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6.3.1.9: trypanothione synthase

This is an abbreviated version!
For detailed information about trypanothione synthase, go to the full flat file.

Word Map on EC 6.3.1.9

Reaction

glutathione
+
glutathionylspermidine
+
ATP
=
N1,N8-bis(glutathionyl)spermidine
+
ADP
+
phosphate

Synonyms

Cf-TS, GenBank AF006615-derived protein GI 3004644, LdTryS, LiTRYS, Synthetase, trypanothione, Synthetase, trypanothione (Crithidia fasciculata strain HS6 gene Cf-TS), T(SH)2 synthetase, TbTryS, TcTryS, TRS, trypanothione synthase, Trypanothione synthetase, Trypanothione synthetase (Crithidia fasciculata strain HS6 gene Cf-TS), trypanothione synthetase-amidase, TryS, TSA, TSH synthetase, tyrS

ECTree

     6 Ligases
         6.3 Forming carbon-nitrogen bonds
             6.3.1 Acid—ammonia (or amine) ligases (amide synthases)
                6.3.1.9 trypanothione synthase

Inhibitors

Inhibitors on EC 6.3.1.9 - trypanothione synthase

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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(Z)-8-(2-(2,4-dihydroxybenzylidene)hydrazinyl)-7-(2-hydroxy-3-phenoxy propyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione
88.5% activity remaining
1,3,5-trimethyl-N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-1H-pyrazole-4-sulfonamide
-
-
1,4,7-trioxo-1lambda5,4lambda5,7lambda5-benzo[1,2-c:3,4-c':5,6-c'']tris[1,2,5]oxadiazole
64.4% activity remaining
1-(1,3-benzothiazol-2-yl)-4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-3-hydroxy-5-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one
83.5% activity remaining
1-(1,3-benzothiazol-2-yl)-4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-5-(4-fluorophenyl)-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one
1-(3-(1-isobutyl-1H-pyrazol-4-yl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(1H-indol-4-yl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(3-chlorophenyl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(3-fluorophenyl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(3-pyridyl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(4-chlorophenyl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-(furan-2-yl)-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(3-phenyl-1H-indazol-1-yl)-3,3-dimethylbutan-2-one
-
-
1-(5-(3,5-dichlorophenyl)-2H-tetrazol-2-yl)-3,3-dimethylbutan-2-one
-
-
1-(5-(3,5-dichlorophenyl)-2H-tetrazol-2-yl)butan-2-one
-
-
1-(5-(3,5-dichlorophenyl)-2H-tetrazol-2-yl)propan-2-one
-
-
1-(5-(3,5-difluorophenyl)-2H-tetrazol-2-yl)-3,3-dimethylbutan-2-one
-
-
1-(5-(3-fluorophenyl)-2H-tetrazol-2-yl)-3,3-dimethylbutan-2-one
-
-
1-(6-chloro-1,3-benzothiazol-2-yl)-4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-3-hydroxy-5-(4-hydroxy-3-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one
1-(6-chloro-1,3-benzothiazol-2-yl)-4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-3-hydroxy-5-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one
1-(6-chloro-1,3-benzothiazol-2-yl)-4-(3,4-dimethoxybenzoyl)-5-(4-fluorophenyl)-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one
1-(tert-butylsulfonylmethyl)-3-(3-fluorophenyl)-1H-indazole
-
-
1-[3-(3-fluorophenyl)-1H-indazol-1-yl]-3,3-dimethylbutan-2-one
-
i.e. DDD85811, inhibits growth of bloodstream Trypanosoma brucei in vitro
1-[5-(3-chloro-4-methylphenyl)-2H-tetrazol-2-yl]-3,3-dimethylbutan-2-one
-
-
2,4-dimethyl-N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]-1,3-thiazole-5-sulfonamide
-
-
2,4-dimethyl-N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]thiophene-3-sulfonamide
-
-
2,6-dichloro-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide
-
-
2,6-dichloro-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]benzenesulfonamide
-
-
2,6-difluoro-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide
-
-
2,6-dimethoxy-N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]benzenesulfonamide
