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Literature summary for 1.3.5.2 extracted from

  • Booker, M.L.; Bastos, C.M.; Kramer, M.L.; Barker, R.H.; Skerlj, R.; Sidhu, A.B.; Deng, X.; Celatka, C.; Cortese, J.F.; Guerrero Bravo, J.E.; Crespo Llado, K.N.; Serrano, A.E.; Angulo-Barturen, I.; Jimenez-Diaz, M.B.; Viera, S.; Garuti, H.; Wittlin, S.; Papastogiannidis, P.; Lin, J.W.; Janse, C.J.; Khan, S.M.
    Novel inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase with anti-malarial activity in the mouse model (2010), J. Biol. Chem., 285, 33054-33064.
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
drug development DHODH represents a potential target for anti-malarial therapy Plasmodium berghei
drug development DHODH represents a potential target for anti-malarial therapy Plasmodium vivax
drug development DHODH represents a potential target for anti-malarial therapy Plasmodium falciparum
medicine DHODH represents a potential target for anti-malarial therapy Plasmodium berghei
medicine DHODH represents a potential target for anti-malarial therapy Plasmodium vivax
medicine DHODH represents a potential target for anti-malarial therapy Plasmodium falciparum

Cloned(Commentary)

Cloned (Comment) Organism
expression of the expression construct pET28b-TEVpfDHODDELTA384–413 in Escherichia coli strain BL21 Plasmodium falciparum

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant His-tagged mutant DHODDELTA384-413 free or in complex with Genz-667348, hanging drop vapour diffusion method, 20°C, mixing reservoir solution A containing 0.16 M ammonium sulfate, 0.1 M sodium acetate, pH 4.4, 14-15% PEG 4000, 25% glycerol, and 10 mM DTT, with an equal volume of 20 mg/ml protein pre-equilibrated with 0.6 mM Genz-667348, and 2 mM dihydroorotate, X-ray diffraction structure determination and analysis at 2.4 A resolution, molecular replacement Plasmodium falciparum

Protein Variants

Protein Variants Comment Organism
additional information deletion of a surface loop in PfDHODH containing amino acid residues 384-413, which facilitates crystallization of the enzyme with the triazolopyrimidine class of inhibitors. An N-terminal deletion that removes the mitochondrial membrane-spanning domain as well as residues that are N-terminal to this region does not lead to better crystal yields. Replacement of the thrombin site and T7 tag sequence in the vector with the TEV protease site Plasmodium falciparum

Inhibitors

Inhibitors Comment Organism Structure
Genz-667348
-
Plasmodium berghei
Genz-667348
-
Plasmodium falciparum
Genz-667348
-
Plasmodium vivax
Genz-668857
-
Plasmodium berghei
Genz-668857
-
Plasmodium falciparum
Genz-668857
-
Plasmodium vivax
Genz-669178
-
Plasmodium berghei
Genz-669178
-
Plasmodium falciparum
Genz-669178
-
Plasmodium vivax
additional information drug screening and identification of a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH, selective for the parasite enzymes over human DHODH, tolerability in the mouse, overview Plasmodium berghei
additional information drug screening and identifictaion of a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolarin vitro potency against DHODH, selective for the parasite enzymes over human DHODH, tolerability in the mouse, overview Plasmodium falciparum
additional information drug screening and identification of a series of N-alkyl-5-(1H-benzimidazol-1-yl)thiophene-2-carboxamides with low nanomolar in vitro potency against DHODH, selective for the parasite enzymes over human DHODH, tolerability in the mouse, overview Plasmodium vivax

Localization

Localization Comment Organism GeneOntology No. Textmining
mitochondrial membrane
-
Plasmodium berghei 31966
-
mitochondrial membrane
-
Plasmodium vivax 31966
-
mitochondrial membrane
-
Plasmodium falciparum 31966
-

Organism

Organism UniProt Comment Textmining
Plasmodium berghei
-
-
-
Plasmodium falciparum Q08210
-
-
Plasmodium vivax
-
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant His-tagged mutant DHODDELTA384-413 from Escherichia coli by affinity chromatography and gel filtration Plasmodium falciparum

Subunits

Subunits Comment Organism
More Plasmodium enzyme structure comparisons, molecular modeling, overview Plasmodium berghei
More Plasmodium enzyme structure comparisons, molecular modeling, overview Plasmodium vivax
More Plasmodium enzyme structure comparisons, molecular modeling, overview Plasmodium falciparum

Synonyms

Synonyms Comment Organism
DHODH
-
Plasmodium berghei
DHODH
-
Plasmodium vivax
DHODH
-
Plasmodium falciparum

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
8
-
assay at Plasmodium berghei
8
-
assay at Plasmodium vivax
8
-
assay at Plasmodium falciparum

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000012
-
pH 8.0, temperature not specified in the publication Plasmodium berghei Genz-668857
0.000014
-
pH 8.0, temperature not specified in the publication Plasmodium berghei Genz-667348
0.000015
-
pH 8.0, temperature not specified in the publication Plasmodium vivax Genz-668857
0.000015
-
pH 8.0, temperature not specified in the publication Plasmodium vivax Genz-669178
0.000022
-
pH 8.0, temperature not specified in the publication Plasmodium falciparum Genz-667348
0.00004
-
pH 8.0, temperature not specified in the publication Plasmodium berghei Genz-669178
0.000042
-
pH 8.0, temperature not specified in the publication Plasmodium vivax Genz-667348
0.000044
-
pH 8.0, temperature not specified in the publication Plasmodium falciparum Genz-668857
0.00005
-
pH 8.0, temperature not specified in the publication Plasmodium falciparum Genz-669178

General Information

General Information Comment Organism
physiological function DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway Plasmodium berghei
physiological function DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway Plasmodium vivax
physiological function DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway Plasmodium falciparum