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6.3.2.2: glutamate-cysteine ligase

This is an abbreviated version!
For detailed information about glutamate-cysteine ligase, go to the full flat file.

Word Map on EC 6.3.2.2

Reaction

ATP
+
L-glutamate
 +
L-cysteine
=
ADP
 +
phosphate
 +
gamma-L-glutamyl-L-cysteine

Synonyms

Ace-GCL, Asuc_1947, AtGCL, bifunctional glutathione synthetase, bifunctional GSH synthetase, bifunctional L-glutathione synthetase, gamma -GCS, gamma-ECL, Gamma-ECS, gamma-GC, gamma-GCS, gamma-GCS-GS, gamma-glutamate-cysteine ligase-glutathione synthetase, gamma-glutamate-cysteine ligase/glutathione synthetase, gamma-glutaminylcysteine synthetase, gamma-glutamycysteine synthetase, gamma-glutamyl-cysteine ligase, gamma-Glutamyl-L-cysteine synthetase, gamma-glutamylcysteine ligase, gamma-glutamylcysteine synthase, gamma-Glutamylcysteine synthetase, gamma-glutamylcysteine synthetase-glutathione synthetase, gamma-Glutamylcysteinyl-synthetase, gammaGCS, GCL, GCLC, Gclc-X2, GCLM, GCS, GCSGS, ghF, GLCL, GLCLC, GLCLR, glutamate cysteine ligase, glutamate cysteine ligase gene, glutamate-cysteine ligase, glutamate-cysteine-ligase, glutamate–cysteine ligase, glutathione biosynthesis bifunctional protein GshAB, GSH1, GshA, gshAB, GshF, GshFAp, GshFAs, GSHI, I79_022778, L-glutamate L-cysteine ligase, More, PAD2, PhGshA II, PSHAa0937, StGCL-GS, Synthetase, gamma-glutamylcysteine

ECTree

     6 Ligases
         6.3 Forming carbon-nitrogen bonds
             6.3.2 Acid—amino-acid ligases (peptide synthases)
                6.3.2.2 glutamate-cysteine ligase

