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600  structures 2372  species 4  interactions 2747  sequences 33  architectures

Family: DHFR_1 (PF00186)

Summary: Dihydrofolate reductase

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Dihydrofolate reductase". More...

Dihydrofolate reductase Edit Wikipedia article

Dihydrofolate reductase
PDB 8dfr EBI.jpg
Crystal structure of chicken liver dihydrofolate reductase. PDB entry 8dfr
Identifiers
EC number 1.5.1.3
CAS number 9002-03-3
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Dihydrofolate reductase
Identifiers
Symbol DHFR_1
Pfam PF00186
Pfam clan CL0387
InterPro IPR001796
PROSITE PDOC00072
SCOP 1dhi
SUPERFAMILY 1dhi
R67 dihydrofolate reductase
PDB 2gqv EBI.jpg
High-resolution structure of a plasmid-encoded dihydrofolate reductase from E.coli. PDB entry 2gqv
Identifiers
Symbol DHFR_2
Pfam PF06442
InterPro IPR009159
SCOP 1vif
SUPERFAMILY 1vif
DHFR
Dihydrofolate reductase 1DRF.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DHFR, DHFRP1, DYR, dihydrofolate reductase
External IDs OMIM: 126060 MGI: 94890 HomoloGene: 56470 GeneCards: DHFR
Targeted by Drug
methotrexate, pemetrexed, pralatrexate, trimetrexate[1]
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000791
NM_001290354
NM_001290357

NM_010049

RefSeq (protein)

NP_000782.1
NP_001277283.1

NP_034179.1

Location (UCSC) Chr 5: 80.63 – 80.65 Mb Chr 13: 92.35 – 92.39 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Dihydrofolate reductase, or DHFR, is an enzyme that reduces dihydrofolic acid to tetrahydrofolic acid, using NADPH as electron donor, which can be converted to the kinds of tetrahydrofolate cofactors used in 1-carbon transfer chemistry. In humans, the DHFR enzyme is encoded by the DHFR gene.[4][5] It is found in the q11→q22 region of chromosome 5.[6] Bacterial species possess distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar.[7]

Structure

A central eight-stranded beta-pleated sheet makes up the main feature of the polypeptide backbone folding of DHFR.[8] Seven of these strands are parallel and the eighth runs antiparallel. Four alpha helices connect successive beta strands.[9] Residues 9 – 24 are termed "Met20" or "loop 1" and, along with other loops, are part of the major subdomain that surround the active site.[10] The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown to be involved in the binding of substrate by the enzyme.[11]

Human DHFR with bound dihydrofolate and NADPH 

Function

Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. While the functional dihydrofolate reductase gene has been mapped to chromosome 5, multiple intronless processed pseudogenes or dihydrofolate reductase-like genes have been identified on separate chromosomes.[12]

Reaction catalyzed by DHFR. 
Tetrahydrofolate synthesis pathway. 

Found in all organisms, DHFR has a critical role in regulating the amount of tetrahydrofolate in the cell. Tetrahydrofolate and its derivatives are essential for purine and thymidylate synthesis, which are important for cell proliferation and cell growth.[13] DHFR plays a central role in the synthesis of nucleic acid precursors, and it has been shown that mutant cells that completely lack DHFR require glycine, an amino acid, and thymidine to grow.[14] DHFR has also been demonstrated as an enzyme involved in the salvage of tetrahydrobiopterin from dihydrobiopterin[15]

Mechanism

The reduction of dihydrofolate to tetrahydrofolate.

