BRENDA - Enzyme Database show

Mechanism of inhibition of trypanothione reductase and glutathione reductase by trivalent organic arsenicals

Cunningham, M.L.; Zvelebil, M.J.J.M.; Fairlamb, A.H.; Eur. J. Biochem. 221, 285-295 (1994)

Data extracted from this reference:

Activating Compound
EC Number
Activating Compound
Commentary
Organism
Structure
1.8.1.7
FAD analogues
-
Homo sapiens
1.8.1.12
additional information
activity is dependent on a redox-active cysteine at the active centre
Crithidia fasciculata
General Stability
EC Number
General Stability
Organism
1.8.1.12
loss of 39% activity after incubation with NADPH at 25°C
Crithidia fasciculata
Inhibitors
EC Number
Inhibitors
Commentary
Organism
Structure
1.8.1.7
Melarsen oxide
2-step process
Homo sapiens
1.8.1.7
Melarsen oxide
i.e. p-(4,6-diamono-s-triazin-2-yl)aminophenylarsenoxide; potent inhibitor, reversible by excess of thiols, more sensitive with NADPH
Trypanosoma brucei gambiense
1.8.1.7
Melarsen oxide
i.e. p-(4,6-diamono-s-triazin-2-yl)aminophenylarsenoxide; potent inhibitor, reversible by excess of thiols, more sensitive with NADPH
Trypanosoma brucei rhodesiense
1.8.1.7
NADPH
protection by NADP+
Homo sapiens
1.8.1.12
arsenite
+ NADPH, slightly
Crithidia fasciculata
1.8.1.12
cymelarsen
+ NADPH
Crithidia fasciculata
1.8.1.12
Melarsen oxide
inhibition is increased in presence of NADPH, inhibition is abolished by melarsen-trypanothione disulfide adduct
Crithidia fasciculata
1.8.1.12
melarsen-trypanothione disulfide adduct
no inhibition
Crithidia fasciculata
1.8.1.12
melarsoprol
+ NADPH, slightly
Crithidia fasciculata
1.8.1.12
NADPH
NADPH inhibits the enzyme at higher concentration and during longer incubation times, enzyme can be protected by NADP+
Crithidia fasciculata
1.8.1.12
phenylarsenoxide
+ NADPH
Crithidia fasciculata
Organism
EC Number
Organism
Primary Accession No. (UniProt)
Commentary
Textmining
1.8.1.7
Bos taurus
-
-
-
1.8.1.7
Homo sapiens
-
-
-
1.8.1.7
Trypanosoma brucei gambiense
-
parasitic protozoa
-
1.8.1.7
Trypanosoma brucei rhodesiense
-
parasitic protozoa
-
1.8.1.12
Crithidia fasciculata
-
-
-
Purification (Commentary)
EC Number
Commentary
Organism
1.8.1.7
-
Homo sapiens
1.8.1.7
-
Bos taurus
1.8.1.12
-
Crithidia fasciculata
Reaction
EC Number
Reaction
Commentary
Organism
1.8.1.7
2 glutathione + NADP+ = glutathione disulfide + NADPH + H+
inhibition mechanism
Homo sapiens
1.8.1.7
2 glutathione + NADP+ = glutathione disulfide + NADPH + H+
analogous to trypanothione reductase
Trypanosoma brucei gambiense
1.8.1.7
2 glutathione + NADP+ = glutathione disulfide + NADPH + H+
analogous to trypanothione reductase
Trypanosoma brucei rhodesiense
Source Tissue
EC Number
Source Tissue
Commentary
Organism
Textmining
1.8.1.7
erythrocyte
-
Homo sapiens
-
1.8.1.7
intestine
mucosa
Bos taurus
-
Specific Activity [micromol/min/mg]
EC Number
Specific Activity Minimum [µmol/min/mg]
Specific Activity Maximum [µmol/min/mg]
Commentary
Organism
1.8.1.7
114
-
purified enzyme
Bos taurus
1.8.1.7
262
-
purified enzyme
Homo sapiens
1.8.1.12
247
-
purified enzyme
Crithidia fasciculata
Substrates and Products (Substrate)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.8.1.7
GSSG + NADPH
-
394761
Homo sapiens
glutathione + NADP+
-
394761
Homo sapiens
?
