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Information on EC 6.3.1.8 - glutathionylspermidine synthase
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EC Tree
6.3.1.8 glutathionylspermidine synthaseIUBMB Comments
Requires magnesium ions. Involved in the synthesis of trypanothione in trypanosomatids. The enzyme from Escherichia coli is bifunctional and also catalyses the glutathionylspermidine amidase (EC 3.5.1.78) reaction, resulting in a net hydrolysis of ATP.
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Word Map
- 6.3.1.8
- trypanothione
-
trypanosomatids
- gsh
- trypanosoma
- leishmania
-
n1,n8-bisglutathionylspermidine
- cruzi
- polyamine
- brucei
- gamma-glu-cys-gly
- ligases
-
protozoa
-
tetrahedral
- mgatp
-
obeys
-
slow-binding
- kinetoplastida
-
anti-parasitic
- phosphinate
-
atp-grasp
- acyl-enzyme
-
polyamine-containing
-
bollinger
-
histidine-dependent
-
glutathione-like
-
aminopropylates
- mg2+-atp
-
glutathionylation
- drug development
- pharmacology
The enzyme appears in viruses and cellular organisms
Synonyms
glutathionylspermidine synthetase, gsp synthetase, ligsps, glutathionylspermidine synthase, bifunctional glutathionylspermidine synthetase/amidase, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
bifunctional glutathionylspermidine synthetase/amidase
Gen Bank AE000381-derived protein GI 1789361
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GenBank U66520-derived protein GI 1813514
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Glutathione:spermidine ligase (ADP-forming)
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Glutathione:spermidine ligase [ADP-forming]
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-
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Glutathionylspermidine synthetase (Crithidia fasciculata strain HS6 gene Cf-GSS)
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Glutathionylspermidine synthetase (Crithidia fasciculata)
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Glutathionylspermidine synthetase/amidase
Gsp synthetase
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-
-
-
GspS
LiGSPS
Protein (Escherichia coli strain K12-MG1655 gene gsp)
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-
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Synthetase, glutathionylspermidine
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-
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Synthetase, glutathionylspermidine (Crithidia fasciculata fragment)
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Synthetase, glutathionylspermidine (Crithidia fasciculata strain HS6 gene Cf-GSS)
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Synthetase, glutathionylspermidine (Crithidia fasciculata)
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Synthetase, glutathionylspermidine (Escherichia coli clone pJBM1 gene gsp)
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Glutathionylspermidine synthetase/amidase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
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-
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glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
gamma-L-glutamyl-L-cysteinyl-glycine + spermidine + ATP = N1-(gamma-L-glutamyl-L-cysteinyl-glycyl)-spermidine + ADP + phosphate
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-
-
glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
the reaction is catalyzed by trypanothione synthase and glutathionylspermidine synthase in Crithidia fasciculata
glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
the reaction is catalyzed by trypanothione synthase, EC 6.3.1.9, and glutathionylspermidine synthase, EC 6.3.1.8, in Crithidia fasciculata
glutathione + spermidine + ATP = glutathionylspermidine + ADP + phosphate
the kinetic mechanism obeys a rapid equilibrium random ter-ter model
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acid amide formation
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-
-
-
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PATHWAY SOURCE
PATHWAYS
BRENDA
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SYSTEMATIC NAME
IUBMB Comments
gamma-L-glutamyl-L-cysteinyl-glycine:spermidine ligase (ADP-forming) [spermidine is numbered so that atom N-1 is in the amino group of the aminopropyl part of the molecule]
Requires magnesium ions. Involved in the synthesis of trypanothione in trypanosomatids. The enzyme from Escherichia coli is bifunctional and also catalyses the glutathionylspermidine amidase (EC 3.5.1.78) reaction, resulting in a net hydrolysis of ATP.
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CAS REGISTRY NUMBER
COMMENTARY
168257-36-1
synthetase, glutathionylspermidine (Escherichia coli clone pJBM1 gene gsp), GenBank AE000381-derived protein GI 1789361, protein (Escherichia coli strain K12-MG1655 gene gsp)
190209-90-6
synthetase, glutathionylspermidine (Crithidia fasciculata), glutathionylspermidine synthetase (Crithidia fasciculata)
209273-40-5
synthetase, glutathionylspermidine (Crithidia fasciculata fragment)
213260-31-2
synthetase, glutathionylspermidine (Crithidia fasciculata strain HS6 gene Cf-GSS), genBank U66520-derived protein GI 1813514, glutathionylspermidine synthetase (Crithidia fasciculata strain HS6 gene Cf-GSS)
9077-09-2
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2 glutathione + spermidine + 2 ATP
N1,N8-bis(glutathionyl)spermidine + 2 ADP + 2 phosphate
trypanothione synthase overall reaction
-
-
?
