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P00375

- DYR_MOUSE

UniProt

P00375 - DYR_MOUSE

Protein

Dihydrofolate reductase

Gene

Dhfr

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 139 (01 Oct 2014)
      Sequence version 3 (23 Jan 2007)
      Previous versions | rss
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    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.

    Catalytic activityi

    5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.1 PublicationPROSITE-ProRule annotation

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei10 – 101NADP; via amide nitrogen and carbonyl oxygen2 Publications
    Binding sitei71 – 711Substrate

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi16 – 227NADP2 Publications
    Nucleotide bindingi55 – 573NADP2 Publications
    Nucleotide bindingi77 – 793NADP2 Publications
    Nucleotide bindingi117 – 1248NADP2 Publications

    GO - Molecular functioni

    1. dihydrofolate reductase activity Source: UniProtKB
    2. dihydrofolic acid binding Source: Ensembl
    3. drug binding Source: UniProtKB
    4. mRNA binding Source: UniProtKB
    5. NADP binding Source: Ensembl

    GO - Biological processi

    1. dihydrofolate metabolic process Source: Ensembl
    2. glycine biosynthetic process Source: InterPro
    3. nucleotide biosynthetic process Source: InterPro
    4. one-carbon metabolic process Source: UniProtKB-KW
    5. response to methotrexate Source: UniProtKB-KW
    6. response to nicotine Source: Ensembl
    7. tetrahydrofolate biosynthetic process Source: UniProtKB-UniPathway
    8. tetrahydrofolate metabolic process Source: UniProtKB

    Keywords - Molecular functioni

    Oxidoreductase

    Keywords - Biological processi

    Methotrexate resistance, One-carbon metabolism

    Keywords - Ligandi

    NADP, RNA-binding

    Enzyme and pathway databases

    ReactomeiREACT_198608. G1/S-Specific Transcription.
    REACT_199047. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
    REACT_206830. E2F mediated regulation of DNA replication.
    REACT_220137. Metabolism of folate and pterines.
    SABIO-RKP00375.
    UniPathwayiUPA00077; UER00158.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Dihydrofolate reductase (EC:1.5.1.3)
    Gene namesi
    Name:Dhfr
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 13

    Organism-specific databases

    MGIiMGI:94890. Dhfr.

    Subcellular locationi

    GO - Cellular componenti

    1. cytosol Source: Reactome

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11Removed1 Publication
    Chaini2 – 187186Dihydrofolate reductasePRO_0000186364Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei33 – 331N6-acetyllysine; alternate1 Publication
    Modified residuei33 – 331N6-succinyllysine; alternate1 Publication

    Keywords - PTMi

    Acetylation

    Proteomic databases

    MaxQBiP00375.
    PaxDbiP00375.
    PRIDEiP00375.

    PTM databases

    PhosphoSiteiP00375.

    Expressioni

    Gene expression databases

    ArrayExpressiP00375.
    BgeeiP00375.
    CleanExiMM_DHFR.
    GenevestigatoriP00375.

    Interactioni

    Subunit structurei

    Homodimer.By similarity

    Protein-protein interaction databases

    IntActiP00375. 2 interactions.
    MINTiMINT-4093753.

    Structurei

    Secondary structure

    1
    187
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi4 – 118
    Beta strandi15 – 195
    Beta strandi24 – 263
    Helixi29 – 4012
    Beta strandi43 – 464
    Beta strandi50 – 545
    Helixi55 – 606
    Helixi63 – 653
    Beta strandi71 – 766
    Beta strandi88 – 936
    Helixi94 – 1018
    Helixi104 – 1096
    Beta strandi113 – 1153
    Helixi119 – 1268
    Beta strandi128 – 1303
    Beta strandi132 – 1398
    Beta strandi146 – 1483
    Turni154 – 1563
    Beta strandi157 – 1593
    Beta strandi171 – 1733
    Beta strandi176 – 18510

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1U70X-ray2.50A2-187[»]
    2FZJX-ray2.00A2-187[»]
    3D80X-ray1.40A2-187[»]
    3D84X-ray1.90X2-187[»]
    3K45X-ray1.60A2-187[»]
    3K47X-ray2.05A2-187[»]
    ProteinModelPortaliP00375.
    SMRiP00375. Positions 2-187.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP00375.

    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.
    HOGENOMiHOG000040235.
    HOVERGENiHBG000773.
    InParanoidiP00375.
    KOiK00287.
    OMAiQINDTID.
    OrthoDBiEOG7V1FS3.
    PhylomeDBiP00375.
    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]

    Sequencei

    Sequence statusi: Complete.