1.8.1.7
GSSG + NADPH
-
394761
Bos taurus
glutathione + NADP+
-
394761
Bos taurus
?
1.8.1.7
GSSG + NADPH
-
394761
Trypanosoma brucei rhodesiense
glutathione + NADP+
-
-
-
?
1.8.1.7
GSSG + NADPH
-
394761
Trypanosoma brucei gambiense
glutathione + NADP+
-
-
-
?
1.8.1.12
trypanothione disulfide + NADPH
-
394761
Crithidia fasciculata
trypanothione + NADP+
-
394761
Crithidia fasciculata
?
Temperature Optimum [°C]
EC Number
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
1.8.1.7
27
-
assay at
Bos taurus
1.8.1.7
27
-
assay at
Homo sapiens
1.8.1.7
27
-
assay at
Trypanosoma brucei gambiense
1.8.1.7
27
-
assay at
Trypanosoma brucei rhodesiense
1.8.1.12
27
-
assay at
Crithidia fasciculata
pH Optimum
EC Number
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
1.8.1.7
7.8
-
assay at
Bos taurus
1.8.1.7
7.8
-
assay at
Homo sapiens
1.8.1.12
7.8
-
assay at
Crithidia fasciculata
Cofactor
EC Number
Cofactor
Commentary
Organism
Structure
1.8.1.7
FAD
FAD enzyme
Bos taurus
1.8.1.7
FAD
FAD enzyme
Trypanosoma brucei gambiense
1.8.1.7
FAD
FAD enzyme
Trypanosoma brucei rhodesiense
1.8.1.7
FAD
FAD enzyme
Homo sapiens
1.8.1.12
FAD
-
Crithidia fasciculata
1.8.1.12
NADPH
-
Crithidia fasciculata
Ki Value [mM]
EC Number
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
1.8.1.12
0.016
-
Melarsen oxide
with melarsen-trypanothione disulfide-adduct
Crithidia fasciculata
1.8.1.12
0.0172
-
Melarsen oxide
with NADPH
Crithidia fasciculata
Activating Compound (protein specific)
EC Number
Activating Compound
Commentary
Organism
Structure
1.8.1.7
FAD analogues
-
Homo sapiens
1.8.1.12
additional information
activity is dependent on a redox-active cysteine at the active centre
Crithidia fasciculata
Cofactor (protein specific)
EC Number
Cofactor
Commentary
Organism
Structure
1.8.1.7
FAD
FAD enzyme
Bos taurus
1.8.1.7
FAD
FAD enzyme
Trypanosoma brucei gambiense
1.8.1.7
FAD
FAD enzyme
Trypanosoma brucei rhodesiense
1.8.1.7
FAD
FAD enzyme
Homo sapiens
1.8.1.12
FAD
-
Crithidia fasciculata
1.8.1.12
NADPH
-
Crithidia fasciculata
General Stability (protein specific)
EC Number
General Stability
Organism
1.8.1.12
loss of 39% activity after incubation with NADPH at 25°C
Crithidia fasciculata
Inhibitors (protein specific)
EC Number
Inhibitors
Commentary
Organism
Structure
1.8.1.7
Melarsen oxide
2-step process
Homo sapiens
1.8.1.7
Melarsen oxide
i.e. p-(4,6-diamono-s-triazin-2-yl)aminophenylarsenoxide; potent inhibitor, reversible by excess of thiols, more sensitive with NADPH
Trypanosoma brucei gambiense
1.8.1.7
Melarsen oxide
i.e. p-(4,6-diamono-s-triazin-2-yl)aminophenylarsenoxide; potent inhibitor, reversible by excess of thiols, more sensitive with NADPH
Trypanosoma brucei rhodesiense
1.8.1.7
NADPH
protection by NADP+
Homo sapiens
1.8.1.12
arsenite
