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Information on EC 1.5.1.3 - dihydrofolate reductase and Organism(s) Plasmodium vivax and UniProt Accession O02604
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1.5.1.3 dihydrofolate reductaseIUBMB Comments
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
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Word Map
- 1.5.1.3
- methotrexate
- antifolate
- plasmodium
- falciparum
- hamster
- malaria
- pyrimethamine
- ovary
-
antimalarial
- leukemia
- dihydropteroate
- thymidine
- pyrimidine
- carinii
- polyglutamates
- pneumocystis
-
hydride
- chloroquine
-
casey
-
drug-resistant
- tmp
-
ccrf-cem
- vivax
- glycinamide
- toxoplasma
-
uncomplicated
-
folate-dependent
- mthfr
- folylpolyglutamate
- pemetrexed
-
sublines
- leucovorin
- tetrahydrobiopterin
-
polyglutamylation
- gondii
-
nontranscribed
- sulfamethoxazole
- trimethoprim-sulfamethoxazole
- quinazoline
- 5-methyltetrahydrofolate
- sepiapterin
- integrons
- dihydropteridine
- analysis
- medicine
- artesunate
- synthesis
-
triazine
-
folinic
- 5,10-methylenetetrahydrofolate
- bh4
- biotechnology
- biopterins
- drug development
- pterins
The taxonomic range for the selected organisms is: Plasmodium vivax
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
dhfr, dihydrofolate reductase, thy-1, dhfr-ts, hdhfr, dihydrofolate reductase-thymidylate synthase, ecdhfr, pcdhfr, r67 dhfr, ts-dhfr, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
7,8-dihydrofolate reductase
-
-
-
-
dehydrogenase, tetrahydrofolate
-
-
-
-
DHFR
-
-
-
-
DHFR type IIIC
-
-
-
-
dihydrofolate reductase-thymidylate synthase
-
-
-
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dihydrofolate reductase:thymidylate synthase
-
-
-
-
dihydrofolic acid reductase
-
-
-
-
dihydrofolic reductase
-
-
-
-
folic acid reductase
-
-
-
-
folic reductase
-
-
-
-
NADPH-dihydrofolate reductase
-
-
-
-
pteridine reductase:dihydrofolate reductase
-
-
-
-
reductase, dihydrofolate
-
-
-
-
tetrahydrofolate dehydrogenase
-
-
-
-
thymidylate synthetase-dihydrofolate reductase
-
-
-
-
Trimethoprim resistance protein
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
-
-, -, -, -
SYSTEMATIC NAME
IUBMB Comments
5,6,7,8-tetrahydrofolate:NADP+ oxidoreductase
The enzyme from animals and some micro-organisms also slowly reduces folate to 5,6,7,8-tetrahydrofolate.
CAS REGISTRY NUMBER
COMMENTARY
9002-03-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
DHFR activity is not essential for virus replication
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
7,8-dihydrofolate + NADPH
5,6,7,8-tetrahydrofolate + NADP+
-
DHFR activity is not essential for virus replication
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
6-ethyl-5-phenylpyrimidine-2,4-diamine
analogue of pyrimethamine lacking the 4-Cl group, effectively inhibits both wild-type and pyrimethamine-resistant mutant S58R/S117N
triclosan
-
specifically targets both wild-type and pyrimethamine-resistant Plasmodium vivax dihydrofolate reductases and selectively inhibits both the wild-type and pyrimethamine-resistant enzymes compared to human DHFR
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DRTS_PLAVI
623
0
71057
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
wild-type and pyrimethamine-resistant mutant S58R/S117N in complex with NADPH and inhibitors pyrimethamine or 6-ethyl-5-phenylpyrimidine-2,4-diamine
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
S58R/S117N
-
double mutant with naturally occurring point mutations, antifolate drug resistant
additional information
additional information
-
analysis of polymorphisms among 129 isolates from different geographical areas in India. A gradual increase in the frequency of mutant genotypes is observed from north to south, while isolates from the Car-Nicobar islands show only mutant genotypes
additional information
expression of mutant AMRU1, i.e. 57L/58R/61M/1117T, in Plasmodium falciparum provides significant protection against pyrimethamine, cycloguanil, and clociguanil. It confers greater resistance to cycloguanil, clociguanil, and WR99210 than the homologous Plasmodium falciparum mutant
additional information
-
