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Information on EC 4.4.1.20 - leukotriene-C4 synthase
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4.4.1.20 leukotriene-C4 synthaseIUBMB Comments
The reaction proceeds in the direction of addition. Not identical with EC 2.5.1.18, glutathione transferase.
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Word Map
- 4.4.1.20
- asthma
- lta4
-
cysteinyl
-
5-lipoxygenase
-
arachidonic
-
eosinophil
-
asthmatic
- flap
- bronchial
-
eicosanoids
- aspirin
- cysteinyl-leukotrienes
-
cys-lts
-
bronchoconstriction
-
5-lipoxygenase-activating
-
cysltr1
-
aspirin-intolerant
-
aspirin-induced
-
mapeg
- 1-chloro-2,4-dinitrobenzene
- montelukast
-
alox5ap
-
bronchoconstrictors
-
a23187-stimulated
-
aspirin-exacerbated
- medicine
- rbl-1
- molecular biology
- drug development
- analysis
The enzyme appears in viruses and cellular organisms
Synonyms
(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate:glutathione leukotriene-transferase (epoxide-ring-opening), EC 2.5.1.37, leukotriene A4:glutathione S-leukotrienyltransferase, leukotriene C4 synthase, leukotriene C4 synthetase, LT C4 synthase, LTC4 synthase, LTC4 synthetase, LTC4S, LTCS, 
more
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
(7E,9E,11Z,14Z)-(5S,6S)-5,6-epoxyicosa-7,9,11,14-tetraenoate:glutathione leukotriene-transferase (epoxide-ring-opening)
-
-
-
-
EC 2.5.1.37
-
-
formerly
-
leukotriene A4:glutathione S-leukotrienyltransferase
-
-
-
-
leukotriene C4 synthase
leukotriene C4 synthetase
LT C4 synthase
LTC4 synthase
LTC4 synthetase
-
-
-
-
LTC4S
synthase, leukotriene C4
-
-
-
-
leukotriene C4 synthase
-
-
-
-
leukotriene C4 synthase
-
leukotriene C4 synthetase
-
-
-
-
LTC4 synthase
-
-
-
-
LTC4 synthase
-
LTC4S
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
leukotriene C4 = leukotriene A4 + glutathione
-
-
-
-
leukotriene C4 = leukotriene A4 + glutathione
random rapid equilibrium mechanism
-
leukotriene C4 = leukotriene A4 + glutathione
the thiolate of glutathione acts as a nucleophile attacking C6 of leukotriene A4 forming a S-C6 bond, a proton is transferred from the guanidinium of Arg31 to the epoxide ring oxygen resulting in opening of the epoxide ring and stabilization of the LTC4 product complex. The tail-to-head orientation appears to be the most likely substrate orientation
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
alkenyl group transfer
additional information
alkenyl group transfer
-
-
-
-
additional information
multiple constructs encoding fusion proteins of green fluorescent protein as the N-terminal part and various truncated variants of human LTC4S as C-terminal part were prepared and transfected into HEK 293/T or COS-7 cells
additional information
-
multiple constructs encoding fusion proteins of green fluorescent protein as the N-terminal part and various truncated variants of human LTC4S as C-terminal part were prepared and transfected into HEK 293/T or COS-7 cells
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PATHWAY SOURCE
PATHWAYS
BRENDA
MetaCyc
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SYSTEMATIC NAME
IUBMB Comments
leukotriene-C4 glutathione-lyase (leukotriene-A4-forming)
The reaction proceeds in the direction of addition. Not identical with EC 2.5.1.18, glutathione transferase.
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CAS REGISTRY NUMBER
COMMENTARY
90698-32-1
-
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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
leukotriene A4 methylester + glutathione
leukotriene C4 methylester
-
pH 7.4, 37°C
-
-
r
leukotriene A4 + glutathione
leukotriene C4
glutathione-enzyme binding structure, overview
i.e. (5S)-hydroxy-(6R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid
-
?
leukotriene A4 + glutathione
leukotriene C4
-
mechanism of leukotriene A4 binding, docking and molecular dynamics simulations using the enzyme crystal structure, PDB ID 2PNO, overview
-
-
?
leukotriene A4 + glutathione
leukotriene C4
glutathione-enzyme binding structure, overview
i.e. (5S)-hydroxy-(6R)-S-glutathionyl-7,9-trans-11,14-cis-eicosatetraenoic acid
-
?
