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Information on EC 6.3.1.9 - trypanothione synthase and Organism(s) Trypanosoma cruzi and UniProt Accession Q9GT49

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IUBMB Comments
The enzyme, characterized from several trypanosomatids (e.g. Trypanosoma cruzi) catalyses two subsequent reactions, leading to production of trypanothione from glutathione and spermidine. Some trypanosomatids (e.g. Crithidia species and some Leishmania species) also contain an enzyme that only carries out the first reaction (cf. EC 6.3.1.8, glutathionylspermidine synthase). The enzyme is bifunctional, and also catalyses the hydrolysis of glutathionylspermidine and trypanothione (cf. EC 3.5.1.78, glutathionylspermidine amidase).
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This record set is specific for:
Trypanosoma cruzi
UNIPROT: Q9GT49
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The taxonomic range for the selected organisms is: Trypanosoma cruzi
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota
Synonyms
trypanothione synthetase, tctrys, ldtrys, tsh synthetase, litrys, tbtrys, trypanothione synthase, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cf-TS
-
-
-
-
GenBank AF006615-derived protein GI 3004644
-
-
-
-
Synthetase, trypanothione
-
-
-
-
Synthetase, trypanothione (Crithidia fasciculata strain HS6 gene Cf-TS)
-
-
-
-
Trypanothione synthetase
-
-
-
-
Trypanothione synthetase (Crithidia fasciculata strain HS6 gene Cf-TS)
-
-
-
-
TSH synthetase
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Acid amide formation
-
-
-
-
PATHWAY SOURCE
PATHWAYS
-
-, -
SYSTEMATIC NAME
IUBMB Comments
spermidine/glutathionylspermidine:glutathione ligase (ADP-forming)
The enzyme, characterized from several trypanosomatids (e.g. Trypanosoma cruzi) catalyses two subsequent reactions, leading to production of trypanothione from glutathione and spermidine. Some trypanosomatids (e.g. Crithidia species and some Leishmania species) also contain an enzyme that only carries out the first reaction (cf. EC 6.3.1.8, glutathionylspermidine synthase). The enzyme is bifunctional, and also catalyses the hydrolysis of glutathionylspermidine and trypanothione (cf. EC 3.5.1.78, glutathionylspermidine amidase).
CAS REGISTRY NUMBER
COMMENTARY hide
130246-69-4
-
213260-30-1
synthetase, trypanothione (Crithidia fasciculata strain HS6 gene Cf-TS) /GenBank AF006615-derived protein GI 3004644 /trypanothione synthetase (Crithidia fasciculata strain HS6 gene Cf-TS)
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
gamma-L-glutamyl-L-cysteinyl-glycine + N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ATP
N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate
show the reaction diagram
glutathione + glutathionylspermidine + ATP
N1,N8-bis(glutathionyl)spermidine + ADP + phosphate
show the reaction diagram
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
show the reaction diagram
-
-
-
?
glutathione + glutathionylspermidine + ATP
N1,N8-bis(glutathionyl)spermidine + ADP + phosphate
show the reaction diagram
-
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
show the reaction diagram
-
-
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
gamma-L-glutamyl-L-cysteinyl-glycine + N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ATP
N1,N8-bis-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate
show the reaction diagram
-
trivial name trypanothione
?
glutathione + glutathionylspermidine + ATP
N1,N8-bis(glutathionyl)spermidine + ADP + phosphate
show the reaction diagram
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
show the reaction diagram
-
-
-
?
glutathione + glutathionylspermidine + ATP
N1,N8-bis(glutathionyl)spermidine + ADP + phosphate
show the reaction diagram
-
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
show the reaction diagram
-
-
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
-
required
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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)-5-(4-fluorophenyl)-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one
90.8% activity remaining
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
97.4% activity remaining
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
98.7% activity remaining
1-(6-chloro-1,3-benzothiazol-2-yl)-4-(3,4-dimethoxybenzoyl)-5-(4-fluorophenyl)-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one
99.6% activity remaining
2-(9-bromo-3-chloro-6-oxo-7,12-dihydroindolo[3,2-d][1]benzazepin-5(6H)-yl)-N-[2-(methylamino)ethyl]acetamide
55.5% activity remaining
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
97.6% activity remaining
4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid
above 100 mM
5-oxo-1H,3H-5lambda5-benzo[1,2-c:4,5-c']bis[1,2,5]oxadiazole
63.5% activity remaining
ammonium sulfate
almost complete inhibition at 500 mM
KCl
approx. 50% inhibition at 500 mM
N,N'-[6-(2,5-dichlorophenyl)pyrido[2,3-d]pyrimidine-2,7-diyl]bis(N'-tert-butylurea)
61.3% activity remaining
N,N'-[6-(2H-1,3-benzodioxol-5-yl)pyrido[2,3-d]pyrimidine-2,7-diyl]bis(N'-tert-butylurea)
52.2% activity remaining
N-[2-(methylamino)ethyl]-2-[6-oxo-9-(trifluoromethyl)-7,12-dihydroindolo[3,2-d][1]benzazepin-5(6H)-yl]acetamide
i.e. FS-554, 40.5% activity remaining
N-[2-amino-6-(2H-1,3-benzodioxol-5-yl)pyrido[2,3-d]pyrimidin-7-yl]-N'-ethylthiourea
65.4% activity remaining
N-[2-amino-6-(naphthalen-2-yl)pyrido[2,3-d]pyrimidin-7-yl]-N'-tert-butylurea
32.3% activity remaining
N1,N10-bis[[4-(propan-2-yl)phenyl]methyl]decane-1,10-diamine
53.5% activity remaining
N1,N12-bis[(4-bromophenyl)methyl]dodecane-1,12-diamine
30.8% activity remaining
N1,N12-bis[(4-chlorophenyl)methyl]dodecane-1,12-diamine
23.8% activity remaining
N1,N3-bis[(4-methoxyphenyl)methyl]propane-1,3-diamine
-
N1,N4-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]butane-1,4-diamine
25.6% activity remaining
N1,N4-bis[[4-(benzyloxy)phenyl]methyl]butane-1,4-diamine
26.6% activity remaining
N1,N6-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]hexane-1,6-diamine
17.0% activity remaining
N1,N6-bis[[4-(benzyloxy)phenyl]methyl]hexane-1,6-diamine
33.4% activity remaining
N1,N8-bis[[4-(benzyloxy)-3-methoxyphenyl]methyl]octane-1,8-diamine
28.9% activity remaining
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
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
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
activates, 107.1% activity
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
activates, 109.7% activity
6-fluoro-3-oxo-4,5-didehydro-2,1,3lambda5-benzoxadiazole
activates, 118.8% activity
8-[(2E)-2-[(2,4-dihydroxyphenyl)methylidene]hydrazinyl]-7-(2-hydroxy-3-phenoxypropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
activates, 161.6% activity
[3-[4-([6-(3,4-dimethoxyphenyl)-7-[(ethylcarbamothioyl)amino]pyrido[2,3-d]pyrimidin-2-yl]amino)phenyl]propyl]molybdenum(1+)
activates, 168.6% activity
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.053
ATP
pH 8.0
0.19
GSH
pH 8.0, with N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine
0.066
N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine
pH 8.0
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2.8
N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine
pH 8.0
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
-
assay at
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 10
approx. 50% of maximal activity at pH 6.6 and pH 9.5 respectively
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
assay at room temperature
37
-
