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Literature summary 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

EC Number Application Comment Organism
1.5.1.3 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

EC Number Protein Variants Comment Organism
1.5.1.3 A16V point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
1.5.1.3 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
1.5.1.3 C59R point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
1.5.1.3 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
1.5.1.3 N51I point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
1.5.1.3 S108N point mutation of the active site residue leads to a widespread resistance of the parasite to the drugs cycloguanil and pyrimethamine Plasmodium falciparum
1.5.1.3 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

EC Number Inhibitors Comment Organism Structure
1.5.1.3 (1E)-1-[4-[(3,5-dichloropyridin-4-yl)oxy]phenyl]ethanone thiosemicarbazone
-
Plasmodium falciparum
1.5.1.3 1-(4-chlorophenyl)-6,6-dimethyl-1,6-dihydro-1,3,5-triazine-2,4-diamine
-
Plasmodium falciparum
1.5.1.3 1-[3-(3,4-dichlorophenoxy)propyloxy]-5-isopropylbiguanide i.e. PS-16 Plasmodium falciparum
1.5.1.3 1-[3-(4-chlorophenoxy)propyloxy]-5-isopropylbiguanide i.e. PS-33 Plasmodium falciparum
1.5.1.3 2,3-bis(hydrazino)quinoxaline
-
Plasmodium falciparum
1.5.1.3 2-[[(4-[[(2-amino-4-oxo-3,4-dihydropyrido[3,2-d]pyrimidin-6-yl)methyl]amino]phenyl)carbonyl]amino]hexanedioic acid
-
Plasmodium falciparum
1.5.1.3 2-[[1-(3-chlorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl]carbonyl]-N-prop-2-en-1-ylhydrazinecarbothioamide
-
Plasmodium falciparum
1.5.1.3 3-[[(4-chlorophenyl)sulfonyl]methyl]-N'-hydroxybenzenecarboximidamide
-
Plasmodium falciparum
1.5.1.3 4-(benzyloxy)benzaldehyde thiosemicarbazone
-
Plasmodium falciparum
1.5.1.3 4-chloro-N-[4-(hydroxycarbamimidoyl)benzyl]benzamide
-
Plasmodium falciparum
1.5.1.3 4-[(3,5-dichloropyridin-4-yl)oxy]-N'-hydroxybenzenecarboximidamide
-
Plasmodium falciparum
1.5.1.3 4-[[3-chloro-5-(trifluoromethyl)pyridin-2-yl]oxy]benzaldehyde thiosemicarbazone
-
Plasmodium falciparum
1.5.1.3 6-[[(2,5-dimethylphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine identified from docking studies Plasmodium falciparum
1.5.1.3 6-[[(3,4-dimethoxyphenyl)amino]methyl]-5-methylpyrido[2,3-d]pyrimidine-2,4-diamine
-
Plasmodium falciparum
1.5.1.3 benzaldehyde semicarbazone
-
Plasmodium falciparum
1.5.1.3 chlorocycloguanil
-
Plasmodium falciparum
1.5.1.3 cycloguanil and prodrug proguanil Plasmodium falciparum
1.5.1.3 methotrexate
-
Plasmodium falciparum
1.5.1.3 methyl 5-[(1E)-N-carbamoylethanehydrazonoyl]-2,3'-bithiophene-5'-carboxylate
-
Plasmodium falciparum
1.5.1.3 pyrimethamine
-
Plasmodium falciparum
1.5.1.3 trimepthoprim
-
Plasmodium falciparum
1.5.1.3 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)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+ Plasmodium falciparum
-
5,6,7,8-tetrahydrofolate + NADP+
-
r

Organism

EC Number Organism UniProt Comment Textmining
1.5.1.3 Plasmodium falciparum
-
-
-

Reaction

EC Number Reaction Comment Organism Reaction ID
1.5.1.3 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)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.5.1.3 7,8-dihydrofolate + NADPH + H+
-
Plasmodium falciparum 5,6,7,8-tetrahydrofolate + NADP+
-
r

Synonyms

EC Number Synonyms Comment Organism
1.5.1.3 DHFR
-
Plasmodium falciparum

Cofactor

EC Number Cofactor Comment Organism Structure
1.5.1.3 NADP+
-
Plasmodium falciparum
1.5.1.3 NADPH
-
Plasmodium falciparum