leukotriene A4 + glutathione
leukotriene C4
free acid, 4°C, pH 7.35
-
-
r
leukotriene A4 + glutathione
leukotriene C4
-
pH 7.4, room temperature
-
-
r
leukotriene A4 free acid + glutathione
leukotriene C4
-
pH 7.4, 37°C
-
-
r
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester
-
-
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester
-
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester
4°C, pH 7.35
-
-
r
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester + H2O
-
-
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester + H2O
-
-
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester + H2O
-
6.5% of the activity with leukotriene A4
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester + H2O
-
-
-
-
?
leukotriene A4 methyl ester + glutathione
leukotriene C4 methyl ester + H2O
-
-
-
-
?
additional information
?
-
binding structure of product analogue S-hexyl GSH to the active site of the enzyme, overview
-
-
?
additional information
?
-
-
binding structure of product analogue S-hexyl GSH to the active site of the enzyme, overview
-
-
?
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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
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-benzoyl-5-(5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl)benzoic acid
i.e. TK04, competitive mode of binding versus leukotriene A4
2-benzoyl-5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]benzoic acid
potent and selective inhibitor, potently inhibits cysteinyl leukotriene biosynthesis in immune cells
5-[5-[(4-chlorophenyl)(cyclopropylmethyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
compound at 6 mg/kg body weight reduces LTE4 levels in peritoneal lavage fluid by 88%and significantly decreases vascular permeability in vivo. Potent and selective inhibitor, potently inhibits cysteinyl leukotriene biosynthesis in immune cells
aspirin
blocks the STAT6-dependent interleukin-4-inducible expression of LTC4S
L-699,333
-
i.e. 2,[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]ethoxy]butanoic acid, reversible, competitive against glutathione and non-competitive against leukotriene A4
zymosan
-
increase in LTC4S activity during differentiation of monocytic Mono Mac 6 cells by presence of leukotriene A4 is reduced by 80% in the presence of zymosan. Treatment with Zymosan for 48 h similarly attenuates LTC4S activity of primary human monocyte-derived macrophages and dendritic cells
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additional information
-
cell treatment with ERK 1/2 specific inhibitor 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126) blocks LTC4S expression, pyrrolidine dithiocarbamate inhibits reactive oxygen species generation and NF-?B activation, which in turn blocks LTC4S expression
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5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
tandem benzophenone amino pyridine inhibitor
5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
potent and selective inhibitor, potently inhibits cysteinyl leukotriene biosynthesis in immune cells
leukotriene C4
-
IC50: 0.0021 mM, inhibits reaction with leukotriene C4 methyl ester
leukotriene C4
leukotriene C4 accumulation inhibits LTC4 synthase activity
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
leukotriene A4
-
presence of leukotriene A4 results in 20fold increased LTC4S activity during differentiation of monocytic Mono Mac 6 cells, which is reduced by 80% in the presence of zymosan
lipopolysaccharide
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from Escherichia coli serotype O26:B26, increases mRNA expression in heart, brain, liver and adrenal gland
additional information
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expression and activity of LTC4S is upregulated after treatment with D-galactosamine/lipopolysaccharide in a fulminant hepatic failure model
-
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.03
glutathione
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
0.04
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
0.095
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
1.2
glutathione
pH 7.8, temperature not specified in the publication, recombinant enzyme
0.07
leukotriene A4
mutant R31Q, 22°C, pH not specified in the publication
0.3
leukotriene A4
-
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
0.1
leukotriene A4
mutant R104S, 22°C, pH not specified in the publication
2.38
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
1.42
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
0.5
leukotriene A4
mutant R104A, 22°C, pH not specified in the publication
0.3
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
0.036
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant enzyme
0.05
leukotriene A4