gamma-Glu-Gly-Gly + spermidine + ATP
N1-(gamma-Glu-Gly-Gly)-spermidine + ADP + phosphate
-
at 14% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-Glu-L-Cys(S-butyl)-Gly + spermidine + ATP
N1-(gamma-Glu-L-Cys(S-butyl)-Gly)-spermidine + ADP + phosphate
-
at 24% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-Glu-L-Cys(S-ethyl)-Gly + spermidine + ATP
N1-(gamma-Glu-L-Cys(S-ethyl)-Gly)-spermidine + ADP + phosphate
-
at 77% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-Glu-L-Cys(S-propyl)-Gly + spermidine + ATP
N1-(gamma-Glu-L-Cys(S-propyl)-Gly)-spermidine + ADP + phosphate
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at 56% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-Glu-L-Ser-Gly + spermidine + ATP
N1-(gamma-Glu-L-Ser-Gly)-spermidine + ADP + phosphate
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at 16% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-L-Glu-L-Ala-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Ala-Gly)-spermidine + ADP + phosphate
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at 28% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-L-Glu-L-alpha-aminobutyryl-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-alpha-aminobutyryl-Gly)-spermidine
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gamma-L-Glu-L-alpha-aminobutyryl-Gly i.e. ophthalmic acid
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-
?
gamma-L-Glu-L-Cys(S-methyl)-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys(S-methyl)-Gly)-spermidine + ADP + phosphate
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at 74% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2-
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate
gamma-L-Glu-L-Ile-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Ile-Gly)-spermidine + ADP + phosphate
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at 70% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
gamma-L-Glu-L-Val-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Val-Gly)-spermidine + ADP + phosphate
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at 88% of the activity with gamma-L-Glu-L-Cys-Gly
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-
?
glutathionylspermidine + H2O
glutathione + spermidine
amidase activity
-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
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?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
-
?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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-
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?
gamma-L-Glu-L-Cys-Gly + spermidine + ATP
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + ADP + phosphate
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?
gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2-
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate
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-
?
gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2-
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate
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-
?
gamma-L-Glu-L-Cys-Gly + spermidine + MgATP2-
N1-(gamma-L-Glu-L-Cys-Gly)-spermidine + MgADP- + phosphate
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substitution of the glycine part abolishes activity
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?
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
synthesis of trypanothione, which is involved in maintaining intracellular thiol redox and in defense against oxidants
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-
?
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
-
the enzyme is involved in the biosynthesis of the trypanosomatid-specific dithiol trypanothione
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?
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
-
key enzyme that participates in the first of two similar steps of trypanothione biosynthesis
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-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
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-
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?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
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-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
trypanothione synthase
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-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
specific for, the enzyme is distinct from the trypanothione synthase, which also catalyzes the reaction but converts glutathionylsperimidine further to trypanothione
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-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
glutathionylspermidine is an intermediate formed in the biosynthesis of trypanothione, an essential metabolite in defence against chemical and oxidative stress in the kinetoplastida
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-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
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-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
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-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
Leishmania infantum MHOM / MA / 67 / ITMAP263
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-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
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trypanothione synthase catalyzes both the reaction of glutathionylspermidine synthase, EC 6.3.1.8, and of trypanothione synthase, EC 6.3.1.9, in Trypanosoma brucei
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-
?
additional information
?
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
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-
?
additional information
?
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
-
-
?
additional information
?
-
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
-
-
?
additional information
?
-
model of ter-reactant mechanism of GspS catalysis and postulated overview
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-
?
additional information
?
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-
model of ter-reactant mechanism of GspS catalysis and postulated overview
-
-
?
additional information
?
-
Escherichia coli proteins YgiC and YjfC, encoded by genes ygiC and yjfC, cannot synthesize G-Sp, GSH, or GSH intermediates, they are no glutathionylspermidine synthetase/amidases, but show ATP-hydrolysis activity
-
-
?
additional information
?
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important reaction in defense against chemical and oxidant stress, thiol redox homeostasis, ribonucleotide metabolism, and drug resistance in parasitic kinetoplastids
-
-
?
additional information
?
-
-
the enzyme is important for several functions, e.g. for detoxification of H2O2 and organic hyperoxids, and ribonucleotide reduction
-
-
?
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
synthesis of trypanothione, which is involved in maintaining intracellular thiol redox and in defense against oxidants
-
-
?
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
-
the enzyme is involved in the biosynthesis of the trypanosomatid-specific dithiol trypanothione
-
-
?
gamma-L-Glutamyl-L-cysteinyl-glycine + spermidine + ATP
?
-
key enzyme that participates in the first of two similar steps of trypanothione biosynthesis
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
trypanothione synthase
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
glutathionylspermidine is an intermediate formed in the biosynthesis of trypanothione, an essential metabolite in defence against chemical and oxidative stress in the kinetoplastida
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
Leishmania infantum MHOM / MA / 67 / ITMAP263
-
-
-
?
glutathione + spermidine + ATP
glutathionylspermidine + ADP + phosphate
-
trypanothione synthase catalyzes both the reaction of glutathionylspermidine synthase, EC 6.3.1.8, and of trypanothione synthase, EC 6.3.1.9, in Trypanosoma brucei
-
-
?
additional information
?