DHFR catalyzes the transfer of a hydride from NADPH to dihydrofolate with an accompanying protonation to produce tetrahydrofolate.[13] In the end, dihydrofolate is reduced to tetrahydrofolate and NADPH is oxidized to NADP+. The high flexibility of Met20 and other loops near the active site play a role in promoting the release of the product, tetrahydrofolate. In particular the Met20 loop helps stabilize the nicotinamide ring of the NADPH to promote the transfer of the hydride from NADPH to dihydrofolate.[10]

Clinical significance

Dihydrofolate reductase deficiency has been linked to megaloblastic anemia.[12] Treatment is with reduced forms of folic acid. Because tetrahydrofolate, the product of this reaction, is the active form of folate in humans, inhibition of DHFR can cause functional folate deficiency. DHFR is an attractive pharmaceutical target for inhibition due to its pivotal role in DNA precursor synthesis. Trimethoprim, an antibiotic, inhibits bacterial DHFR while methotrexate, a chemotherapy agent, inhibits mammalian DHFR. However, resistance has developed against some drugs, as a result of mutational changes in DHFR itself.[16]

DHFR mutations cause a rare autosomal recessive inborn error of folate metabolism that results in megaloblastic anemia, pancytopenia and severe cerebral folate deficiency which can be corrected by folinic acid supplementation .[17]

Therapeutic applications

Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage.

DHFR can be targeted in the treatment of cancer. DHFR is responsible for the levels of tetrahydrofolate in a cell, and the inhibition of DHFR can limit the growth and proliferation of cells that are characteristic of cancer. Methotrexate, a competitive inhibitor of DHFR, is one such anticancer drug that inhibits DHFR.[18] Other drugs include trimethoprim and pyrimethamine. These three are widely used as antitumor and antimicrobial agents.[19]

Trimethoprim has shown to have activity against a variety of Gram-positive bacterial pathogens.[20] However, resistance to trimethoprim and other drugs aimed at DHFR can arise due to a variety of mechanisms, limiting the success of their therapeutical uses.[21][22][23] Resistance can arise from DHFR gene amplification, mutations in DHFR, decrease in the uptake of the drugs, among others. Regardless, trimethoprim and sulfamethoxazole in combination has been used as an antibacterial agent for decades.[20]

Folic acid is necessary for growth,[24] and the pathway of the metabolism of folic acid is a target in developing treatments for cancer. DHFR is one such target. A regimen of fluorouracil, doxorubicin, and methotrexate was shown to prolong survival in patients with advanced gastric cancer.[25] Further studies into inhibitors of DHFR can lead to more ways to treat cancer.

Bacteria also need DHFR to grow and multiply and hence inhibitors selective for bacterial DHFR have found application as antibacterial agents.[20]

Classes of small-molecules employed as inhibitors of dihydrofolate reductase include diaminoquinazoline & diaminopyrroloquinazoline,[26] diaminopyrimidine, diaminopteridine and diaminotriazines.[27]

Potential anthrax treatment

Structural alignment of dihydrofolate reductase from Bacillus anthracis (BaDHFR), Staphylococcus aureus (SaDHFR), Escherichia coli (EcDHFR), and Streptococcus pneumoniae (SpDHFR).

Dihydrofolate reductase from Bacillus anthracis (BaDHFR) a validated drug target in the treatment of the infectious disease, anthrax. BaDHFR is less sensitive to trimethoprim analogs than is dihydrofolate reductase from other species such as Escherichia coli, Staphylococcus aureus, and Streptococcus pneumoniae. A structural alignment of dihydrofolate reductase from all four species shows that only BaDHFR has the combination phenylalanine and tyrosine in positions 96 and 102, respectively.

BaDHFR's resistance to trimethoprim analogs is due to these two residues (F96 and Y102), which also confer improved kinetics and catalytic efficiency.[28] Current research uses active site mutants in BaDHFR to guide lead optimization for new antifolate inhibitors.[28]

As a research tool

DHFR has been used as a tool to detect protein–protein interactions in a protein-fragment complementation assay (PCA).

CHO cells

DHFR lacking CHO cells are the most commonly used cell line for the production of recombinant proteins. These cells are transfected with a plasmid carrying the dhfr gene and the gene for the recombinant protein in a single expression system, and then subjected to selective conditions in thymidine-lacking medium. Only the cells with the exogenous DHFR gene along with the gene of interest survive.