mutant R31A, 22°C, pH not specified in the publication
additional information
additional information
Michaelis-Menten kinetics
-
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
84
glutathione
-
pH 7.8, temperature not specified in the publication, recombinant enzyme
26
glutathione
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
32
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
74.3
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
74.3
glutathione
-
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
84
glutathione
pH 7.8, temperature not specified in the publication, recombinant enzyme
17.7
leukotriene A4
-
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
12
leukotriene A4
-
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
16.8
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
17.7
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
81
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant enzyme
0.5
leukotriene A4
mutant R104S, 22°C, pH not specified in the publication
0.66
leukotriene A4
mutant R104A, 22°C, pH not specified in the publication
1.4
leukotriene A4
mutant R31A, 22°C, pH not specified in the publication
1.8
leukotriene A4
mutant R31Q, 22°C, pH not specified in the publication
11.7
leukotriene A4
wild-type, 22°C, pH not specified in the publication
12
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
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kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
68
glutathione
pH 7.8, temperature not specified in the publication, recombinant enzyme
730
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
730
glutathione
-
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
810
glutathione
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
870
glutathione
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
4.1
glutathione
wild-type, cosubstrate leukotriene A4 methyl ester, pH 7.0, 22°C
2300
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant enzyme
26
leukotriene A4
mutant R31Q, 22°C, pH not specified in the publication
1.3
leukotriene A4
mutant R104A, 22°C, pH not specified in the publication
5
leukotriene A4
mutant R104S, 22°C, pH not specified in the publication
7
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116F
11
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant mutant W116A
40
leukotriene A4
-
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
28
leukotriene A4
mutant R31A, 22°C, pH not specified in the publication
40
leukotriene A4
pH 7.8, temperature not specified in the publication, recombinant wild-type enzyme
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Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000037
2-benzoyl-5-(5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl)benzoic acid
pH 7.8, temperature not specified in the publication, recombinant enzyme
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000135
2-benzoyl-5-(5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl)benzoic acid
Mus musculus
pH 7.8, temperature not specified in the publication, recombinant enzyme
0.000116
2-benzoyl-5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]benzoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.000095
5-[5-[(4-chlorophenyl)(cyclopropylmethyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.000017 - 0.000124
5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
0.0021
leukotriene C4
Cavia porcellus
-
IC50: 0.0021 mM, inhibits reaction with leukotriene C4 methyl ester
0.000124
5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.000017
5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid
Homo sapiens
cell-free assay, the substrate LTA4 is produced in situ, 37°C, pH not specified in the publication
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.8
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pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
5 - 8.8
-
pH 5.5: about 25% of maximal activity, pH 8.8: about 45% of maximal activity
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pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional enzyme, acts as glutathione transferase and LTC4 synthase
UniProt
brenda
-
644484, 644485, 644486, 644488, 644489, 644491, 644492, 644493, 644495, 644497, 644498, 644499, 644501, 644502, 644503, 644504, 644508
-
-
brenda
-
664161, 665246, 665347, 665848, 666717, 666794, 666938, 677457, 678958, 679295, 681027, 682093, 682094
SwissProt
brenda
-
-
-
brenda
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
co-localization for 5-lipoxygenase activating protein, LTC4 synthase, cyclooxygenase-1 and prostaglandin D2 synthase in nasal biopsies. 10-43% of LTC4 synthase-positive cells being macrophages in perennial and seasonal allergic rhinitis biopsies. In the rhinitic biopsies, LTC4 synthase is detectable in 6-76% of macrophages
brenda
and tentacle, second highest expression level
brenda
and respiratory tree, second highest expression level
brenda
additional information
co-localization for 5-lipoxygenase activating protein, LTC4 synthase, cyclooxygenase-1 and prostaglandin D2 synthase in nasal biopsies, 10% of LTC4 synthase-positive cells being eosinophils in perennial and seasonal allergic rhinitis biopsies. In the rhinitic biopsies, LTC4 synthase is detectable in 19% of eosinophils
brenda
-
enzyme activity is significantly altered during the development of nephrotic serum nephritis, alterations occur during the initial inflammatory phase of the disease
brenda
-
derived from cord blood, expression of two C4 leukotriene synthase isoenzymes
brenda
co-localization for 5-lipoxygenase activating protein, LTC4 synthase, cyclooxygenase-1 and prostaglandin D2 synthase in nasal biopsies, 22-26% of LTC4 synthase-positive cells being mast cells in perennial and seasonal allergic rhinitis biopsies. In the rhinitic biopsies, LTC4 synthase is detectable in 10-38% of mast cells, but it does not localize to mast cells in the normal biopsies
brenda
additional information
ubiquitously expressed in all examined tissues
brenda
additional information
-
ubiquitously expressed in all examined tissues
brenda
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
emanating from the vasopressinergic magnocellular neurons of the hypothalamic paraventricular, supraoptic and suprachiasmatic nuclei as well as the retrochiasmatic area to the pars nervosa of the pituitary gland. It is also observed in the axons of the extrahypothalamic system
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
-
the active site of leukotriene A4 synthase is localized in the lumen of the endoplasmic reticulum
brenda
5-lipoxygenase activating protein- and LTC4S-fusion proteins co-localize
brenda
integral membrane protein in the outer leaflet of the nuclear envelope and in the endoplasmic reticulum
brenda
integral membrane protein in the outer leaflet of the nuclear envelope and in the endoplasmic reticulum
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
is localized to the outer nuclear membrane, is associated with 5-lipoxygenase activating protein and 5-lipoxygenase. Exclusion from the inner nuclear membrane
brenda
in close association with 5-lipoxygenase activating protein
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
-
the enzyme is chiefly membrane-bound, although the cytosol contains some activity
brenda
-
the active site of leukotriene A4 synthase is localized in the lumen of the nucear envelope and endoplasmic reticulum
brenda
5-lipoxygenase activating protein- and LTC4S-fusion proteins co-localize at the nuclear envelope
brenda
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
physiological function
additional information
evolution
the enzyme belongs to the superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism, which consists of six integral membrane proteins
evolution
the enzyme belongs to the superfamily of membrane-associated proteins in eicosanoid and glutathione metabolism, which consists of six integral membrane proteins. Although structural differences near the active site and along the C-terminal alpha-helix V suggest that the mouse and human enzymes may function differently in vivo
physiological function
-
A-444C polymorphism on the LTC4S gene is associated with aspirin-induced urticaria. The C allele is more frequent in patients with the cutaneous pattern of aspirin-induced urticaria and in patients with low skin reactivity to histamine. There is no association between A-444C and asthma, atopy, or total IgE levels
physiological function
LTC4S interacts in vitro with both 5-lipoxygenase activating protein and 5-lipoxygenase, these interactions involve distinct parts of LTC4S. 5-lipoxygenase activating protein binds to the N-terminal part/first hydrophobic region of LTC4S, whereas 5-lipoxygenase binds to the second hydrophilic loop of LTC4S. Direct interaction of 5-lipoxygenase and LTC4S in ionophore-stimulated (but not unstimulated) cells
physiological function
perennial allergic rhinitis biopsies show 3fold more cells immunostaining for LTC4 synthase compared with seasonal allergic rhinitis biopsies but this is not significant compared with normal biopsies, probably because normal biopsies show relatively high variability for LTC4 synthase
physiological function
-
leukotrienes are a family of drug-like molecules involved in the pathobiology of bronchial asthma and are responsible for smooth muscle contraction
physiological function
the enzyme catalyzes the conjugation reaction between the fatty acid leukotriene A4 and GSH to form the pro-inflammatory leukotriene C4, an important mediator of asthma
physiological function
the enzyme catalyzes the conjugation reaction between the fatty acid leukotriene A4 and GSH to form the pro-inflammatory leukotriene C4, an important mediator of asthma