-
-
2-((tert-butylsulfonyl)methyl)-4-(2-fluorophenyl)thiazole
-
-
2-((tert-butylsulfonyl)methyl)-4-(2-methylphenyl)thiazole
-
-
2-((tert-butylsulfonyl)methyl)-4-(3-chlorophenyl)thiazole
-
-
2-((tert-butylsulfonyl)methyl)-4-(3-methoxyphenyl)thiazole
-
-
2-((tert-butylsulfonyl)methyl)-4-(phenyl)thiazole
-
-
2-(3-(3-fluorophenyl)-1H-indazol-1-yl)-1-(piperidin-1-yl)ethanone
-
-
2-(3-(3-fluorophenyl)-1H-indazol-1-yl)-N,N-dimethylacetamide
-
-
2-(3-(3-fluorophenyl)-1H-indazol-1-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)acetamide
-
-
2-(3-(3-fluorophenyl)-1H-indazol-1-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)acetamide
-
-
2-(5-(3,5-dichlorophenyl)-2H-tetrazol-2-yl)-N,N-dimethylacetamide
-
-
2-(5-(3,5-difluorophenyl)-2H-tetrazol-2-yl)-1-phenylethanone
-
-
2-(9-bromo-3-chloro-6-oxo-7,12-dihydroindolo[3,2-d][1]benzazepin-5(6H)-yl)-N-[2-(methylamino)ethyl]acetamide
2-(tert-butylsulfonylmethyl)-4-(3-trifluoromethylphenyl)thiazole
-
-
2-methyl-N-((5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl)propane-2-sulfonamide
-
-
2-[3-(3-fluorophenyl)-1H-indazol-1-yl]-1-(piperidin-1-yl)ethanone
-
i.e. DDD86243, inhibits growth of bloodstream Trypanosoma brucei in vitro. Exposure to DDD86243 at 2 x EC50 for 72 h decreases intracellular trypanothione levels to less than 10% of wild type, with a corresponding 5fold increase in the precursor metabolite, glutathione
3,3-dimethyl-1-(3-(1-methyl-1H-indol-4-yl)-1H-indazol-1-yl)butan-2-one
-
-
3,3-dimethyl-1-(3-(naphthalen-2-yl)-1H-indazol-1-yl)butan-2-one
-
-
3,3-dimethyl-1-(3-(pyridin-4-yl)-1H-indazol-1-yl)butan-2-one
-
-
3,3-dimethyl-1-(3-(thiophen-3-yl)-1H-indazol-1-yl)butan-2-one
-
-
3,3-dimethyl-1-(5-phenyl-2H-tetrazol-2-yl)butan-2-one
-
-
3,3-dimethyl-1-[5-[3-(trifluoromethyl)phenyl]-2H-tetrazol-2-yl]butan-2-one
-
-
3,3-dimethyl-1-[5-[4-(trifluoromethyl)phenyl]-2H-tetrazol-2-yl]butan-2-one
-
-
3,5-dichloro-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide
-
-
3-((3-(3-fluorophenyl)-1H-indazol-1-yl)methyl)-5-methylisoxazole
-
-
3-((3-(3-fluorophenyl)-1H-indazol-1-yl)methyl)-5-phenylisoxazole
-
-
3-(3-fluorophenyl)-1-(pyridin-2-ylmethyl)-1H-indazole
-
-
3-(3-fluorophenyl)-1-(pyridin-3-ylmethyl)-1H-indazole
-
-
3-(tert-butylsulfonylmethyl)-1-(3-fluorophenyl)-1H-indazole
-
-
3-(tert-butylsulfonylmethyl)-1-phenyl-1H-indazole
-
-
4-((3-(3-fluorophenyl)-1H-indazol-1-yl)methyl)-2,5-dimethyloxazole
-
-
4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-3-hydroxy-1-(6-methoxy-1,3-benzothiazol-2-yl)-5-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one
4-(2,3-dihydro-1,4-benzodioxine-6-carbonyl)-3-hydroxy-5-(4-methoxyphenyl)-1-(6-methyl-1,3-benzothiazol-2-yl)-1,5-dihydro-2H-pyrrol-2-one
83.9% activity remaining
4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid
above 100 mM
4-acetyl-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide
-
-
4-methoxy-N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]benzenesulfonamide
-
-
4-methoxy-N-[[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]benzenesulfonamide
-
-
4-methyl-N-[(2-phenyl-1,3-thiazol-4-yl)methyl]benzenesulfonamide
-
-
5-oxo-1H,3H-5lambda5-benzo[1,2-c:4,5-c']bis[1,2,5]oxadiazole
6-fluoro-3-oxo-4,5-didehydro-2,1,3lambda5-benzoxadiazole
84.1% activity remaining
ammonium sulfate
almost complete inhibition at 500 mM
betulin
competitive inhibition
buthionine sulfoximine
-
-
conessine
competitive allosteric inhibition
DL-(S,R)-buthionine sulfoximine
-
DL-(S,R)-BSO, a multitarget inhibitor of trypanothione synthesis, in vivo effects on nonthiol-supplied epimastigote cells, on Cys-supplied epimastigote cells, and on GSH-supplied epimastigote cells, overview. Inhibition of gamma-glutamylcysteine synthetase and trypanothione synthetase. Wild-type Trypanosoma brucei cells are not restored by supplementing with 0.08 mM GSH. The the L-(S,R)-BSO stereoisomer is more potent that the the D-(S,R)-BSO. Inhibitor docking analysis, binding structure
