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Literature summary extracted from

  • Sarma, G.N.; Savvides, S.N.; Becker, K.; Schirmer, M.; Schirmer, R.H.; Karplus, P.A.
    Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development (2003), J. Mol. Biol., 328, 893-907.
    View publication on PubMed

Application

EC Number Application Comment Organism
1.8.1.7 pharmacology enzyme is a target for enzyme inhibitor and antimalarial drug development Plasmodium falciparum

Cloned(Commentary)

EC Number Cloned (Comment) Organism
1.8.1.7
-
 Homo sapiens
1.8.1.7 expression of strain K1 wild-type and mutant enzymes in Escherichia coli Plasmodium falciparum

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
1.8.1.7 purified recombinant strain K1 wild-type enzyme, enzyme is dialyzed against EDTA for 3 h, hanging drop vapour diffusion method, protein solution contains 10 mg/ml protein, mixed with an equal volume of reservoir solution containing 14% w/v PEG monomethylether 550, 70 mM NaCl, 70 mM bicine, pH 8.7-9.0, 20°C, one week, X-ray diffraction structure determination and analysis at 3.0 A resolution, molecular replacement Plasmodium falciparum

Protein Variants

EC Number Protein Variants Comment Organism
1.8.1.7 additional information construction of a deletion mutant lacking residues 317-349 forms a dimeric FAD-free apoenzyme Plasmodium falciparum

Inhibitors

EC Number Inhibitors Comment Organism Structure
1.8.1.7 1-methyl-4-(2-methyl-1,3-dioxo-2,3,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-5(1H)-yl)pyridinium poor inhibitor Homo sapiens
1.8.1.7 2-methyl-5-(1-naphthyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 2-methyl-5-(1-naphthyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 2-methyl-5-pyridin-4-yl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 2-methyl-5-pyridin-4-yl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 5-(1-anthryl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 5-(1-anthryl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione poor inhibitor Plasmodium falciparum
1.8.1.7 5-(4-chlorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 5-(4-chlorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 5-(4-chlorophenyl)-8-fluoro-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 5-(4-chlorophenyl)-8-fluoro-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 5-(pentafluorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 5-(pentafluorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 8-azido-5-(4-chlorophenyl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Homo sapiens
1.8.1.7 8-azido-5-(4-chlorophenyl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione
-
 Plasmodium falciparum
1.8.1.7 ethyl [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate
-
 Homo sapiens
1.8.1.7 ethyl [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate
-
 Plasmodium falciparum
1.8.1.7 ethyl [5-(3-chlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate
-
 Homo sapiens
1.8.1.7 additional information ethyl [5-(3-chlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate and 1-methyl-4-(2-methyl-1,3-dioxo-2,3,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-5(1H)-yl)pyridinium are no inhibitors for the parasite enzyme, numerous noncompetitive inhibitors bind to the large helices-containing cavity at the dimer interface which therefore is a target for selective drugs Plasmodium falciparum
1.8.1.7 [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetic acid binds to the large helices-containing cavity at the dimer interface Homo sapiens
1.8.1.7 [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetic acid
-
 Plasmodium falciparum

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
1.8.1.7 0.045
-
 glutathione disulfide chloroquine-sensitive strain D10, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.065
-
 glutathione disulfide chloroquine-resistant strain FCR3, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.071
-
 glutathione disulfide chloroquine-sensitive strain 3D7, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.073
-
 glutathione disulfide chloroquine-sensitive strain S106, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.074
-
 glutathione disulfide chloroquine-resistant strain Dd2, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.076
-
 glutathione disulfide chloroquine-sensitive strain HB3, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.08
-
 glutathione disulfide chloroquine-resistant strain 7G8, pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.088
-
 glutathione disulfide chloroquine-resistant strain K1, pH 6.9, 25°C Plasmodium falciparum

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
1.8.1.7 glutathione disulfide + NADPH Plasmodium falciparum
-
 glutathione + NADP+
-
 r
1.8.1.7 glutathione disulfide + NADPH Homo sapiens
-
 glutathione + NADP+
-
 r
1.8.1.7 additional information Plasmodium falciparum the antioxidant enzyme is important in the parasite sensitive to oxidative stress ?
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
1.8.1.7 Homo sapiens P00390
-
-
1.8.1.7 Plasmodium falciparum
-
 chloroquine-resistant and chloroquine-sensitive strains, overview, intraerythrocytic parasite
-

Reaction

EC Number Reaction Comment Organism Reaction ID
1.8.1.7 2 glutathione + NADP+ = glutathione disulfide + NADPH + H+ active site structure Homo sapiens
a
1.8.1.7 2 glutathione + NADP+ = glutathione disulfide + NADPH + H+ active site structure, Cys39/Cys44 are involved Plasmodium falciparum
a

