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P00375 (DYR_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 135. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (4) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Dihydrofolate reductase

EC=1.5.1.3
Gene names
Name:Dhfr
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length187 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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 activity

5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH. Ref.14

Pathway

Cofactor biosynthesis; tetrahydrofolate biosynthesis; 5,6,7,8-tetrahydrofolate from 7,8-dihydrofolate: step 1/1.

Subunit structure

Homodimer By similarity.

Sequence similarities

Belongs to the dihydrofolate reductase family.

Contains 1 DHFR (dihydrofolate reductase) domain.

Ontologies

Keywords
   Biological processMethotrexate resistance
One-carbon metabolism
   LigandNADP
RNA-binding
   Molecular functionOxidoreductase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processdihydrofolate metabolic process

Inferred from electronic annotation. Source: Ensembl

glycine biosynthetic process

Inferred from electronic annotation. Source: InterPro

nucleotide biosynthetic process

Inferred from electronic annotation. Source: InterPro

one-carbon metabolic process

Inferred from electronic annotation. Source: UniProtKB-KW

response to methotrexate

Inferred from electronic annotation. Source: UniProtKB-KW

response to nicotine

Inferred from electronic annotation. Source: Ensembl

tetrahydrofolate biosynthetic process

Inferred from electronic annotation. Source: UniProtKB-UniPathway

tetrahydrofolate metabolic process

Inferred from sequence or structural similarity. Source: UniProtKB

   Cellular_componentcytosol

Traceable author statement. Source: Reactome

   Molecular_functionNADP binding

Inferred from electronic annotation. Source: Ensembl

dihydrofolate reductase activity

Inferred from sequence or structural similarity. Source: UniProtKB

dihydrofolic acid binding

Inferred from electronic annotation. Source: Ensembl

drug binding

Inferred from sequence or structural similarity. Source: UniProtKB

mRNA binding

Inferred from sequence or structural similarity. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.5
Chain2 – 187186Dihydrofolate reductase
PRO_0000186364

Regions

Domain4 – 185182DHFR
Nucleotide binding16 – 227NADP
Nucleotide binding55 – 573NADP
Nucleotide binding77 – 793NADP
Nucleotide binding117 – 1248NADP
Region31 – 366Substrate binding

Sites

Binding site101NADP; via amide nitrogen and carbonyl oxygen
Binding site711Substrate

Amino acid modifications

Modified residue331N6-acetyllysine; alternate Ref.10
Modified residue331N6-succinyllysine; alternate Ref.10

Natural variations

Natural variant231L → R in a form with an abnormally low affinity for methotrexate. Ref.11
Natural variant321F → W in L-5178-Y cell line; methotrexate-resistant, requires 2 nucleotide substitutions.

Experimental info

Sequence conflict41P → A in AAA37637. Ref.6
Sequence conflict141N → D in CAA39544. Ref.3
Sequence conflict1231Q → E AA sequence Ref.5
Sequence conflict1231Q → E in AAA37525. Ref.8
Sequence conflict1241E → Q AA sequence Ref.5
Sequence conflict1281Q → E AA sequence Ref.5
Sequence conflict1741K → D AA sequence Ref.5

Secondary structure

........................................ 187
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P00375 [UniParc].

Last modified January 23, 2007. Version 3.
Checksum: 47AEF15F879B119C

FASTA18721,606
        10         20         30         40         50         60 
MVRPLNCIVA VSQNMGIGKN GDLPWPPLRN EFKYFQRMTT TSSVEGKQNL VIMGRKTWFS 

        70         80         90        100        110        120 
IPEKNRPLKD RINIVLSREL KEPPRGAHFL AKSLDDALRL IEQPELASKV DMVWIVGGSS 

       130        140        150        160        170        180 
VYQEAMNQPG HLRLFVTRIM QEFESDTFFP EIDLGKYKLL PEYPGVLSEV QEEKGIKYKF 


EVYEKKD 

« Hide

References

« Hide 'large scale' references
[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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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 expand/collapse EMBL AC list , 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.
PIRRDMSD. S13096.
RefSeqNP_034179.1. NM_010049.3.
UniGeneMm.23695.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1U70X-ray2.50A2-186[»]
2FZJX-ray2.00A2-186[»]
3D80X-ray1.40A2-187[»]
3D84X-ray1.90X2-187[»]
3K45X-ray1.60A2-187[»]
3K47X-ray2.05A2-187[»]
ProteinModelPortalP00375.
SMRP00375. Positions 2-187.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActP00375. 2 interactions.
MINTMINT-4093753.

Chemistry

BindingDBP00375.
ChEMBLCHEMBL4564.

PTM databases

PhosphoSiteP00375.

Proteomic databases

PaxDbP00375.
PRIDEP00375.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000022218; ENSMUSP00000022218; ENSMUSG00000021707.
GeneID13361.
KEGGmmu:13361.
UCSCuc007rkl.1. mouse.

Organism-specific databases

CTD1719.
MGIMGI:94890. Dhfr.

Phylogenomic databases

eggNOGCOG0262.
HOGENOMHOG000040235.
HOVERGENHBG000773.
InParanoidP00375.
KOK00287.
OMASDTFFSE.
OrthoDBEOG7V1FS3.
PhylomeDBP00375.
TreeFamTF317636.

Enzyme and pathway databases

ReactomeREACT_188937. Metabolism.
SABIO-RKP00375.
UniPathwayUPA00077; UER00158.

Gene expression databases

ArrayExpressP00375.
BgeeP00375.
CleanExMM_DHFR.
GenevestigatorP00375.

Family and domain databases

Gene3D3.40.430.10. 1 hit.
InterProIPR012259. DHFR.
IPR024072. DHFR-like_dom.
IPR017925. DHFR_CS.
IPR001796. DHFR_dom.
[Graphical view]
PfamPF00186. DHFR_1. 1 hit.
[Graphical view]
PRINTSPR00070. DHFR.
SUPFAMSSF53597. SSF53597. 1 hit.
PROSITEPS00075. DHFR_1. 1 hit.
PS51330. DHFR_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

EvolutionaryTraceP00375.
NextBio283696.
PROP00375.
SOURCESearch...

Entry information

Entry nameDYR_MOUSE
AccessionPrimary (citable) accession number: P00375
Secondary accession number(s): P70693 expand/collapse secondary AC list , Q61485, Q61487, Q61579
Entry history
Integrated into UniProtKB/Swiss-Prot: July 21, 1986
Last sequence update: January 23, 2007
Last modified: April 16, 2014
This is version 135 of the entry and version 3 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

PATHWAY comments

Index of metabolic and biosynthesis pathways

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot