Dihydrofolate reductase - Mus musculus (Mouse)

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Reviewed, UniProtKB/Swiss-Prot P00375 (DYR_MOUSE)

Last modified February 9, 2010. Version 102. History...

Clusters with 100%, 90%, 50% identity |

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
Dihydrofolate reductase
EC=1.5.1.3

Gene names

Name:

Dhfr

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

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Protein attributes

Sequence length	187 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	Key enzyme in folate metabolism. Catalyzes an essential reaction for de novo glycine and purine synthesis, and for DNA precursor synthesis.
Catalytic activity	5,6,7,8-tetrahydrofolate + NADP⁺ = 7,8-dihydrofolate + NADPH.
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.

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Ontologies

Keywords
Biological process	Methotrexate resistance One-carbon metabolism
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	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 oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	NADP or NADPH binding Inferred from electronic annotation. Source: InterPro dihydrofolate reductase activity Inferred from sequence or structural similarity. Source: UniProtKB drug binding Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

Removed Ref.5

Chain

2 – 187

186

Dihydrofolate reductase

PRO_0000186364

Regions

Domain

4 – 185

182

DHFR

Nucleotide binding

16 – 22

NADP

Nucleotide binding

55 – 57

NADP

Nucleotide binding

77 – 79

NADP

Nucleotide binding

117 – 124

NADP

Region

31 – 36

Substrate binding

Sites

Binding site

NADP; via amide nitrogen and carbonyl oxygen

Binding site

Substrate

Natural variations

Natural variant

L → R in a form with an abnormally low affinity for methotrexate.

Natural variant

F → W in L5178Y cell line; methotrexate-resistant.

Experimental info

Sequence conflict

P → A Ref.6

Sequence conflict

N → D in CAA39544. Ref.3

Sequence conflict

123

Q → E AA sequence Ref.5

Sequence conflict

123

Q → E in AAA37525. Ref.8

Sequence conflict

124

E → Q AA sequence Ref.5

Sequence conflict

128

Q → E AA sequence Ref.5

Sequence conflict

174

K → D AA sequence Ref.5

Secondary structure

187

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

P00375-1 [UniParc].

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

187

21,606

        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

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References

	« Hide 'large scale' referencesShow '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: 6282858] [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: 6573667] [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: 2263462] [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: 15489334] [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: 762074] [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: 2982814] [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: 6244105] [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: 360074] [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: 6121807] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 163-187.
[10]	"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: 15681865] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) IN COMPLEX WITH NADP AND METHOTREXATE, CHARACTERIZATION OF METHOTREXATE-RESISTANT VARIANT ARG-23.
[11]	"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: 17019704] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) IN COMPLEX WITH NADP AND SYNTHETIC INHIBITOR.
[12]	"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: 18703847] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.40 ANGSTROMS) IN COMPLEXES WITH NADP AND SYNTHETIC INHIBITOR.
[13]	"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: 19748785] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.60 ANGSTROMS) IN COMPLEXES WITH NADP AND SYNTHETIC INHIBITOR, CATALYTIC ACTIVITY.
+	Additional computationally mapped references.

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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

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.

IPI

IPI00230042.

PIR

RDMSD. S13096.

RefSeq

NP_034179.1.

UniGene

Mm.23695

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1U70	X-ray	2.50	A	2-186	[»]
2FZJ	X-ray	2.00	A	2-186	[»]
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	[»]

ModBase

Search...

Protein-protein interaction databases

STRING

P00375.

PTM databases

PhosphoSite

P00375.

Proteomic databases

PRIDE

P00375.

Genome annotation databases

Ensembl

ENSMUST00000022218; ENSMUSP00000022218; ENSMUSG00000021707; Mus musculus. [Genome view]

GeneID

13361.

KEGG

mmu:13361.

UCSC

uc007rkl.1. mouse.

Organism-specific databases

CTD

13361.

MGI

MGI:94890. Dhfr.

Phylogenomic databases

eggNOG

maNOG18401.

HOGENOM

HBG665708.

HOVERGEN

P00375.

InParanoid

P00375.

OMA

PLNCIVA.

OrthoDB

EOG97M4J0.

PhylomeDB

P00375.

Enzyme and pathway databases

BRENDA

1.5.1.3. 244.

Gene expression databases

ArrayExpress

P00375.

Bgee

P00375.

CleanEx

MM_DHFR.

Genevestigator

P00375.

GermOnline

ENSMUSG00000021707. Mus musculus.

Family and domain databases

InterPro

IPR012259. DHFR.
IPR017925. Dihydrofolate_reductase_CS.
IPR001796. Dihydrofolate_reductase_dom.
[Graphical view]

Pfam

PF00186. DHFR_1. 1 hit.
[Graphical view]

PRINTS

PR00070. DHFR.

PROSITE

PS00075. DHFR_1. 1 hit.
PS51330. DHFR_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

283696.

SOURCE

Search...

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Entry information

Entry name

DYR_MOUSE

Accession

Primary (citable) accession number: P00375
Secondary accession number(s): P70693

Q61579

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	February 9, 2010
This is version 102 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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