Interactions

Dihydrofolate reductase has been shown to interact with GroEL[29] and Mdm2.[30]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article
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FluoropyrimidineActivity_WP1601 go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to PubChem Compound go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to pathway article go to pathway article go to article go to article go to article go to article go to article go to WikiPathways go to article go to article go to article go to article go to article go to article go to article go to article go to article
|{{{bSize}}}px|alt=Fluorouracil (5-FU) Activity edit]]
Fluorouracil (5-FU) Activity edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "FluoropyrimidineActivity_WP1601". 

References

  1. ^ "Drugs that physically interact with Dihydrofolate reductase view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ Chen MJ, Shimada T, Moulton AD, Harrison M, Nienhuis AW (December 1982). "Intronless human dihydrofolate reductase genes are derived from processed RNA molecules". Proceedings of the National Academy of Sciences of the United States of America. 79 (23): 7435–9. doi:10.1073/pnas.79.23.7435. PMC 347354Freely accessible. PMID 6961421. 
  5. ^ Chen MJ, Shimada T, Moulton AD, Cline A, Humphries RK, Maizel J, Nienhuis AW (March 1984). "The functional human dihydrofolate reductase gene". The Journal of Biological Chemistry. 259 (6): 3933–43. PMID 6323448. 
  6. ^ Funanage VL, Myoda TT, Moses PA, Cowell HR (October 1984). "Assignment of the human dihydrofolate reductase gene to the q11----q22 region of chromosome 5". Molecular and Cellular Biology. 4 (10): 2010–6. PMC 369017Freely accessible. PMID 6504041. 
  7. ^ Smith SL, Patrick P, Stone D, Phillips AW, Burchall JJ (November 1979). "Porcine liver dihydrofolate reductase. Purification, properties, and amino acid sequence". The Journal of Biological Chemistry. 254 (22): 11475–84. PMID 500653. 
  8. ^ Matthews DA, Alden RA, Bolin JT, Freer ST, Hamlin R, Xuong N, Kraut J, Poe M, Williams M, Hoogsteen K (July 1977). "Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate". Science. 197 (4302): 452–5. doi:10.1126/science.17920. PMID 17920. 
  9. ^ Filman DJ, Bolin JT, Matthews DA, Kraut J (November 1982). "Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. II. Environment of bound NADPH and implications for catalysis". The Journal of Biological Chemistry. 257 (22): 13663–72. PMID 6815179. 
  10. ^ a b Osborne MJ, Schnell J, Benkovic SJ, Dyson HJ, Wright PE (August 2001). "Backbone dynamics in dihydrofolate reductase complexes: role of loop flexibility in the catalytic mechanism". Biochemistry. 40 (33): 9846–59. doi:10.1021/bi010621k. PMID 11502178. 
  11. ^ Bolin JT, Filman DJ, Matthews DA, Hamlin RC, Kraut J (November 1982). "Crystal structures of Escherichia coli and Lactobacillus casei dihydrofolate reductase refined at 1.7 A resolution. I. General features and binding of methotrexate". The Journal of Biological Chemistry. 257 (22): 13650–62. PMID 6815178. 
  12. ^ a b "Entrez Gene: DHFR dihydrofolate reductase". 
  13. ^ a b Schnell JR, Dyson HJ, Wright PE (2004). "Structure, dynamics, and catalytic function of dihydrofolate reductase". Annual Review of Biophysics and Biomolecular Structure. 33 (1): 119–40. doi:10.1146/annurev.biophys.33.110502.133613. PMID 15139807. 
  14. ^ Urlaub G, Chasin LA (July 1980). "Isolation of Chinese hamster cell mutants deficient in dihydrofolate reductase activity". Proceedings of the National Academy of Sciences of the United States of America. 77 (7): 4216–20. doi:10.1073/pnas.77.7.4216. PMC 349802Freely accessible. PMID 6933469. 
  15. ^ Crabtree MJ, Tatham AL, Hale AB, Alp NJ, Channon KM (October 2009). "Critical role for tetrahydrobiopterin recycling by dihydrofolate reductase in regulation of endothelial nitric-oxide synthase coupling: relative importance of the de novo biopterin synthesis versus salvage pathways". The Journal of Biological Chemistry. 284 (41): 28128–36. doi:10.1074/jbc.M109.041483. PMC 2788863Freely accessible. PMID 19666465. 