glutathione
GSH
substrate inhibition
KCl
approx. 50% inhibition at 500 mM
Melarsen oxide
-
-
methyl (3-phenyl-1H-indazol-1-yl)acetate
-
-
N,N'-[6-(2,5-dichlorophenyl)pyrido[2,3-d]pyrimidine-2,7-diyl]bis(N'-tert-butylurea)
N,N'-[6-(2H-1,3-benzodioxol-5-yl)pyrido[2,3-d]pyrimidine-2,7-diyl]bis(N'-tert-butylurea)
N,N-dibenzyl-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N,N-diethyl-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N,N-diethyl-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetamide
-
-
N-(1-phenylethyl)-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-(2-(dimethylamino)ethyl)-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N-(2-methoxyethyl)-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-(2-phenylethyl)-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-(3-(1H-imidazol-1-yl)propyl)-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N-(3-(dimethylamino)propyl)-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N-(4-chlorobenzyl)-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N-(4-chlorobenzyl)-2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1Hindazol-1-yl)acetamide
-
-
N-(4-[methyl[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]sulfamoyl]phenyl)acetamide
-
-
N-(4-[[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]sulfamoyl]phenyl)acetamide
-
-
N-(butan-2-yl)-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-(thiophen-2-ylmethyl)-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-cyclohexyl-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-methyl-(3-(dimethylamino)propyl)-2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamide
-
-
N-phenyl-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-propyl-2-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]acetamide
-
-
N-[(2-phenyl-1,3-thiazol-4-yl)methyl]naphthalene-2-sulfonamide
-
-
N-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]benzenesulfonamide
-
-
N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]naphthalene-1-sulfonamide
-
-
N-[(5-methyl-2-phenyl-2H-1,2,3-triazol-4-yl)methyl]thiophene-2-sulfonamide
-
-
N-[2-(methylamino)ethyl]-2-[6-oxo-9-(trifluoromethyl)-7,12-dihydroindolo[3,2-d][1]benzazepin-5(6H)-yl]acetamide
N-[2-amino-6-(2H-1,3-benzodioxol-5-yl)pyrido[2,3-d]pyrimidin-7-yl]-N'-ethylthiourea
N-[2-amino-6-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-7-yl]-N'-tert-butylurea
N-[4-([[3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl]sulfamoyl)phenyl]acetamide
-
-
N-[4-([[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]sulfamoyl)phenyl]acetamide
-
-
N-[[3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl]benzenesulfonamide
-
-
N-[[3-(2-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]benzenesulfonamide
-
-
N1,N10-bis[[4-(propan-2-yl)phenyl]methyl]decane-1,10-diamine
N1,N12-bis[(4-bromophenyl)methyl]dodecane-1,12-diamine
N1,N12-bis[(4-chlorophenyl)methyl]dodecane-1,12-diamine
N1,N3-bis[(4-methoxyphenyl)methyl]propane-1,3-diamine
-
N1,N4-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]butane-1,4-diamine
N1,N4-bis[[4-(benzyloxy)phenyl]methyl]butane-1,4-diamine
N1,N6-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]hexane-1,6-diamine
N1,N6-bis[[4-(benzyloxy)phenyl]methyl]hexane-1,6-diamine
N1,N8-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]octane-1,8-diamine
nifurtimox
-
-
Pentamidine
-
-
prochlorperazine
-
inhibitor DDD66604, binding mode and structure, overview
tert-butyl-4-(2-(2-(3-(3-fluorophenyl)-1H-indazol-1-yl)acetamido)ethyl)piperazine-1-carboxylate
-
-
tomatine
competitive inhibition versus spermidine, uncompetitive inhibition with respect to ATP and GSH
triostam
-
-
trypanothione
-
competitive feedback inhibition
uvaol
competitive allosteric inhibition
[3-[4-([6-(3,4-dimethoxyphenyl)-7-[(ethylcarbamothioyl)amino]pyrido[2,3-d]pyrimidin-2-yl]amino)phenyl]propyl]molybdenum(1+)
81.3% activity remaining
additional information
-