expression of mutant AMRU1, i.e. 57L/58R/61M/1117T, in Plasmodium falciparum provides significant protection against pyrimethamine, cycloguanil, and clociguanil. It confers greater resistance to cycloguanil, clociguanil, and WR99210 than the homologous Plasmodium falciparum mutant
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
RENATURED/Commentary
ORGANISM
UNIPROT
LITERATURE
wild-type and mutant, renaturation from inclusion bodies due to expression in E. coli, 200 mM KCl, 20 mM potassium phosphate, pH 7.0, 0.1 mM EDTA, 10 mM dithiothreitol
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
expression of bifunctional dihydrofolate reductase-thymidylate synthase in plasmodium falciparum to assess interaction with antifolates
medicine
medicine
-
enzyme is a target of several anti-folate inhibitory drugs to combat bacteria, protozoa and cancer
medicine
-
analysis of polymorphisms among 129 isolates from different geographical areas in India. A gradual increase in the frequency of mutant genotypes is observed from north to south, while isolates from the Car-Nicobar islands show only mutant genotypes
medicine
-
identification of synonymous and non-synonymous single nucleotide polymorphisms in the Plasmodium vivax dihydrolfolate reductase gene isolated from patients from Colombia, India, Indonesia, Papua New Guinea, Sri Lanka, thailand, and Vanuatu. The double mutant 58R/117N allele has evolved from several origins, because the 58R is encoded by at least 3 different codons. The triple 58R/61M/117T and quadruple 57L/61M/117T/173F, 57I/58R/61M/117T and 57L/58R/61M/117T mutant alleles had at least three independent origins in Thailand, Indonesia, and Papua New Guinea/Vanuatu
medicine
-
in 451 blood samples from Plasmodium vivax cases in Sri Lanka, 68.9% showed dihydrofolate reductase wild-type haplotype. The double mutant F57L/S58R haplotype was the most frequently observed mutant with 24.4%, while the triple mutant F57L/S58R/S117N was only identified once. A significantly higher frequency of mutant haplotypes is observed in the Northern districts
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Tahar, R.; de Pecoulas, P.E.; Basco, L.K.; Chiadmi, M.; Mazabraud, A.
Kinetic properties of dihydrofolate reductase from wild-type and mutant Plasmodium vivax expressed in Escherichia coli
Mol. Biochem. Parasitol.
113
241-249
2001
Plasmodium vivax
Kongsaeree, P.; Khongsuk, P.; Leartsakulpanich, U.; Chitnumsub, P.; Tarnchompoo, B.; Walkinshaw, M.D.; Yuthavong, Y.
Crystal structure of dihydrofolate reductase from Plasmodium vivax: pyrimethamine displacement linked with mutation-induced resistance
Proc. Natl. Acad. Sci. USA
102
13046-13051
2005
Plasmodium vivax (O02604), Plasmodium vivax
Prajapati, S.K.; Joshi, H.; Valecha, N.; Reetha, A.M.; Eapen, A.; Kumar, A.; Das, M.K.; Yadav, R.S.; Rizvi, M.A.; Dash, A.P.
Allelic polymorphism in the Plasmodium vivax dihydrofolate reductase gene among Indian field isolates
Clin. Microbiol. Infect.
13
331-334
2007
Plasmodium vivax
ONeil, M.T.; Korsinczky, M.L.; Gresty, K.J.; Auliff, A.; Cheng, Q.
A novel Plasmodium falciparum expression system for assessing antifolate resistance caused by mutant P. vivax dihydrofolate reductase-thymidylate synthase
J. Infect. Dis.
196
467-474
2007
Plasmodium vivax (Q00NX3), Plasmodium vivax
Schousboe, M.L.; Rajakaruna, R.S.; Salanti, A.; Hapuarachchi, H.C.; Galappaththy, G.N.; Bygbjerg, I.C.; Amerasinghe, P.H.; Konradsen, F.; Alifrangis, M.
Island-wide diversity in single nucleotide polymorphisms of the Plasmodium vivax dihydrofolate reductase and dihydropteroate synthetase genes in Sri Lanka
Malar. J.
6
28
2007
Plasmodium vivax
Hawkins, V.N.; Auliff, A.; Prajapati, S.K.; Rungsihirunrat, K.; Hapuarachchi, H.C.; Maestre, A.; ONeil, M.T.; Cheng, Q.; Joshi, H.; Na-Bangchang, K.; Sibley, C.H.
Multiple origins of resistance-conferring mutations in Plasmodium vivax dihydrofolate reductase
Malar. J.
7
72
2008
Plasmodium vivax
Carrasco, M.P.; Fotoran, W.L.; Cubillos, E.F.G.; Wunderlich, G.; Grotli, M.; Hollfelder, F.; Jackson, V.; King, R.D.; Oliver, S.G.
Plasmodium dihydrofolate reductase is a second enzyme target for the antimalarial action of triclosan
Sci. Rep.
8
1038
2018
Plasmodium falciparum, Plasmodium vivax
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