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
trypanothione dependent redox metabolism, overview. Trypanothione synthetase catalyzes the ligation of two molecules of gluthatione to one of spermidine using the energy provided by two ATP molecules. Trypanothione reductase maintains trypanothione in the reduced state at expenses of NADPH, which can be supplied by the oxidative phase of the pentose phosphate pathway via glucose 6-phosphate dehydrogenase
physiological function
in pathogenic trypanosomatids, a single enzyme, trypanothione synthetase (TryS), catalyzes trypanothione biosynthesis, which is indispensable for parasite survival. Reduced trypanothione is involved in multiple functions such as the detoxification of xenobiotics, cell proliferation, defense against oxidants and protein thiol-redox homeostasis
additional information
-
docking study and structure homology modeling using Leishmania major TryS, PDB ID 2VOB, structure as template, overview
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
64000
gel filtration
73560
deduced from nucleotide sequence
73740
MALDI mass spectrometry
73744
1 * 73744, MALDI mass spectrometry
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
introduction of the trypanothione synthetase and reductase genes from Trypanosoma cruzi into Escherichia coli results in decreased intracellular levels of reactive oxygen species. Escherichia coli genomic DNA is protected from radiation-induced DNA damage by 4.6fold in the presence of trypanothione compared to control bacteria. The transgenic Escherichia coli expressing trypanothione are 4.3fold more resistant to killing by 137Cs gamma-radiation
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His-tagged enzyme from Escherichia coli strains BL21(DE3) or Tuner (DE3) by affinity chromatography
recombinant His-tagged TcTryS, Ni2+-affinity, anion exchange
recombinant enzyme from Escherichia coli strain BL21(DE3)
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression in Escherichia coli and Saccharomyces cerevisiae
gene TRS, recombinant expression of N-terminally His-tagged enzyme in Escherichia coli strains BL21(DE3) or Tuner (DE3)
expression in Escherichia coli
-
gene tryS, recombinant expression in Escherichia coli strain BL21(DE3)
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Oza, S.L.; Tetaud, E.; Ariyanayagam, M.R.; Warnon, S.S.; Fairlamb, A.H.
A Single Enzyme Catalyses Formation of Trypanothione from Glutathione and Spermidine in Trypanosoma cruzi
J. Biol. Chem.
277
35853-35861
2002
Trypanosoma cruzi (Q9GT49), Trypanosoma cruzi
Manually annotated by BRENDA team
Fitzgerald, M.P.; Madsen, J.M.; Coleman, M.C.; Teoh, M.L.; Westphal, S.G.; Spitz, D.R.; Radi, R.; Domann, F.E.
Transgenic biosynthesis of trypanothione protects Escherichia coli from radiation-induced toxicity
Radiat. Res.
174
290-296
2010
Trypanosoma cruzi
Manually annotated by BRENDA team
Vazquez, C.; Mejia-Tlachi, M.; Gonzalez-Chavez, Z.; Silva, A.; Rodriguez-Zavala, J.S.; Moreno-Sanchez, R.; Saavedra, E.
Buthionine sulfoximine is a multitarget inhibitor of trypanothione synthesis in Trypanosoma cruzi
FEBS Lett.
591
3881-3894
2017
Trypanosoma cruzi, Trypanosoma cruzi DTU I
Manually annotated by BRENDA team
Benitez, D.; Medeiros, A.; Fiestas, L.; Panozzo-Zenere, E.A.; Maiwald, F.; Prousis, K.C.; Roussaki, M.; Calogeropoulou, T.; Detsi, A.; Jaeger, T.; Sarlauskas, J.; Peterlin Masic, L.; Kunick, C.; Labadie, G.R.; Flohe, L.; Comini, M.A.
Identification of novel chemical scaffolds inhibiting trypanothione synthetase from pathogenic trypanosomatids
PLoS Negl. Trop. Dis.
10
e0004617
2016
Leishmania infantum (A4I2Z3), Leishmania infantum, Trypanosoma brucei brucei (Q8IEX1), Trypanosoma cruzi (Q9GT49), Trypanosoma cruzi, Trypanosoma cruzi CL Brener (Q9GT49), Trypanosoma brucei brucei 427 (Q8IEX1), Leishmania infantum JPCM5 /MHOM / MA / 67 / ITMAP263 (A4I2Z3)
Manually annotated by BRENDA team