physiological function
GST2 knock-down by specific siRNA significantly depresses LTC4 contents with 27.0 % decrease at 24 h. Reactive oxygen species levels are elevated by 40.1% in vitro. Increased expression of GST2 leads to 1.56fold increase in LTC4 synthase activity
physiological function
in coincubations of platelets and polymorphonuclear leukocytes, inhibition of LTC4S leads to shunting of LTA4 toward anti-inflammatory lipoxin A4, which is significantly enhanced by simultaneous inhibition of LTA4H
physiological function
transcellular LTC4 biosynthesis takes place between neutrophils or 5-lipoxygenase-expressing HEK293 cells that produce LTA4 from arachidonic acid and HEK293 cells expressing LTC4S that transform LTA4 to LTC4
additional information
enzyme residue Trp116 is not essential for catalysis but helps position the omega-end of leukotriene A4
additional information
-
enzyme residue Trp116 is not essential for catalysis but helps position the omega-end of leukotriene A4
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). LTC4S_BOVIN
150
3
16701
Swiss-Prot
Secretory Pathway (Reliability: 1)
LTC4S_CAVPO
150
3
16748
Swiss-Prot
Secretory Pathway (Reliability: 2)
LTC4S_HUMAN
150
3
16567
Swiss-Prot
Secretory Pathway (Reliability: 1)
LTC4S_MOUSE
150
3
16814
Swiss-Prot
Secretory Pathway (Reliability: 1)
LTC4S_RAT
150
3
16850
Swiss-Prot
Secretory Pathway (Reliability: 1)
GSTM4_HUMAN
218
0
25561
Swiss-Prot
other Location (Reliability: 5)
GSTM4_MOUSE
218
0
25519
Swiss-Prot
other Location (Reliability: 5)
GSTM4_RAT
218
0
25553
Swiss-Prot
other Location (Reliability: 5)
MGST2_BOVIN
146
2
16483
Swiss-Prot
Secretory Pathway (Reliability: 2)
MGST2_HUMAN
147
2
16621
Swiss-Prot
Secretory Pathway (Reliability: 2)
MGST2_MOUSE
147
2
16786
Swiss-Prot
Secretory Pathway (Reliability: 2)
MGST3_HUMAN
152
4
16516
Swiss-Prot
Secretory Pathway (Reliability: 3)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
18000
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
trimer
additional information
trimer
-
the enzyme exists as a trimer, where the active site is formed at the interface of two of the three monomers
additional information
forms homo-oligomers of LTCS fusion proteins with Renilla luciferase
additional information
-
forms homo-oligomers of LTCS fusion proteins with Renilla luciferase
additional information
-
the major components migrate as 18000 Da, 37000 Da, 48000 Da and 60000 Da proteins in SDS-PAGE
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphoprotein
-
phosphoregulation of LTC4S, as increased activity during MM6 cell differentiation correlates with reduced phosphorylation of 70-kDa ribosomal protein S6 kinase, which can phosphorylate purified LTC4S. The ribosomal protein S6 kinase inhibitor rapamycin at 20 nM doubles LTC4S activity of undifferentiated MM6 cells, and protein kinase A and C inhibitors H-89, CGP-53353, and staurosporine reverse the zymosan-induced suppression of LTC4S activity
phosphoprotein
residue Ser36 is the major p70S6k phosphorylation site, along with a low frequency site at Thr40
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified enzyme in apoform or in complex with either one of three product analogues, S-hexyl-, 4-phenyl-butyl-, and 2-hydroxy-4-phenyl-butyl-glutathione, sitting drop vapor diffusion, mixing of 0.001 ml of 3.5 mg/ml protein solution containing 1 mM GSH with 0.001 ml of reservoir solution containing 1.8-2.2 M NH4SO4, 0.2 M NaCl, and 0.1 M sodium cacodylate, pH 6.1-6.8, 1-4 days, room temperature, soaking in 1 mM ligand solutions, X-ray diffraction structure determination and analysis at 2.4-3.2 A resolution
-
wild-type to 1.9 A resolution, space group F23. Mutants R31A and R104A, space groups F23 and C222, respectively. The architecture for GSH binding is conserved. The GSH binding site is a V-shaped cleft at each intermonomer interface in the LTC4S trimer, and nine amino acid residues directly participate in the GSH binding. Residue R30 multiply binds the carboxyl group of the gamma-glutamyl moiety, and R104 interacts with both the thiol group and the carbonyl group of the cysteinyl moiety of GSH. The side chain of R31 is flexible in the crystal structure
the interaction of residue R104 with the thiol group of GSH reduces its pKa to allow formation of a thiolate anion and subsequent nucleophilic attack at C6 of LTA4.Crystal structure of mutant R31Q at 2.1 A reveals a Q31 side chain pointing away from the active site
comparative molecular dynamic analysis. Residue Ser36 upon phosphorylation will pull the first luminal loop of LTC4S toward the neighboring subunit of the functional homotrimer, thereby forming hydrogen bonds with catalytic residue Arg104 in the adjacent subunit. The phosphorylation-induced interaction leads to a reduction of the catalytic activity
