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10  structures 10  species 0  interactions 10  sequences 1  architecture

Family: DHFR_2 (PF06442)

Summary: R67 dihydrofolate reductase

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

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R67 dihydrofolate reductase Provide feedback

R67 dihydrofolate reductase is a plasmid encoded enzyme that provides resistance to the antibacterial drug trimethoprim. The R67 dihydrofolate reductase does not share significant similarity to the chromosomal encoded dihydrofolate reductase [1].

Literature references

  1. Narayana N, Matthews DA, Howell EE, Nguyen-huu X; , Nat Struct Biol 1995;2:1018-1025.: A plasmid-encoded dihydrofolate reductase from trimethoprim-resistant bacteria has a novel D2-symmetric active site. PUBMED:7583655 EPMC:7583655

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR009159

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 ].

This entry represents a plasmid-encoded DHFR which shows a high level of resistance to the antibiotic trimethoprim. It is a homotetramer with an unusual pore, which contains the active site, passing through the middle of the molecule [ PUBMED:7583655 ]. Its structure is unrelated to that of chromosomal DHFRs.

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan ETAP (CL0610), which has the following description:

According to SCOP the domains in this superfamily have an SH3 like barrel fold.

The clan contains the following 4 members:

DHFR_2 FeThRed_A NHase_beta PSI_PsaE


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 and the UniProtKB sequence database. More...

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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

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Seed source: Pfam-B_27527 (release 9.0)
Previous IDs: DHFR;
Type: Domain
Sequence Ontology: SO:0000417
Author: Finn RD
Number in seed: 3
Number in full: 10
Average length of the domain: 68.40 aa
Average identity of full alignment: 47 %
Average coverage of the sequence by the domain: 62.01 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.0 25.0
Trusted cut-off 27.2 38.7
Noise cut-off 24.3 20.1
Model length: 78
Family (HMM) version: 13
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Species distribution

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Colour assignments

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


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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_2 domain has been found. There are 10 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 sequence.

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