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P00375

- DYR_MOUSE

UniProt

P00375 - DYR_MOUSE

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Protein

Dihydrofolate reductase

Gene

Dhfr

Organism
Mus musculus (Mouse)
Status
Reviewed - 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.

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
Complete GO annotation...

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
Complete GO annotation...

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

BgeeiP00375.
CleanExiMM_DHFR.
ExpressionAtlasiP00375. baseline and differential.
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 – 118Combined sources
Beta strandi15 – 195Combined sources
Beta strandi24 – 263Combined sources
Helixi29 – 4012Combined sources
Beta strandi43 – 464Combined sources
Beta strandi50 – 545Combined sources
Helixi55 – 606Combined sources
Helixi63 – 653Combined sources
Beta strandi71 – 766Combined sources
Beta strandi88 – 936Combined sources
Helixi94 – 1018Combined sources
Helixi104 – 1096Combined sources
Beta strandi113 – 1153Combined sources
Helixi119 – 1268Combined sources
Beta strandi128 – 1303Combined sources
Beta strandi132 – 1398Combined sources
Beta strandi146 – 1483Combined sources
Turni154 – 1563Combined sources
Beta strandi157 – 1593Combined 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
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

        10         20         30         40         50
MVRPLNCIVA VSQNMGIGKN GDLPWPPLRN EFKYFQRMTT TSSVEGKQNL
60 70 80 90 100
VIMGRKTWFS IPEKNRPLKD RINIVLSREL KEPPRGAHFL AKSLDDALRL
110 120 130 140 150
IEQPELASKV DMVWIVGGSS VYQEAMNQPG HLRLFVTRIM QEFESDTFFP
160 170 180
EIDLGKYKLL PEYPGVLSEV QEEKGIKYKF EVYEKKD
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:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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:
PDBei
RCSB PDBi
PDBji
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

ChiTaRSi Dhfr. mouse.
EvolutionaryTracei P00375.
NextBioi 283696.
PROi P00375.
SOURCEi Search...

Gene expression databases

Bgeei P00375.
CleanExi MM_DHFR.
ExpressionAtlasi P00375. baseline and differential.
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

« Hide 'large scale' publications
  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: November 26, 2014
This is version 141 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