHFR.
    SUPFAMiSSF53597. SSF53597. 1 hit.
    PROSITEiPS00075. DHFR_1. 1 hit.
    PS51330. DHFR_2. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Publicationsi

    « Hide 'large scale' publications
    1. "The functional human dihydrofolate reductase gene."
      Chen M.-J., Shimada T., Moulton A.D., Cline A., Humphries R.K., Maizel J., Nienhuis A.W.
      J. Biol. Chem. 259:3933-3943(1984) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    2. "The nucleotide sequence of the cDNA coding for the human dihydrofolic acid reductase."
      Masters J.N., Attardi G.
      Gene 21:59-63(1983) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    3. "Human dihydrofolate reductase gene organization. Extensive conservation of the G + C-rich 5' non-coding sequence and strong intron size divergence from homologous mammalian genes."
      Yang J.K., Masters J.N., Attardi G.
      J. Mol. Biol. 176:169-187(1984) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
    5. "The DNA sequence and comparative analysis of human chromosome 5."
      Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.
      , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
      Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
      Tissue: Eye.
    7. Cited for: TISSUE SPECIFICITY, VARIANT DHFRD PHE-80.
    8. Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
    9. "The former annotated human pseudogene dihydrofolate reductase-like 1 (DHFRL1) is expressed and functional."
      McEntee G., Minguzzi S., O'Brien K., Ben Larbi N., Loscher C., O'Fagain C., Parle-McDermott A.
      Proc. Natl. Acad. Sci. U.S.A. 108:15157-15162(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: CATALYTIC ACTIVITY, RNA-BINDING, BIOPHYSICOCHEMICAL PROPERTIES.
    10. "Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria."
      Anderson D.D., Quintero C.M., Stover P.J.
      Proc. Natl. Acad. Sci. U.S.A. 108:15163-15168(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    11. "Crystal structure of human dihydrofolate reductase complexed with folate."
      Oefner C., D'Arcy A., Winkler F.K.
      Eur. J. Biochem. 174:377-385(1988) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) IN COMPLEX WITH FOLATE.
    12. "Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate."
      Davies J.F., Delcamp T.J., Prendergast N.J., Ashford V.A., Freisheim J.H., Kraut J.
      Biochemistry 29:9467-9479(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEXES WITH FOLATE AND 5-DEAZAFOLATE, SUBUNIT.
    13. "Sequence-specific 1H and 15N resonance assignments for human dihydrofolate reductase in solution."
      Stockman B.J., Nirmala N.R., Wagner G., Delcamp T.J., Deyarman M.T., Freisheim J.H.
      Biochemistry 31:218-229(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR.
    14. "Methotrexate-resistant variants of human dihydrofolate reductase with substitutions of leucine 22. Kinetics, crystallography, and potential as selectable markers."
      Lewis W.S., Cody V., Galitsky N., Luft J.R., Pangborn W., Chunduru S.K., Spencer H.T., Appleman J.R., Blakley R.L.
      J. Biol. Chem. 270:5057-5064(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) IN COMPLEXES WITH NADPH; PIRITREXIM AND METOTHREXATE, MUTAGENESIS OF LEU-23.
    15. "Comparison of two independent crystal structures of human dihydrofolate reductase ternary complexes reduced with nicotinamide adenine dinucleotide phosphate and the very tight-binding inhibitor PT523."
      Cody V., Galitsky N., Luft J.R., Pangborn W., Blakley R.L., Gangjee A.
      Biochemistry 36:13897-13903(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
    16. "Structure-based design and synthesis of lipophilic 2,4-diamino-6-substituted quinazolines and their evaluation as inhibitors of dihydrofolate reductases and potential antitumor agents."
      Gangjee A., Vidwans A.P., Vasudevan A., Queener S.F., Kisliuk R.L., Cody V., Li R., Galitsky N., Luft J.R., Pangborn W.
      J. Med. Chem. 41:3426-3434(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEXES WITH NADPH AND QUINAZOLINE INHIBITORS, CATALYTIC ACTIVITY.
    17. "Atomic structures of human dihydrofolate reductase complexed with NADPH and two lipophilic antifolates at 1.09 A and 1.05 A resolution."
      Klon A.E., Heroux A., Ross L.J., Pathak V., Johnson C.A., Piper J.R., Borhani D.W.
      J. Mol. Biol. 320:677-693(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.05 ANGSTROMS) IN COMPLEXES WITH NADP AND THE SYNTHETIC INHIBITORS SRI-9439 AND SRI-9662, FUNCTION, CATALYTIC ACTIVITY.