Inhibitors

Inhibitors on EC 6.3.2.2 - glutamate-cysteine ligase

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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(2S)-2-amino-4-[(2R,S)-2-carboxy-3-hydroxypropyl-(R,S)-sulfonimidoyl]butanoic acid
-
slow-binding, irreversible inactivation, ATP-dependent, a N-phosphorylated reaction intermediate is tightly bound to the enzyme, mechanism-based
(2S)-2-amino-4-[(2R,S)-2-carboxy-3-phenylpropyl-(R,S)-sulfonimidoyl]butanoic acid
-
weak, reversible inhibition
(2S)-2-amino-4-[(2R,S)-2-carboxybutyl-(R,S)-sulfonimidoyl]butanoic acid
-
slow-binding, irreversible inactivation, ATP-dependent, a N-phosphorylated reaction intermediate is tightly bound to the enzyme, mechanism-based
(2S)-2-amino-4-[(2R,S)-2-carboxyhexyl-(R,S)-sulfonimidoyl]butanoic acid
-
slow-binding, irreversible inactivation, ATP-dependent, a N-phosphorylated reaction intermediate is tightly bound to the enzyme, mechanism-based
(2S)-2-amino-4-[(2R,S)-2-carboxyoctyl-(R,S)-sulfonimidoyl]butanoic acid
-
weak, reversible inhibition
(2S)-2-amino-4-[(2R,S)-2-carboxypropyl-(R,S)-sulfonimidoyl]butanoic acid
-
slow-binding, irreversible inactivation, ATP-dependent, a N-phosphorylated reaction intermediate is tightly bound to the enzyme, mechanism-based
(2S)-2-amino-4-[2-carboxyethyl-(R,S)-sulfonimidoyl]butanoic acid
-
slow-binding, irreversible inactivation, ATP-dependent, a N-phosphorylated reaction intermediate is tightly bound to the enzyme, mechanism-based
2-mercaptoethanol
-
-
4-hydroxy-2-nonenal
-
treatment with 4-hydroxy-2-nonenal results in the dose-dependent adduction of both monomeric GCLC and GCLM. 4-Hydroxy-2-nonenal-mediated adduction of monomeric GCLC results in a dose-dependent increase in GCLC enzymatic activity. Treatment of GCL holoenzyme causes a dose-dependent decrease in GCL activity. 4-Hydroxy-2-nonenal-mediated inhibition of GCL holoenzyme activity is associated with a reduction in the levels of heterodimeric GCL holoenzyme complex due to increase in high molecular weight complexes. 4-Hydroxy-2-nonenal modification simultaneously activates monomeric GCLC activity and prevents its ability to heterodimerize with GCLM and form functional GCL holoenzyme
4-Methylene glutamate
4-methylene-L-glutamate
weak, competitive
5'-ADP
-
-
5'-AMP
-
-
5-Chloro-4-oxo-L-norvaline
irreversible, binding is reduced by L-glutamate, increased by L-alpha-aminobutyrate, and is completely dependent on divalent cations
acetaminophen
-
treatment promotes the loss of glutamate cysteine ligase in liver. Activation of glycogen synthase kinase 3beta is a key mediator of the initial phase of acetaminophen-induced liver injury through modulating GCL and Mcl-1 degradation, as well as JNK activation in liver. The silencing of glycogen synthase kinase 3beta decreases the loss of hepatic GCL, and promotes greater GSH recovery in liver following acetaminophen treatment
Ag+
-
complete inactivation
alpha-Methyl-DL-glutamate
-
-
antimony
-
heterozygous mutants with one allele inactivated show a significant decreased survival in the presence of antimony
ATP
-
substrate inhibition of mutant R179A, when only one other substrate is saturating
beta-Methylglutamate
-
-
buthionine sulfone
-
buthionine sulfoxime
-
buthionine sulfoximine
carbon tetrachloride
-
a single dose of 1589 mg/kg body weight of carbon tetrachloride causes changes in CGL activity and glutathione content in multiple organs of deer mice. Hepatic GCL activity and GSH content are depleted substantially, renal GCL activity increases. Blood, brain and heart GCL activities increase, whereas GSH contents decrease significantly
ciprofibrate
-
inhibits expression of heavy subunit
cis-1-Amino-1,3-dicarboxycyclohexane
-
-
Co2+
-
22% residual activity
Cu2+
-
27% residual activity
cystamine
cysteamine
D-3-amino-1-chloro-2-pentanone
diquat
-
inhibits expression of heavy subunit
dithioerythritol
-
-
dithiothreitol
DL-2-Amino-4-phosphonobutanoate
-
-
DL-alpha-Aminomethylglutarate
-
-
DL-Aminoadipate
-
weak
gamma-Glu-2-aminobutanoyl-Gly
-
i.e. ophthalmic acid, inhibits only slightly, but inhibits much more after treatment of the holoenzyme with DTT, the recombinant and isolated heavy subunit enzyme is substantially inhibited without DTT
gamma-glutamylcysteine
-
-
gamma-L-Glu-L-Cys
-
gamma-methylene-D-glutamate
-
gamma-Methylglutamate
glutathione
iodoacetamide
L-2-Amino-4-oxo-5-chloropentanoate
-
inactivation requires very low concentration, 0.003-0.006 mM, of Mg2+ or certain other divalent cations, L-Glu, but not D-Glu protects competitively against inactivation, protection is increased in the presence of ATP or ADP
L-2-aminohexanedioate
-
i.e. L-alpha-aminoadipate
L-3-Amino-1-chloro-2-pentanone
-
highly potent irreversible inactivator
L-alpha-aminobutyrate
-
substrate inhibition of mutant R179A, when only one other substrate is saturating
L-buthionine sulfone
competitive, reversible
L-buthionine sulfoximine
L-buthionine-(S,R)-sulfoximine
-
cotreatment with L-buthionine-(S,R)-sulfoximine, 1-methyl-4-phenylpyridinium and fibroblast growth factor 9 inhibits increased neuron viability compared to the group treated with 1-methyl-4-phenylpyridinium and fibroblast growth factor 9, to levels comparable to those of the 1-methyl-4-phenylpyridinium-treated group
L-buthionine-R,S-sulfoximine
i.e. BSO, specific, irreversible
L-buthionine-R-sulfoximine
L-buthionine-S-sulfoximine
L-buthionine-SR-sulfoximine
L-cysteine
L-glutamic acid gamma-monohydroxamate
-
ATP-dependent irreversible inactivation, loss of 90% activity within 3 days, inactivation mechanism, no inactivation occurs in absence of ATP or with AMP-PNP
L-glutamine
inhibition of enzyme activity in tumor tissue
L-Homocysteate
-
-
L-Homocysteine sulfinate
-
-
L-methionine
-
inhibits expression of heavy subunit
lipopolysaccharides
-
inhibits expression of heavy subunit
-
methionine
-
inhibits induction of GSH1 expression, independently of GSH
methionine sulfoximine
MgATP2-
Monodansylcystamine
-
-
N-Methyl-L-glutamate
-
-
N-[2(2-Aminoethyl)-dithioethyl]4-azido-2-nitrobenzeneamine
-
-
NADP+
NADPH
NF-kappaB
-
inhibits induction of enzyme expression by other substances, e.g. buthionine sulfoximine or tert-butylhydroquinone
-
Ni2+
-
complete inactivation
oxidative stress
-
heterozygous mutants with one allele inactivated are more susceptible to oxidative stresses in vitro as promastigotes and show decreased survival inside activated macrophages producing reactive oxygen or nitrogen species
-
Pb2+
-
in deer mice exposed to Pb, or Pb together with Cu and Zn via drinking water for 4 weeks. GCL activities are not significantly affected by treatments. Metal-contaminated soils do not lead to significant effects in pups via lactation, 50-day exposure alters glutathione content marginally, while 100-day exposure results in marked GCL activity depletion. After 100-day exposure, GCL activities of the medium soil-, high soil- and Pb-treated deer mice are only 53%, 40% and 46% of the control, respectively
Prothionine sulfoximine
S-(S-Methyl)cysteamine
-
-
S-butyl-DL-homocysteine-SR-sulfoximine
S-nitroso-L-cysteine
inactivation, prevented by pretreatment with ATP and L-SR-buthionine sulfoximine in absence of Mg2+
S-nitroso-L-cysteinylglycine
inactivation, prevented by pretreatment with ATP and L-SR-buthionine sulfoximine in absence of Mg2+
S-sulfo-homocysteine
-
S-sulfo-L-cysteine
-
S-sulfocysteine
S-sulfohomocysteine
Selenocystamine
-
-
Thiocholine disulfide
-
-
threo-beta-Hydroxy-DL-glutamate
-
-
threo-gamma-Hydroxy-L-glutamate
-
-
trans-1-Amino-1,3-dicarboxycyclohexane
-
-
Trinitrobenzene sulfonate
additional information
-