Source Tissue

EC Number Source Tissue Comment Organism Textmining
1.8.1.7 erythrocyte
-
 Homo sapiens
-
1.8.1.7 trophozoite
-
 Plasmodium falciparum
-

Specific Activity [micromol/min/mg]

EC Number Specific Activity Minimum [µmol/min/mg] Specific Activity Maximum [µmol/min/mg] Comment Organism
1.8.1.7 0.009
-
 chloroquine-sensitive strain D10, crude extract Plasmodium falciparum
1.8.1.7 0.013
-
 chloroquine-resistant strains 7G8 and FCR3, crude extract Plasmodium falciparum
1.8.1.7 0.022
-
 chloroquine-resistant strain Dd2, crude extract Plasmodium falciparum
1.8.1.7 0.023
-
 chloroquine-sensitive strain S106, crude extract Plasmodium falciparum
1.8.1.7 0.033
-
 chloroquine-sensitive strain 3D7, crude extract Plasmodium falciparum
1.8.1.7 0.035
-
 chloroquine-sensitive strain HB3, crude extract Plasmodium falciparum
1.8.1.7 0.047
-
 chloroquine-resistant strain K1, crude extract Plasmodium falciparum

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
1.8.1.7 glutathione disulfide + NADPH
-
 Plasmodium falciparum glutathione + NADP+
-
 r
1.8.1.7 glutathione disulfide + NADPH
-
 Homo sapiens glutathione + NADP+
-
 r
1.8.1.7 additional information the antioxidant enzyme is important in the parasite sensitive to oxidative stress Plasmodium falciparum ?
-
 ?

Subunits

EC Number Subunits Comment Organism
1.8.1.7 dimer determination of shape and electrostatics of the large helices-containing cavity at the dimer interface Plasmodium falciparum
1.8.1.7 More enzyme structure comparison with the human enzyme, active site structure Plasmodium falciparum
1.8.1.7 More human enzyme structure comparison with the enzyme from Plasmodium falciparum, human parasite, active site structure Homo sapiens

Synonyms

EC Number Synonyms Comment Organism
1.8.1.7 glutathione reductase
-
 Plasmodium falciparum
1.8.1.7 glutathione reductase
-
 Homo sapiens
1.8.1.7 GR
-
 Plasmodium falciparum
1.8.1.7 GR
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
1.8.1.7 25
-
 assay at Plasmodium falciparum
1.8.1.7 25
-
 assay at Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
1.8.1.7 6.9
-
 assay at Plasmodium falciparum
1.8.1.7 6.9
-
 assay at Homo sapiens

Cofactor

EC Number Cofactor Comment Organism Structure
1.8.1.7 FAD
-
 Homo sapiens
1.8.1.7 FAD flavoenzyme, interaction with Asp311 and Leu352, binding domain structure Plasmodium falciparum
1.8.1.7 NADPH binding site structure Plasmodium falciparum
1.8.1.7 NADPH binding site structure Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
1.8.1.7 0.0004
-
 5-(4-chlorophenyl)-8-fluoro-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0005
-
 2-methyl-5-(1-naphthyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0006
-
 5-(4-chlorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0014
-
 8-azido-5-(4-chlorophenyl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0019
-
 5-(pentafluorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.0025
-
 5-(pentafluorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0025
-
 2-methyl-5-pyridin-4-yl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0025
-
 5-(1-anthryl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0054
-
 5-(4-chlorophenyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.0059
-
 5-(4-chlorophenyl)-8-fluoro-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.0062
-
 8-azido-5-(4-chlorophenyl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.0066
-
 ethyl [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0072
-
 [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetic acid pH 6.9, 25°C Homo sapiens
1.8.1.7 0.0093
-
 ethyl [5-(3-chlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate pH 6.9, 25°C Homo sapiens
1.8.1.7 0.011
-
 2-methyl-5-(1-naphthyl)-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.013
-
 ethyl [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetate pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.014
-
 [5-(3,5-dichlorophenyl)-1,3-dioxo-3,5,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-2(1H)-yl]acetic acid pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.015
-
 2-methyl-5-pyridin-4-yl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.2
-
 5-(1-anthryl)-2-methyl-5a,9a-dihydropyrido[3,4-b]quinoxaline-1,3(2H,5H)-dione pH 6.9, 25°C Plasmodium falciparum
1.8.1.7 0.2
-
 1-methyl-4-(2-methyl-1,3-dioxo-2,3,5a,9a-tetrahydropyrido[3,4-b]quinoxalin-5(1H)-yl)pyridinium pH 6.9, 25°C Homo sapiens