    18. "Analysis of two polymorphic forms of a pyrido[2,3-d]pyrimidine N9-C10 reversed-bridge antifolate binary complex with human dihydrofolate reductase."
      Cody V., Galitsky N., Luft J.R., Pangborn W., Gangjee A.
      Acta Crystallogr. D 59:654-661(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
    19. "Analysis of three crystal structure determinations of a 5-methyl-6-N-methylanilino pyridopyrimidine antifolate complex with human dihydrofolate reductase."
      Cody V., Luft J.R., Pangborn W., Gangjee A.
      Acta Crystallogr. D 59:1603-1609(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH INHIBITOR.
    20. "Structure determination of tetrahydroquinazoline antifolates in complex with human and Pneumocystis carinii dihydrofolate reductase: correlations between enzyme selectivity and stereochemistry."
      Cody V., Luft J.R., Pangborn W., Gangjee A., Queener S.F.
      Acta Crystallogr. D 60:646-655(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) IN COMPLEX WITH NADPH AND INHIBITOR, MUTAGENESIS OF GLN-36 AND ASN-65, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES.
    21. "Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH."
      Cody V., Luft J.R., Pangborn W.
      Acta Crystallogr. D 61:147-155(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEXES WITH NADP AND METHOTREXATE, MUTAGENESIS OF LEU-23.
    22. "Solution structure of human dihydrofolate reductase in its complex with trimethoprim and NADPH."
      Kovalevskaya N.V., Smurnyy Y.D., Polshakov V.I., Birdsall B., Bradbury A.F., Frenkiel T., Feeney J.
      J. Biomol. NMR 33:69-72(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: STRUCTURE BY NMR IN COMPLEX WITH TRIMETHOPRIM AND NADPH.
    23. "Novel boron-containing, nonclassical antifolates: synthesis and preliminary biological and structural evaluation."
      Reynolds R.C., Campbell S.R., Fairchild R.G., Kisliuk R.L., Micca P.L., Queener S.F., Riordan J.M., Sedwick W.D., Waud W.R., Leung A.K., Dixon R.W., Suling W.J., Borhani D.W.
      J. Med. Chem. 50:3283-3289(2007) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND BORON-CONTAINING INHIBITORS, CATALYTIC ACTIVITY.
    24. "Correlations of inhibitor kinetics for Pneumocystis jirovecii and human dihydrofolate reductase with structural data for human active site mutant enzyme complexes."
      Cody V., Pace J., Makin J., Piraino J., Queener S.F., Rosowsky A.
      Biochemistry 48:1702-1711(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.23 ANGSTROMS) IN COMPLEXES WITH NADP AND THE SYNTHETIC INHIBITOR PY957, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF GLN-36 AND ASN-65.
    25. "Multiple conformers in active site of human dihydrofolate reductase F31R/Q35E double mutant suggest structural basis for methotrexate resistance."
      Volpato J.P., Yachnin B.J., Blanchet J., Guerrero V., Poulin L., Fossati E., Berghuis A.M., Pelletier J.N.
      J. Biol. Chem. 284:20079-20089(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.70 ANGSTROMS) OF MUTANT ARG-32/GLU-36 IN COMPLEX WITH METHOTREXATE AND NADP, MUTAGENESIS OF PHE-32 AND GLN-36, CATALYTIC ACTIVITY.
    26. "Design, synthesis, and X-ray crystal structure of classical and nonclassical 2-amino-4-oxo-5-substituted-6-ethylthieno[2,3-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors and as potential antitumor agents."
      Gangjee A., Li W., Kisliuk R.L., Cody V., Pace J., Piraino J., Makin J.
      J. Med. Chem. 52:4892-4902(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.24 ANGSTROMS) OF 1-187.
    27. "Dihydrofolate reductase deficiency due to a homozygous DHFR mutation causes megaloblastic anemia and cerebral folate deficiency leading to severe neurologic disease."
      Cario H., Smith D.E., Blom H., Blau N., Bode H., Holzmann K., Pannicke U., Hopfner K.P., Rump E.M., Ayric Z., Kohne E., Debatin K.M., Smulders Y., Schwarz K.
      Am. J. Hum. Genet. 88:226-231(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: VARIANT DHFRD VAL-153.

    Entry informationi

    Entry nameiDYR_HUMAN
    AccessioniPrimary (citable) accession number: P00374
    Secondary accession number(s): B4DDD2, Q14130, Q6IRW8
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 21, 1986
    Last sequence update: January 23, 2007
    Last modified: June 24, 2015
    This is version 173 of the entry and version 2 of the sequence. [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, Reference proteome

    Documents

    1. Human chromosome 5
      Human chromosome 5: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.