Reviewed, UniProtKB/Swiss-Prot P00374 (DYR_HUMAN)

Names and origin

Protein names

Recommended name:
    Dihydrofolate reductase
    EC=1.5.1.3

Gene names

Name:	DHFR
AND
Name:	DHFRP1

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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.

General annotation (Comments)

Catalytic activity	5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH.
Pathway	Cofactor biosynthesis; tetrahydrofolate biosynthesis; tetrahydrofolate from dihydrofolate: step 1/1.
Miscellaneous	The reaction catalyzed by this enzyme represents an essential step for de novo glycine and purine synthesis, DNA precursor synthesis, and for the conversion of dUMP to dTMP.
Sequence similarities	Belongs to the dihydrofolate reductase family. Contains 1 DHFR (dihydrofolate reductase) domain.

Ontologies

Keywords
Biological process	One-carbon metabolism
Ligand	NADP
Molecular function	Oxidoreductase
Technical term	3D-structure
Gene Ontology (GO)
Biological process	glycine biosynthetic process Non-traceable author statement. Source: UniProtKB nucleotide biosynthetic process Non-traceable author statement. Source: UniProtKB one-carbon compound 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 Ref.2 Non-traceable author statement. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed

Chain

2 – 187

186

Dihydrofolate reductase

PRO_0000186362

Regions

Domain

4 – 185

182

DHFR

Experimental info

Sequence conflict

113

1

V → L in AAH70280. Ref.4

Secondary structure

1

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187

Helix Strand Turn

Details...

Beta strand

5 – 11

7

Beta strand

16 – 19

4

Helix

29 – 40

12

Beta strand

48 – 54

7

Helix

55 – 60

6

Helix

63 – 65

3

Beta strand

71 – 76

6

Beta strand

88 – 93

6

Helix

94 – 101

8

Turn

104 – 109

6

Beta strand

110 – 115

6

Helix

119 – 125

7

Beta strand

132 – 139

8

Beta strand

146 – 148

3

Turn

154 – 156

3

Beta strand

157 – 159

3

Beta strand

171 – 173

3

Beta strand

176 – 185

10

Sequences

	Sequence		Length	Mass (Da)
	P00374-1 [UniParc]. Last modified January 23, 2007. Version 2. Checksum: EBDF3D1EC73E1566	FASTA	187	21,453
	10 20 30 40 50 60 MVGSLNCIVA VSQNMGIGKN GDLPWPPLRN EFRYFQRMTT TSSVEGKQNL VIMGKKTWFS 70 80 90 100 110 120 IPEKNRPLKG RINLVLSREL KEPPQGAHFL SRSLDDALKL TEQPELANKV DMVWIVGGSS 130 140 150 160 170 180 VYKEAMNHPG HLKLFVTRIM QDFESDTFFP EIDLEKYKLL PEYPGVLSDV QEEKGIKYKF EVYEKND

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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: 6323448] [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: 6687716] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[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: 6235374] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[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]. Tissue: Eye.
[5]	Colinge J., Superti-Furga G., Bennett K.L. Submitted (OCT-2008) to UniProtKB Cited for: IDENTIFICATION [LARGE SCALE ANALYSIS], MASS SPECTROMETRY.
[6]	"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: 3383852] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
[7]	"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: 2248959] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
[8]	"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: 9374868] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
[9]	"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: 1731871] [Abstract] Cited for: STRUCTURE BY NMR.
+	Additional computationally mapped references.

Web resources

Wikipedia

Dihydrofolate reductase entry

Cross-references

Sequence databases

EMBLGenBankDDBJ

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.
BC000192 mRNA. Translation: AAH00192.1.
BC003584 mRNA. Translation: AAH03584.2.
BC070280 mRNA. Translation: AAH70280.1.
BC071996 mRNA. Translation: AAH71996.1.

IPI

IPI00030357.

PIR

RDHUD. A22551.

RefSeq

NP_000782.1.

UniGene

Hs.592364
Hs.648635

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1BOZ	X-ray	2.10	A	2-187	[»]
1DHF	X-ray	2.30	A/B	2-187	[»]
1DLR	X-ray	2.30	A	2-186	[»]
1DLS	X-ray	2.30	A	2-186	[»]
1DRF	X-ray	2.00	A	2-187	[»]
1HFP	X-ray	2.10	A	2-186	[»]
1HFQ	X-ray	2.10	A	2-186	[»]
1HFR	X-ray	2.10	A	2-186	[»]
1KMS	X-ray	1.09	A	2-186	[»]
1KMV	X-ray	1.05	A	2-186	[»]
1MVS	X-ray	1.90	A	1-187	[»]
1MVT	X-ray	1.80	A	1-187	[»]
1OHJ	X-ray	2.50	A	2-187	[»]
1OHK	X-ray	2.50	A	2-187	[»]
1PD8	X-ray	2.10	A	2-186	[»]
1PD9	X-ray	2.20	A	2-186	[»]
1PDB	X-ray	2.20	A	2-186	[»]
1S3U	X-ray	2.50	A	2-186	[»]
1S3V	X-ray	1.80	A	2-186	[»]
1S3W	X-ray	1.90	A	2-186	[»]
1U71	X-ray	2.20	A	2-186	[»]
1U72	X-ray	1.90	A	2-186	[»]
1YHO	NMR	-	A	2-186	[»]
2C2S	X-ray	1.40	A/B	2-186	[»]
2C2T	X-ray	1.50	A/B	2-186	[»]
2DHF	X-ray	2.30	A/B	2-187	[»]

ModBase

Search...

PTM databases

PhosphoSite

P00374.

2-D gel databases

HSC-2DPAGE

P00374.

Genome annotation databases

Ensembl

ENSG00000188985. Homo sapiens. [Contig view]

GeneID

1719.

KEGG

hsa:1719.

Organism-specific databases

GeneCards

GC05M079957.
GC18M022002.

H-InvDB

HIX0004995.
HIX0021723.
HIX0059796.

HGNC

HGNC:2861. DHFR.
HGNC:2862. DHFRP1.

MIM

126060. gene+phenotype.

Orphanet

35858. Graesbeck-Imerslund disease.

PharmGKB

PA143.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P00374.

HOVERGEN

P00374.

OMA

P00374. LAHFKRT.

Enzyme and pathway databases

BRENDA

1.5.1.3. 247.

Reactome

REACT_11193. Metabolism of vitamins and cofactors.
REACT_152. Cell Cycle, Mitotic.

Gene expression databases

ArrayExpress

P00374.

Bgee

P00374.

CleanEx

HS_DHFR.

GermOnline

ENSG00000188985. Homo sapiens.

Family and domain databases

InterPro

IPR012259. DHFR.
IPR001796. DHFR_reg.
IPR017925. Dihydrofolate_reductase_CS.
[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

BindingDB

P00374.

DrugBank

DB00250. Dapsone.
DB01093. Dimethyl sulfoxide.
DB00555. Lamotrigine.
DB00563. Methotrexate.
DB00157. NADH.
DB00642. Pemetrexed.
DB01131. Proguanil.
DB00205. Pyrimethamine.
DB00440. Trimethoprim.
DB01157. Trimetrexate.

NextBio

6964.

SOURCE

Search...

Entry information

Entry name

DYR_HUMAN

Accession

Primary (citable) accession number: P00374
Secondary accession number(s): Q14130, Q6IRW8

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	January 23, 2007
Last modified:	June 16, 2009
This is version 109 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)