purified enzyme in apoform or in complex with either one of three product analogues, S-hexyl-, 4-phenyl-butyl-, and 2-hydroxy-4-phenyl-butyl-glutathione, sitting drop vapor diffusion, mixing of 0.001 ml of 3.5 mg/ml protein solution containing 1 mM GSH with 0.001 ml of reservoir solution containing 1.8-2.2 M NH4SO4, 0.2 M NaCl, and 0.1 M sodium cacodylate, pH 6.1-6.8, 1-4 days, room temperature, soaking in 1 mM ligand solutions, X-ray diffraction structure determination and analysis at 2.4-3.2 A resolution
molecular docking of inhibitors 2-benzoyl-5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]benzoic acid, 5-[5-[(4-chlorophenyl)(methyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid, 5-[5-[(4-chlorophenyl)(cyclopropylmethyl)amino]pyridine-2-carbonyl]-2-(4-methoxybenzoyl)benzoic acid. Inhibitors interact with catalytic residues R104 and R31
LTC4S crystallized with glutathione, The structure is determined by the multiwavelength anomalous diffraction method by using the diffraction images from native LTC4S and a selenomethionine-substituted Leu121Met mutant
large number of parameters are important in obtaining big and well-ordered 2D crystals of LTC4S. Order can be induced by a combination of dividing/selecting fractions during the purification as well as a low lipid-to-protein ratio. To obtain a favorable diameter, salt (optimal: 50 mM), temperature (optimal: 23-24°C), glycerol (optimal: 20%), and initial detergent concentration (optimal: 1%) have to be controlled. Several crystal forms can be grown, namely the plane group symmetries of p2, p3, p312, and two different unit cell sizes of plane group symmetry p321 with unit cell dimensions of a = b = 73.4 A, c = 120 and the second p321 type with larger unit cell size of a = b = 83.0 A, c = 120. Four transmembrane alpha-helices present, to 7.5 A resolution
-
its apo and GSH-complexed forms to 2.00 and 2.15 A resolution, using the sitting drop vapour diffusion technique
purified enzyme in apoform or in complex with substrate glutathione or product analogue S-hexyl-GSH, mixing of 0.001 ml of 3.5 mg/ml protein in 0.03% w/v DDM w/v, 20 mM Tris pH 8.0, 100 mM NaCl, and 0.5 mM TCEP, with or without 1 mM GSH, with 0.001 ml of reservoir solution containing 1.8-2.2 M NH4SO4, 0.2 M NaCl and 0.1 M Na cacodylate pH 6.1-6.8, for S-hexyl GSH-enzyme crystals, S-hexyl GSH is added to mother liquor and soaking of apo-crystals, X-ray diffraction structure determination and analysis at 2.65-2.7 A resolution
sitting drop vapour diffusion method using the MbClass and MbClass II suites
-
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
R51I
R90A
substrate leukotriene A4, 6% of wild-type activity, substrate leukotriene A4 methyl ester, 21% ot wild-type activity
R31Q
R31A
W116A
site-directed mutagenesis, altered kinetics compared to the wild-type enzyme
Y97F
-
mutation increases the Km-value for the recombinant enzyme for glutathione
Y93F
Y59F
-
mutation increases the Km-value for the recombinant enzyme for glutathione
W116F
site-directed mutagenesis, the mutant shows a 3fold increased turnover of leukotriene A4 compared to the wild-type enzyme
W116A
-
site-directed mutagenesis, altered kinetics compared to the wild-type enzyme
V49F
-
mutation increases the Km-value for the recombinant enzyme for glutathione
S36E
phosphomimetic mutant, displays about 20 % of wild-type activity. Mutant shows poor lipid substrate binding
L121M
-
by site-directed mutagenesis to prepare the selenomethionine-substituted LTC4S, the mutant yeast clone is grown with selenomethionine, purified and crystallized similarly to the wild-type enzyme
LTCS(114-150)
N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(1-88)
C-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(1-58)
C-terminally truncated protein, gives no bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(1-24)
C-terminally truncated protein, gives no bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(1-115)
C-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(23-115)
C- and N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
L121M
by site-directed mutagenesis to prepare the selenomethionine-substituted LTC4S, the mutant yeast clone is grown with selenomethionine, purified and crystallized similarly to the wild-type enzyme
G1072A
-
the mutation is associated with the risk of ischemic cerebrovascular disease
E4K
causes allergic diseases in patients such as bronchial asthma or allergic dermatitis
C56S
A52S
-
mutation increases the Km-value for the recombinant enzyme for glutathione
N55A
-
mutation increases the Km-value for the recombinant enzyme for glutathione
R104Q
substrate leukotriene A4, 2% of wild-type activity. No activity with substrate leukotriene A4 methyl ester
R104A
N55A
-
mutation increases the Km-value for the recombinant enzyme for glutathione