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
-
-
?
additional information
?
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
-
-
?
additional information
?
-
-
the trypanothione synthase also converts glutathionylspermidine further to trypanothione catalyzing the reaction of EC 6.3.1.9
-
-
?
additional information
?
-
Escherichia coli proteins YgiC and YjfC, encoded by genes ygiC and yjfC, cannot synthesize G-Sp, GSH, or GSH intermediates, they are no glutathionylspermidine synthetase/amidases, but show ATP-hydrolysis activity
-
-
?
additional information
?
-
-
important reaction in defense against chemical and oxidant stress, thiol redox homeostasis, ribonucleotide metabolism, and drug resistance in parasitic kinetoplastids
-
-
?
additional information
?
-
-
the enzyme is important for several functions, e.g. for detoxification of H2O2 and organic hyperoxids, and ribonucleotide reduction
-
-
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2-[[([2-[(4-amino-4-carboxybutanoyl)amino]propanoyl]amino)methyl](hydroxy)phosphoryl]ethyl)(hydroxy)dioxophosphate(1-)
inhibits the reaction in the presence of spermidine
4-[(14-ammonio-5-hydroxy-1-methyl-5-oxido-2-oxo-6-oxa-3,10-diaza-5-phosphatetradec-1-yl)amino]-1-carboxy-4-oxobutan-1-aminium
-
4-[[2-([[[4-[(4-ammoniobutyl)amino]butyl](hydroxy)phosphoryl]methyl]amino)-1-methyl-2-oxoethyl]amino]-1-carboxy-4-oxobutan-1-aminium
-
gamma-glutamyl-N-[[(3-aminopropoxy)(2-phosphonoethyl)phosphoryl]methyl]alaninamide
-
Hydrogen O-[3-[N-(4-Aminobutyl)amino]propyl][[(gamma-glutamylalanyl)amino]methyl]phosphonate
-
-
N1-glutathionylspermidine analogs
-
selective inhibitors against EC 6.3.1.8 and EC 3.5.1.78 activities provide evidence of interdomain communication in the bifunctional enzyme
Phosphinate
behaves as a slow-binding bisubstrate inhibitor, competitive with respect to GSH and spermidine
phosphinate analogue of glutathionylspermidine
slow tight-binding inhibition
phosphonate
acts as a a simple ground state analogue of glutathione
phosphonate analogue of glutathionylspermidine
classical, linear competitive inhibition with respect to GSH
additional information
-
a series of glutathione analogs where the glycine moiety is substituted for other amino acids can act as inhibitors
-
additional information
H2O2 leads to inhibition of the amidase activity, while the glutathionylspermidine synthase activity is almost unaffected
-
additional information
-
design, synthesis, and biochemical evaluation of phosphonate and phosphonamidate analogs of glutathionylspermidine as inhibitors
-
additional information
-
the enzyme mediates resistance to H2O2 and organic hyperoxids, and to trypanocidic drugs
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.052
ATP
pH 7.2, 25°C, recombinant trypanothione synthase performing the glutathionylspermidine synthase reaction
0.171
glutathione
pH 7.3, 25°C, synthetase activity of the C79A mutant
1.175
glutathione
pH 7.2, 25°C, recombinant trypanothione synthase performing the glutathionylspermidine synthase reaction
0.096
MgADP-
pH 7.3, 25°C, synthetase activity of the C79A mutant
0.078
spermidine
pH 7.3, 25°C, synthetase activity of the C79A mutant
7.424
spermidine
pH 7.2, 25°C, recombinant trypanothione synthase performing the glutathionylspermidine synthase reaction
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4.2
spermidine
pH 7.2, 25°C, recombinant trypanothione synthase performing the glutathionylspermidine synthase reaction
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.006
4-[(14-ammonio-5-hydroxy-1-methyl-5-oxido-2-oxo-6-oxa-3,10-diaza-5-phosphatetradec-1-yl)amino]-1-carboxy-4-oxobutan-1-aminium
-
0.0000078
4-[[2-([[[4-[(4-ammoniobutyl)amino]butyl](hydroxy)phosphoryl]methyl]amino)-1-methyl-2-oxoethyl]amino]-1-carboxy-4-oxobutan-1-aminium
-
0.019
phosphinate analogue of glutathionylspermidine
pH 7.2, 25°C
0.156
phosphonate analogue of glutathionylspermidine
pH 7.2, 25°C
additional information
additional information
inhibition kinetics and mechanism, model of ter-reactant mechanism of GspS catalysis and postulated, overview
-
additional information
additional information
-
inhibition kinetics and mechanism, model of ter-reactant mechanism of GspS catalysis and postulated, overview
-
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
2
about, purified recombinant trypanothione synthase performing the glutathionylspermidine synthase reaction
additional information
additional information
-
enzyme cloned in Escherichia coli and Saccharomyces cerevisiae is inactive
additional information
enzyme cloned in Escherichia coli and Saccharomyces cerevisiae is inactive
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.2
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
25
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM