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InterPro: IPR012262 Bifunctional dihydrofolate reductase/thymidylate synthase
Protein matches
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UniProtKB Matches: 96 proteins |
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Accession
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IPR012262 DHFR-TS |
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Type
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Family |
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Signatures
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InterPro Relationships
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Contains
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IPR000398 Thymidylate synthase, C-terminal
IPR001796 Dihydrofolate reductase domain
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GO Term annotation
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Process
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GO:0006730 one-carbon metabolic process
GO:0055114 oxidation reduction
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Function
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GO:0004146 dihydrofolate reductase activity
GO:0004799 thymidylate synthase activity
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InterPro annotation
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 Entry Details in BioMart
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Abstract
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This group represents a bifunctional dihydrofolate reductase/thymidylate synthase found in some plant species and protozoal parasites including malarial species and trypanosomes. In other species dihydrofolate reductase and thymidilate synthase are encoded on separate polypeptides.
Thymidylate synthase (EC:2.1.1.45) [1] catalyzes the reductive methylation of dUMP to dTMP with concomitant conversion of 5,10-methylenetetrahydrofolate to dihydrofolate:
5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP
This provides the sole de novo pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer [2]. The enzyme is important for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process can cause various biological and genetic abnormalities. A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate). The sequence around the active site of this enzyme is conserved from phages to vertebrates.
Dihydrofolate reductase (DHFR) (EC:1.5.1.3) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate:
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+
This is an essential step in de novo synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) [3], 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 [4].
As this enzyme is essential in both nucleic acid and amino acid biosynthesis, it is an important target of antiparasitic drugs. Resistance to antimalarial drugs that target this enzyme is often due to mutations that prevent drug binding but maintain enzyme activity. The structure of the wild-type and drug resistant malarial enzymes provides insights into the development of resistance and suggests approaches for the design of new drugs against this target [5].
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Structural links
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Database links
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Publications
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1.
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Benkovic SJ.
On the mechanism of action of folate- and biopterin-requiring enzymes.
Annu. Rev. Biochem. 49 227-51 1980
[PubMed: 6996564]
http://dx.doi.org/10.1146/annurev.bi.49.070180.001303
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2.
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Hardy LW, Finer-Moore JS, Montfort WR, Jones MO, Santi DV, Stroud RM.
Atomic structure of thymidylate synthase: target for rational drug design.
Science 235 448-55 1987
[PubMed: 3099389]
http://www.sciencemag.org/cgi/content/abstract/235/4787/448
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3.
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Trimble JJ, Murthy SC, Bakker A, Grassmann R, Desrosiers RC.
A gene for dihydrofolate reductase in a herpesvirus.
Science 239 1145-7 1988
[PubMed: 2830673]
http://www.sciencemag.org/cgi/content/abstract/239/4844/1145
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4.
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Oefner C, D'Arcy A, Winkler FK.
Crystal structure of human dihydrofolate reductase complexed with folate.
Eur. J. Biochem. 174 377-85 1988
[PubMed: 3383852]
http://dx.doi.org/10.1111/j.1432-1033.1988.tb14108.x
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5.
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Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y.
Insights into antifolate resistance from malarial DHFR-TS structures.
Nat. Struct. Biol. 10 357-65 2003
[PubMed: 12704428]
http://dx.doi.org/10.1038/nsb921
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Additional Reading
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Anderson AC.
Two crystal structures of dihydrofolate reductase-thymidylate synthase from Cryptosporidium hominis reveal protein-ligand interactions including a structural basis for observed antifolate resistance.
Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 61 2005 258-62
[PubMed: 16511011]
http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=EBI&pubmedid=16511011&action=stream&blobtype=pdf
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Kongsaeree P, Khongsuk P, Leartsakulpanich U, Chitnumsub P, Tarnchompoo B, Walkinshaw MD, Yuthavong Y.
Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance.
Proc. Natl. Acad. Sci. U.S.A. 102 2005 13046-51
[PubMed: 16135570]
http://dx.doi.org/10.1073/pnas.0501747102
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O'Neil RH, Lilien RH, Donald BR, Stroud RM, Anderson AC.
Phylogenetic classification of protozoa based on the structure of the linker domain in the bifunctional enzyme, dihydrofolate reductase-thymidylate synthase.
J. Biol. Chem. 278 2003 52980-7
[PubMed: 14555647]
http://dx.doi.org/10.1074/jbc.M310328200
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Doan LT, Martucci WE, Vargo MA, Atreya CE, Anderson KS.
Nonconserved residues Ala287 and Ser290 of the Cryptosporidium hominis thymidylate synthase domain facilitate its rapid rate of catalysis.
Biochemistry 46 2007 8379-91
[PubMed: 17580969]
http://dx.doi.org/10.1021/bi700531r
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InterPro 23.1
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