Application | Comment | Organism |
---|---|---|
medicine | PfDHODH is a promising target for chemotherapeutic intervention in prevention of malaria | Plasmodium falciparum |
medicine | promising new target for chemotherapeutic intervention in prevention of malaria, synthesized inhibitors prevent growth of cultured parasites at low micromolar concentrations, interaction of inhibitors with amino acid residues F188, H185, and R265 | Plasmodium falciparum |
medicine | promising new target for chemotherapeutic intervention in prevention of malaria, synthesized inhibitors show considerable lower affinity for the human DHODH enzyme relative to the Plasmodium DHODH enzyme | Homo sapiens |
Cloned (Comment) | Organism |
---|---|
expression in Escherichia coli pyrD using a construct with His-tag fusion | Homo sapiens |
expression in Escherichia coli pyrD using a construct with His-tag fusion | Plasmodium falciparum |
Protein Variants | Comment | Organism |
---|---|---|
F188A | considerable changes in the binding affinities of the inhibitors without dramatically affecting the substrate binding affinities | Plasmodium falciparum |
F188A | kcat for reaction of L-dihydroorotate + decylubiquinone is 78% of the wild-type value. IC50-value for 2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester 513fold higher than wild-type value | Plasmodium falciparum |
H185A | considerable changes in the binding affinities of the inhibitors without dramatically affecting the substrate binding affinities | Plasmodium falciparum |
H185A | kcat for reaction of L-dihydroorotate + decylubiquinone is 8.9% of the wild-type value. IC50-value for 2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester 775fold higher than wild-type value | Plasmodium falciparum |
R265K | considerable changes in the binding affinities of the inhibitors without dramatically affecting the substrate binding affinities | Plasmodium falciparum |
R265K | kcat for reaction of L-dihydroorotate + decylubiquinone is 102% of the wild-type value. IC50-value for 2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester 33.8fold higher than wild-type value | Plasmodium falciparum |
Inhibitors | Comment | Organism | Structure |
---|---|---|---|
2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester | IC50: 0.491 mM | Homo sapiens | |
2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester | IC50: 0.00044 mM | Plasmodium falciparum | |
diethyl [(1H-benzimidazol-5-ylamino)methylidene]propanedioate | - |
Plasmodium falciparum | |
diethyl [(1H-indazol-5-ylamino)methylidene]propanedioate | - |
Plasmodium falciparum | |
diethyl [(5a,9a-dihydrodibenzo[b,d]thiophen-2-ylamino)methylidene]propanedioate | - |
Plasmodium falciparum | |
diethyl [(biphenyl-3-ylamino)methylidene]propanedioate | - |
Plasmodium falciparum | |
diethyl [(biphenyl-4-ylamino)methylidene]propanedioate | - |
Plasmodium falciparum | |
diethyl {[(2-methylphenyl)amino]methylidene}propanedioate | - |
Plasmodium falciparum | |
diethyl {[(4-methylphenyl)amino]methylidene}propanedioate | - |
Plasmodium falciparum | |
ethyl (2Z)-3-(biphenyl-3-ylamino)-2-cyanoprop-2-enoate | - |
Plasmodium falciparum | |
ethyl (2Z)-3-(biphenyl-4-ylamino)-2-cyanoprop-2-enoate | - |
Plasmodium falciparum | |
additional information | DHODH-specific inhibitors with low nanomolar binding affinities bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate | Homo sapiens | |
additional information | DHODH-specific inhibitors with low nanomolar binding affinities bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate | Plasmodium falciparum |
KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|
0.013 | - |
decylubiquinone | wild-type enzyme | Plasmodium falciparum | |
0.013 | - |
dihydroorotate | wild-type | Plasmodium falciparum | |
0.013 | - |
decylubiquinone | mutant enzyme R265A | Plasmodium falciparum | |
0.013 | - |
dihydroorotate | mutant R265K | Plasmodium falciparum | |
0.017 | - |
decylubiquinone | mutant enzyme F188A | Plasmodium falciparum | |
0.017 | - |
dihydroorotate | mutant F188A | Plasmodium falciparum | |
0.019 | - |
decylubiquinone | mutant enzyme H185A | Plasmodium falciparum | |
0.019 | - |
dihydroorotate | mutant H185A | Plasmodium falciparum | |
0.031 | - |
L-dihydroorotate | wild-type enzyme | Plasmodium falciparum | |
0.033 | - |
L-dihydroorotate | mutant enzyme H185A | Plasmodium falciparum | |
0.033 | - |
L-dihydroorotate | mutant enzyme R265K | Plasmodium falciparum | |
0.035 | - |
L-dihydroorotate | mutant enzyme F188A | Plasmodium falciparum |
Organism | UniProt | Comment | Textmining |
---|---|---|---|
Homo sapiens | - |
- |
- |
Plasmodium falciparum | Q08210 | - |
- |
Purification (Comment) | Organism |
---|---|
by nickel agarose chromatography | Homo sapiens |
by nickel agarose chromatography | Plasmodium falciparum |
Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
---|---|---|---|---|---|---|
dihydroorotate + acceptor | - |
Homo sapiens | orotate + reduced acceptor | - |
? | |
dihydroorotate + acceptor | - |
Plasmodium falciparum | orotate + reduced acceptor | - |
? | |
L-dihydroorotate + decylubiquinone | - |
Homo sapiens | orotate + reduced decylubiquinone | - |
? | |
L-dihydroorotate + decylubiquinone | - |
Plasmodium falciparum | orotate + reduced decylubiquinone | - |
? |
Synonyms | Comment | Organism |
---|---|---|
DHODH | - |
Homo sapiens |
DHODH | - |
Plasmodium falciparum |
HsDHODH | - |
Homo sapiens |
PfDHODH | - |
Plasmodium falciparum |
Turnover Number Minimum [1/s] | Turnover Number Maximum [1/s] | Substrate | Comment | Organism | Structure |
---|---|---|---|---|---|
1.4 | - |
L-dihydroorotate | mutant enzyme H185A | Plasmodium falciparum | |
1.4 | - |
dihydroorotate | mutant H185A | Plasmodium falciparum | |
12.3 | - |
L-dihydroorotate | mutant enzyme F188A | Plasmodium falciparum | |
12.3 | - |
dihydroorotate | mutant F188A | Plasmodium falciparum | |
15.8 | - |
L-dihydroorotate | wild-type enzyme | Plasmodium falciparum | |
15.8 | - |
dihydroorotate | wild-type | Plasmodium falciparum | |
16.1 | - |
L-dihydroorotate | mutant enzyme R265K | Plasmodium falciparum | |
16.1 | - |
dihydroorotate | mutant R265K | Plasmodium falciparum |
Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
---|---|---|---|---|---|
0.00005 | - |
2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester | - |
Plasmodium falciparum | |
0.0604 | - |
2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester | - |
Homo sapiens |
IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
---|---|---|---|---|---|
0.00044 | - |
IC50: 0.00044 mM | Plasmodium falciparum | 2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester | |
0.491 | - |
IC50: 0.491 mM | Homo sapiens | 2-cyano-3-(9-ethyl-9H-carbazol-3-ylamino)acrylic acid ethyl ester |