+ NADPH, slightly
Crithidia fasciculata
1.8.1.12
cymelarsen
+ NADPH
Crithidia fasciculata
1.8.1.12
Melarsen oxide
inhibition is increased in presence of NADPH, inhibition is abolished by melarsen-trypanothione disulfide adduct
Crithidia fasciculata
1.8.1.12
melarsen-trypanothione disulfide adduct
no inhibition
Crithidia fasciculata
1.8.1.12
melarsoprol
+ NADPH, slightly
Crithidia fasciculata
1.8.1.12
NADPH
NADPH inhibits the enzyme at higher concentration and during longer incubation times, enzyme can be protected by NADP+
Crithidia fasciculata
1.8.1.12
phenylarsenoxide
+ NADPH
Crithidia fasciculata
Ki Value [mM] (protein specific)
EC Number
Ki Value [mM]
Ki Value maximum [mM]
Inhibitor
Commentary
Organism
Structure
1.8.1.12
0.016
-
Melarsen oxide
with melarsen-trypanothione disulfide-adduct
Crithidia fasciculata
1.8.1.12
0.0172
-
Melarsen oxide
with NADPH
Crithidia fasciculata
Purification (Commentary) (protein specific)
EC Number
Commentary
Organism
1.8.1.7
-
Homo sapiens
1.8.1.7
-
Bos taurus
1.8.1.12
-
Crithidia fasciculata
Source Tissue (protein specific)
EC Number
Source Tissue
Commentary
Organism
Textmining
1.8.1.7
erythrocyte
-
Homo sapiens
-
1.8.1.7
intestine
mucosa
Bos taurus
-
Specific Activity [micromol/min/mg] (protein specific)
EC Number
Specific Activity Minimum [µmol/min/mg]
Specific Activity Maximum [µmol/min/mg]
Commentary
Organism
1.8.1.7
114
-
purified enzyme
Bos taurus
1.8.1.7
262
-
purified enzyme
Homo sapiens
1.8.1.12
247
-
purified enzyme
Crithidia fasciculata
Substrates and Products (Substrate) (protein specific)
EC Number
Substrates
Commentary Substrates
Literature (Substrates)
Organism
Products
Commentary (Products)
Literature (Products)
Organism (Products)
Reversibility
1.8.1.7
GSSG + NADPH
-
394761
Homo sapiens
glutathione + NADP+
-
394761
Homo sapiens
?
1.8.1.7
GSSG + NADPH
-
394761
Bos taurus
glutathione + NADP+
-
394761
Bos taurus
?
1.8.1.7
GSSG + NADPH
-
394761
Trypanosoma brucei rhodesiense
glutathione + NADP+
-
-
-
?
1.8.1.7
GSSG + NADPH
-
394761
Trypanosoma brucei gambiense
glutathione + NADP+
-
-
-
?
1.8.1.12
trypanothione disulfide + NADPH
-
394761
Crithidia fasciculata
trypanothione + NADP+
-
394761
Crithidia fasciculata
?
Temperature Optimum [°C] (protein specific)
EC Number
Temperature Optimum [°C]
Temperature Optimum Maximum [°C]
Commentary
Organism
1.8.1.7
27
-
assay at
Bos taurus
1.8.1.7
27
-
assay at
Homo sapiens
1.8.1.7
27
-
assay at
Trypanosoma brucei gambiense
1.8.1.7
27
-
assay at
Trypanosoma brucei rhodesiense
1.8.1.12
27
-
assay at
Crithidia fasciculata
pH Optimum (protein specific)
EC Number
pH Optimum Minimum
pH Optimum Maximum
Commentary
Organism
1.8.1.7
7.8
-
assay at
Bos taurus
1.8.1.7
7.8
-
assay at
Homo sapiens
1.8.1.12
7.8
-
assay at
Crithidia fasciculata