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

    P00375-1 [UniParc]FASTAAdd to Basket

    « Hide

    MVRPLNCIVA VSQNMGIGKN GDLPWPPLRN EFKYFQRMTT TSSVEGKQNL    50
    VIMGRKTWFS IPEKNRPLKD RINIVLSREL KEPPRGAHFL AKSLDDALRL 100
    IEQPELASKV DMVWIVGGSS VYQEAMNQPG HLRLFVTRIM QEFESDTFFP 150
    EIDLGKYKLL PEYPGVLSEV QEEKGIKYKF EVYEKKD 187
    Length:187
    Mass (Da):21,606
    Last modified:January 23, 2007 - v3
    Checksum:i47AEF15F879B119C
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti4 – 41P → A in AAA37637. (PubMed:2982814)Curated
    Sequence conflicti14 – 141N → D in CAA39544. (PubMed:2263462)Curated
    Sequence conflicti123 – 1231Q → E AA sequence (PubMed:762074)Curated
    Sequence conflicti123 – 1231Q → E in AAA37525. (PubMed:360074)Curated
    Sequence conflicti124 – 1241E → Q AA sequence (PubMed:762074)Curated
    Sequence conflicti128 – 1281Q → E AA sequence (PubMed:762074)Curated
    Sequence conflicti174 – 1741K → D AA sequence (PubMed:762074)Curated

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti23 – 231L → R in a form with an abnormally low affinity for methotrexate.
    Natural varianti32 – 321F → W in L-5178-Y cell line; methotrexate-resistant, requires 2 nucleotide substitutions.

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    V00734 mRNA. Translation: CAA24112.1.
    X56066 mRNA. Translation: CAA39544.1.
    BC005796 mRNA. Translation: AAH05796.1.
    M10071 Genomic DNA. Translation: AAA37637.1.
    L26316 mRNA. Translation: AAA37523.1.
    J00387
    , J00382, J00383, J00384, J00385, J00386 Genomic DNA. Translation: AAA37638.1.
    V00731 mRNA. Translation: CAB43539.2.
    M10722 mRNA. Translation: AAA37524.1.
    M10811 mRNA. Translation: AAA37525.1.
    V00733 Genomic DNA. Translation: CAA24111.1.
    CCDSiCCDS26680.1.
    PIRiS13096. RDMSD.
    RefSeqiNP_034179.1. NM_010049.3.
    UniGeneiMm.23695.

    Genome annotation databases

    EnsembliENSMUST00000022218; ENSMUSP00000022218; ENSMUSG00000021707.
    GeneIDi13361.
    KEGGimmu:13361.
    UCSCiuc007rkl.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    V00734 mRNA. Translation: CAA24112.1 .
    X56066 mRNA. Translation: CAA39544.1 .
    BC005796 mRNA. Translation: AAH05796.1 .
    M10071 Genomic DNA. Translation: AAA37637.1 .
    L26316 mRNA. Translation: AAA37523.1 .
    J00387
    , J00382 , J00383 , J00384 , J00385 , J00386 Genomic DNA. Translation: AAA37638.1 .
    V00731 mRNA. Translation: CAB43539.2 .
    M10722 mRNA. Translation: AAA37524.1 .
    M10811 mRNA. Translation: AAA37525.1 .
    V00733 Genomic DNA. Translation: CAA24111.1 .
    CCDSi CCDS26680.1.
    PIRi S13096. RDMSD.
    RefSeqi NP_034179.1. NM_010049.3.
    UniGenei Mm.23695.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1U70 X-ray 2.50 A 2-187 [» ]
    2FZJ X-ray 2.00 A 2-187 [» ]
    3D80 X-ray 1.40 A 2-187 [» ]
    3D84 X-ray 1.90 X 2-187 [» ]
    3K45 X-ray 1.60 A 2-187 [» ]
    3K47 X-ray 2.05 A 2-187 [» ]
    ProteinModelPortali P00375.
    SMRi P00375. Positions 2-187.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi P00375. 2 interactions.
    MINTi MINT-4093753.

    Chemistry

    BindingDBi P00375.
    ChEMBLi CHEMBL4564.

    PTM databases

    PhosphoSitei P00375.

    Proteomic databases

    MaxQBi P00375.
    PaxDbi P00375.
    PRIDEi P00375.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000022218 ; ENSMUSP00000022218 ; ENSMUSG00000021707 .
    GeneIDi 13361.
    KEGGi mmu:13361.
    UCSCi uc007rkl.1. mouse.

    Organism-specific databases

    CTDi 1719.
    MGIi MGI:94890. Dhfr.

    Phylogenomic databases

    eggNOGi COG0262.
    HOGENOMi HOG000040235.
    HOVERGENi HBG000773.
    InParanoidi P00375.
    KOi K00287.
    OMAi QINDTID.
    OrthoDBi EOG7V1FS3.
    PhylomeDBi P00375.
    TreeFami TF317636.

    Enzyme and pathway databases

    UniPathwayi UPA00077 ; UER00158 .
    Reactomei REACT_198608. G1/S-Specific Transcription.
    REACT_199047. Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation.
    REACT_206830. E2F mediated regulation of DNA replication.
    REACT_220137. Metabolism of folate and pterines.
    SABIO-RK P00375.