  16. ^ Cowman AF, Lew AM (November 1989). "Antifolate drug selection results in duplication and rearrangement of chromosome 7 in Plasmodium chabaudi". Molecular and Cellular Biology. 9 (11): 5182–8. PMC 363670Freely accessible. PMID 2601715. 
  17. ^ Banka S, Blom HJ, Walter J, Aziz M, Urquhart J, Clouthier CM, Rice GI, de Brouwer AP, Hilton E, Vassallo G, Will A, Smith DE, Smulders YM, Wevers RA, Steinfeld R, Heales S, Crow YJ, Pelletier JN, Jones S, Newman WG (February 2011). "Identification and characterization of an inborn error of metabolism caused by dihydrofolate reductase deficiency". American Journal of Human Genetics. 88 (2): 216–25. doi:10.1016/j.ajhg.2011.01.004. PMID 21310276. 
  18. ^ Li R, Sirawaraporn R, Chitnumsub P, Sirawaraporn W, Wooden J, Athappilly F, Turley S, Hol WG (January 2000). "Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs". Journal of Molecular Biology. 295 (2): 307–23. doi:10.1006/jmbi.1999.3328. PMID 10623528. 
  19. ^ Benkovic SJ, Fierke CA, Naylor AM (March 1988). "Insights into enzyme function from studies on mutants of dihydrofolate reductase". Science. 239 (4844): 1105–10. doi:10.1126/science.3125607. PMID 3125607. 
  20. ^ a b c Hawser S, Lociuro S, Islam K (March 2006). "Dihydrofolate reductase inhibitors as antibacterial agents". Biochemical Pharmacology. 71 (7): 941–8. doi:10.1016/j.bcp.2005.10.052. PMID 16359642. 
  21. ^ Narayana N, Matthews DA, Howell EE, Nguyen-huu X (November 1995). "A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site". Nature Structural Biology. 2 (11): 1018–25. doi:10.1038/nsb1195-1018. PMID 7583655. 
  22. ^ Huennekens FM (June 1996). "In search of dihydrofolate reductase". Protein Science. 5 (6): 1201–8. doi:10.1002/pro.5560050626. PMC 2143423Freely accessible. PMID 8762155. 
  23. ^ Banerjee D, Mayer-Kuckuk P, Capiaux G, Budak-Alpdogan T, Gorlick R, Bertino JR (July 2002). "Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase". Biochimica et Biophysica Acta. 1587 (2-3): 164–73. doi:10.1016/S0925-4439(02)00079-0. PMID 12084458. 
  24. ^ Bailey SW, Ayling JE (September 2009). "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake". Proceedings of the National Academy of Sciences of the United States of America. 106 (36): 15424–9. doi:10.1073/pnas.0902072106. PMC 2730961Freely accessible. PMID 19706381. 
  25. ^ Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M (July 1993). "Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer". Cancer. 72 (1): 37–41. doi:10.1002/1097-0142(19930701)72:1<37::AID-CNCR2820720109>3.0.CO;2-P. PMID 8508427. 
  26. ^ Srinivasan B, Skolnick J (May 2015). "Insights into the slow-onset tight-binding inhibition of Escherichia coli dihydrofolate reductase: detailed mechanistic characterization of pyrrolo [3,2-f] quinazoline-1,3-diamine and its derivatives as novel tight-binding inhibitors". The FEBS Journal. 282 (10): 1922–38. doi:10.1111/febs.13244. PMC 4445455Freely accessible. PMID 25703118. 
  27. ^ Srinivasan B, Tonddast-Navaei S, Skolnick J (October 2015). "Ligand binding studies, preliminary structure-activity relationship and detailed mechanistic characterization of 1-phenyl-6,6-dimethyl-1,3,5-triazine-2,4-diamine derivatives as inhibitors of Escherichia coli dihydrofolate reductase". European Journal of Medicinal Chemistry. 103: 600–14. doi:10.1016/j.ejmech.2015.08.021. PMID 26414808. 
  28. ^ a b Beierlein JM, Karri NG, Anderson AC (October 2010). "Targeted mutations of Bacillus anthracis dihydrofolate reductase condense complex structure−activity relationships". Journal of Medicinal Chemistry. 53 (20): 7327–36. doi:10.1021/jm100727t. PMC 3618964Freely accessible. PMID 20882962. 
  29. ^ Mayhew M, da Silva AC, Martin J, Erdjument-Bromage H, Tempst P, Hartl FU (February 1996). "Protein folding in the central cavity of the GroEL-GroES chaperonin complex". Nature. 379 (6564): 420–6. doi:10.1038/379420a0. PMID 8559246. 
  30. ^ Maguire M, Nield PC, Devling T, Jenkins RE, Park BK, Polański R, Vlatković N, Boyd MT (May 2008). "MDM2 regulates dihydrofolate reductase activity through monoubiquitination". Cancer Research. 68 (9): 3232–42. doi:10.1158/0008-5472.CAN-07-5271. PMC 3536468Freely accessible. PMID 18451149. 

