Literature summary for 1.3.5.2 extracted from

Heikkil�, T.; Ramsey, C.; Davies, M.; Galtier, C.; Stead, A.M.W.; Johnson, A.P.; Fishwick, C.W.G.; Boa, A.N.; McConkey, G.A.
Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase (2007), J. Med. Chem., 50, 186-191.

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Application

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(Commentary)

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

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

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 [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

Organism	UniProt	Comment	Textmining
Homo sapiens	-	-	-
Plasmodium falciparum	Q08210	-	-

Purification (Commentary)

Purification (Comment)	Organism
by nickel agarose chromatography	Homo sapiens
by nickel agarose chromatography	Plasmodium falciparum

Substrates and Products (Substrate)

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

Synonyms	Comment	Organism
DHODH	-	Homo sapiens
DHODH	-	Plasmodium falciparum
HsDHODH	-	Homo sapiens
PfDHODH	-	Plasmodium falciparum

Turnover Number [1/s]

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 [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	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

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Release 2023.1 (January 2023)