    Miscellaneous databases

    EvolutionaryTracei P00375.
    NextBioi 283696.
    PROi P00375.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P00375.
    Bgeei P00375.
    CleanExi MM_DHFR.
    Genevestigatori P00375.

    Family and domain databases

    Gene3Di 3.40.430.10. 1 hit.
    InterProi IPR012259. DHFR.
    IPR024072. DHFR-like_dom.
    IPR017925. DHFR_CS.
    IPR001796. DHFR_dom.
    [Graphical view ]
    Pfami PF00186. DHFR_1. 1 hit.
    [Graphical view ]
    PRINTSi PR00070. DHFR.
    SUPFAMi SSF53597. SSF53597. 1 hit.
    PROSITEi PS00075. DHFR_1. 1 hit.
    PS51330. DHFR_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Structure of amplified normal and variant dihydrofolate reductase genes in mouse sarcoma S180 cells."
      Crouse G.F., Simonsen C.C., McEwan R.N., Schimke R.T.
      J. Biol. Chem. 257:7887-7897(1982) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    2. "Isolation and expression of an altered mouse dihydrofolate reductase cDNA."
      Simonsen C.C., Levinson A.D.
      Proc. Natl. Acad. Sci. U.S.A. 80:2495-2499(1983) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    3. "Isolation and characterization of a variant dihydrofolate reductase cDNA from methotrexate-resistant murine L5178Y cells."
      McIvor R.S., Simonsen C.C.
      Nucleic Acids Res. 18:7025-7032(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    4. "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].
      Strain: FVB/N.
      Tissue: Mammary gland.
    5. "The amino acid sequence of dihydrofolate reductase from the mouse lymphoma L1210."
      Stone D., Paterson S.J., Raper J.H., Phillips A.W.
      J. Biol. Chem. 254:480-488(1979) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 2-187.
      Tissue: Lymphoma.
    6. "Heterogeneity at the 5' termini of mouse dihydrofolate reductase mRNAs. Evidence for multiple promoter regions."
      McGrogan M., Simonsen C.C., Smouse D.T., Farnham P.J., Schimke R.T.
      J. Biol. Chem. 260:2307-2314(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-28.
    7. "Structure and genomic organization of the mouse dihydrofolate reductase gene."
      Nunberg J.H., Kaufman R.J., Chang A.C.Y., Cohen S.N., Schimke R.T.
      Cell 19:355-364(1980) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 1-24; 50-127 AND 154-187.
    8. "Phenotypic expression in E. coli of a DNA sequence coding for mouse dihydrofolate reductase."
      Chang A.C.Y., Nunberg J.H., Kaufman R.J., Erlich H.A., Schimke R.T., Cohen S.N.
      Nature 275:617-624(1978) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1-24 AND 50-127.
    9. "Nucleotide sequence surrounding multiple polyadenylation sites in the mouse dihydrofolate reductase gene."
      Setzer D.R., McGrogan M., Schimke R.T.
      J. Biol. Chem. 257:5143-5147(1982) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 163-187.
    10. "SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
      Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
      Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-33, SUCCINYLATION [LARGE SCALE ANALYSIS] AT LYS-33, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
      Tissue: Embryonic fibroblast and Liver.
    11. "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 (2.50 ANGSTROMS) IN COMPLEX WITH NADP AND METHOTREXATE, CHARACTERIZATION OF METHOTREXATE-RESISTANT VARIANT ARG-23.
    12. "New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent 5-(omega-carboxy(alkyloxy) trimethoprim derivatives reveals conformational correlations with activity and novel parallel ring stacking interactions."
      Cody V., Pace J., Chisum K., Rosowsky A.
      Proteins 65:959-969(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH NADP AND SYNTHETIC INHIBITOR.
    13. "Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2,4-diamino-6-(2'-hydroxydibenz[b,f]azepin-5-yl)methylpteridine."
      Cody V., Pace J., Rosowsky A.
      Acta Crystallogr. D 64:977-984(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND SYNTHETIC INHIBITOR.
    14. "Design, synthesis, and X-ray crystal structures of 2,4-diaminofuro[2,3-d]pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors."
      Gangjee A., Li W., Lin L., Zeng Y., Ihnat M., Warnke L.A., Green D.W., Cody V., Pace J., Queener S.F.
      Bioorg. Med. Chem. 17:7324-7336(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEXES WITH NADP AND SYNTHETIC INHIBITOR, CATALYTIC ACTIVITY.

    Entry informationi

    Entry nameiDYR_MOUSE
    AccessioniPrimary (citable) accession number: P00375
    Secondary accession number(s): P70693
    , Q61485, Q61487, Q61579
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 21, 1986
    Last sequence update: January 23, 2007
    Last modified: October 1, 2014
    This is version 139 of the entry and version 3 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    3. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    4. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3