Further reading

External links

This article incorporates text from the public domain Pfam and InterPro IPR001796

This article incorporates text from the public domain Pfam and InterPro IPR009159

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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Dihydrofolate reductase Provide feedback

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External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001796

Dihydrofolate reductase (DHFR) (EC) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in de novo synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [PUBMED:2830673], and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. Although DHFR is found ubiquitously in prokaryotes and eukaryotes, and is found in all dividing cells, maintaining levels of fully reduced folate coenzymes, the catabolic steps are still not well understood [PUBMED:3383852].

Bacterial species possesses distinct DHFR enzymes (based on their pattern of binding diaminoheterocyclic molecules), but mammalian DHFRs are highly similar [PUBMED:500653]. The active site is situated in the N-terminal half of the sequence, which includes a conserved Pro-Trp dipeptide; the tryptophan has been shown [PUBMED:6815178] to be involved in the binding of substrate by the enzyme. Its central role in DNA precursor synthesis, coupled with its inhibition by antagonists such as trimethoprim and methotrexate, which are used as anti-bacterial or anti-cancer agents, has made DHFR a target of anticancer chemotherapy. However, resistance has developed against some drugs, as a result of changes in DHFR itself [PUBMED:2601715].

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan DHFred (CL0387), which has the following description:

Superfamily contains the dihydrofolate reductases and the RibD C-terminal domain-like including HTP reductase families.

The clan contains the following 2 members:

DHFR_1 RibD_C

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(60)
Full
(2747)
Representative proteomes UniProt
(13139)
NCBI
(16245)
Meta
(1190)
RP15
(705)
RP35
(1954)
RP55
(3351)
RP75
(5262)
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  Seed
(60)
Full
(2747)
Representative proteomes UniProt
(13139)
NCBI
(16245)
Meta
(1190)
RP15
(705)
RP35
(1954)
RP55
(3351)
RP75
(5262)
Alignment:
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  Seed
(60)
Full
(2747)
Representative proteomes UniProt
(13139)
NCBI
(16245)
Meta
(1190)
RP15
(705)
RP35
(1954)
RP55
(3351)
RP75
(5262)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

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Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: DiHfolate_red;
Type: Domain
Author: Finn RD, Griffiths-Jones SR
Number in seed: 60
Number in full: 2747
Average length of the domain: 158.70 aa
Average identity of full alignment: 31 %
Average coverage of the sequence by the domain: 76.44 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 25.0 25.0
Noise cut-off 24.9 24.8
Model length: 161
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

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Interactions

There are 4 interactions for this family. More...

Thymidylat_synt Thymidylat_synt V-set DHFR_1

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the DHFR_1 domain has been found. There are 600 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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