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Literature summary for 1.5.1.3 extracted from

  • Adane, L.; Bharatam, P.V.
    Modelling and informatics in the analysis of P. falciparum DHFR enzyme inhibitors (2008), Curr. Med. Chem., 15, 1552-1569.
    View publication on PubMed

Application

Application Comment Organism
drug development the enzyme is a target for antifolate drugs. The parasite develops resistance to several used antifolates via mutations in the active site, e.g. point mutations of residues Ala16, Ile51, Cys59, Ser108 and Ile164, overview Plasmodium falciparum

Protein Variants

Protein Variants Comment Organism
A16V point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
A16V/N51I/C59R/S108N point mutations of the active site residues lead to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine, binding structure modelling, overview Plasmodium falciparum
C59R point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
C59R/S108N point mutations of the active site residues lead to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine, binding structure modelling, overview Plasmodium falciparum
N51I point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
S108N point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
S108T point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum

Inhibitors

Inhibitors Comment Organism Structure
(1E)-1-[4-[(3,5-dichloropyridin-4-yl)oxy]phenyl]ethanone thiosemicarbazone
-
Plasmodium falciparum
1-(4-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
Plasmodium falciparum
1-[3-(3,4-dichlorophenoxy)propyloxy]-5-isopropylbiguanide i.e. PS-16 Plasmodium falciparum
1-[3-(4-chlorophenoxy)propyloxy]-5-isopropylbiguanide i.e. PS-33 Plasmodium falciparum
2,3-bis(hydrazino)quinoxaline
-
Plasmodium falciparum
2-[[(4-[[(2-amino-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]phenyl)carbonyl]amino]hexanedioic acid
-
Plasmodium falciparum
2-[[1-(3-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl]-N-prop-2-en-1-ylhydrazinecarbothioamide
-
Plasmodium falciparum
3-[[(4-chlorophenyl)sulfonyl]methyl]-N'-hydroxybenzenecarboximidamide
-
Plasmodium falciparum
4-(benzyloxy)benzaldehyde thiosemicarbazone
-
Plasmodium falciparum
4-chloro-N-[4-(hydroxycarbamimidoyl)benzyl]benzamide
-
Plasmodium falciparum
4-[(3,5-dichloropyridin-4-yl)oxy]-N'-hydroxybenzenecarboximidamide
-
Plasmodium falciparum
4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy]benzaldehyde thiosemicarbazone
-
Plasmodium falciparum
6-[[(2,5-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine identified from docking studies Plasmodium falciparum
6-[[(3,4-dimethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
Plasmodium falciparum
benzaldehyde semicarbazone
-
Plasmodium falciparum
chlorocycloguanil
-
Plasmodium falciparum
cycloguanil and prodrug proguanil Plasmodium falciparum
methotrexate
-
Plasmodium falciparum
methyl 5-[(1E)-N-carbamoylethanehydrazonoyl]-2,3'-bithiophene-5'-carboxylate
-
Plasmodium falciparum
pyrimethamine
-
Plasmodium falciparum
trimepthoprim
-
Plasmodium falciparum
WR99210 and PS-15 W99210 prodrug. Active site binding structure of wild-type enzyme, and mutants C59R/S108N and A16V/N51I/C59R/S108N, overview Plasmodium falciparum

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
7,8-dihydrofolate + NADPH + H+ Plasmodium falciparum
-
5,6,7,8-tetrahydrofolate + NADP+
-
r

Organism

Organism UniProt Comment Textmining
Plasmodium falciparum
-
-
-

Reaction

Reaction Comment Organism Reaction ID
5,6,7,8-tetrahydrofolate + NADP+ = 7,8-dihydrofolate + NADPH + H+ Ala16, Ile51, Cys59, Ser108 and Ile164 are active site residues, catalytic mechanism, overview Plasmodium falciparum

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
7,8-dihydrofolate + NADPH + H+
-
Plasmodium falciparum 5,6,7,8-tetrahydrofolate + NADP+
-
r

Synonyms

Synonyms Comment Organism
DHFR
-
Plasmodium falciparum

Cofactor

Cofactor Comment Organism Structure
NADP+
-
Plasmodium falciparum
NADPH
-
Plasmodium falciparum