A444C
-
the mutation is associated with the risk of ischemic cerebrovascular disease
LTCS(87-150)
N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(57-150)
N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(23-150)
N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
LTCS(23-115)
-
C- and N-terminally truncated protein, gives a bioluminescence resonance energy transfer signal when fused to Renilla luciferase
additional information
R31A
substrate leukotriene A4, 6% of wild-type activity. No activity with substrate leukotriene A4 methyl ester
Y93F
reduces the enzyme activity to less than 1% of the wild-type enzyme, shift in the pH-optimum
Y93F
-
activity of the mutant enzyme is less than 1% of the wild-type enzyme, shift in pH optimum of the residual activity to that of spontaneous conjugation
Y93F
-
mutation increases the Km-value for the recombinant enzyme for glutathione
R104A
substrate leukotriene A4, 2% of wild-type activity. No activity with substrate leukotriene A4 methyl ester
additional information
-
resequencing the gene coding for leukotriene C4 synthase in an population with extreme risk of venous thromboembolism, ischemic stroke and myocardial infarction, among more than 1500 individuals, reveals 17 unknown mutations, of which four are likely to change protein function, i.e. 211G>A, with minor allele frequency, IVS3 + 1G>A, 374G>A and 451_453+10del. Age and sex adjusted odds ratios for venous thromboembolism are 2.0 for IVS3+1G>A heterozygotes versus wild-type, and 1.9 for any mutation heterozygote versus wild-type. Corresponding values are 2.0 and 1.5 for ischemic stroke, and 1.0 and 1.2 for myocardial infarction
additional information
-
the LTC4S2 variant in LTC4 confers a 1.807fold increase in stroke when present at 2 copies, whereas the LTBR_2 variant in the LTB4R/LTB4R2 gene region confers a 1.671fold increase in stroke risk when present at 1 or more copies, LTBR_2 and LTBR_6, confer relative risks of 2.371 and 2.081 in cardioembolic stroke, variants in leukotriene C4 synthase confer a 1.5fold increase in risk of small vessel disease
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TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
-
3 min, 50 min loss of activity, 10 mM glutathione completely protects against inactivation
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
partially purified enzyme requires substrate stabilization for long-term storage
-
reduced glutathione irreversibly inactivates the enzyme when present during freeze/thaw cycles and storage at concentrations above 5 mM
-
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, enzyme in the membrane fraction from human platelets can be stored without major loss of activity
-
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
affinity chromatography purification based on specific interaction between leukotriene C4 synthase and microsomal glutathione S-transferase which ocurs in the presence of magnesium ion
-
extraction with a Triton X-100/Triton-DOC mixture, two affinity chromatography steps and gel filtration
Ni-Sepharose column chromatography, S-hexylglutathione agarose chromatography, and Superdex 200 gel filtration
-
partial
solubilized with sodium deoxycholic acid and DDM, four steps of column chromatography, including affinity chromatography with S-hexyl GSH
the recombinant enzyme from Schizosaccharomyces pombe, to apparent homogeneity
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
COS-7 cells transfected with either human or cloned mouse leukotriene C4 synthase cDNA by DEAE-dextran transfection
expressed as an N-terminal hexa-histidine-tagged fusion protein in Pichia pastoris KM71H cells
-
expression in Escherichia coli, construction of an enhanced green fluorescent protein under the control of the mouse leukotriene C4 synthase promoter
preparation of pRluc-LTC4S and pGFPLTC4S (full length and truncated forms). Full length and truncated forms of LTC4S excised from the pGFP vector and subcloned in frame with GST in a pGEX vector and transformed into Escherichia coli Y1090. Full length LTC4S subcloned into a pDsRed vector. HEK 293/T cells co-transfected with pRluc-LTC4S and pGFP fusion constructs. COS-7 cells co-transfected with GFP-5-lipoxygenase activating protein and dsRed-LTC4S
recombinant expression of wild-type and mutant enzymes in Pichia pastoris strain KM71H
COS-7 cells transfected with either human or cloned mouse leukotriene C4 synthase cDNA by DEAE-dextran transfection
-
COS-7 cells transfected with either human or cloned mouse leukotriene C4 synthase cDNA by DEAE-dextran transfection
-
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
hepatic mRNA expression of LTC4S is decreased in presence of NO donor O2-vinyl-1-(pyrrolidin-1-yl)-diazen-1-ium-1,2-diolate, i.e. V-PYRRO/NO. Downregulation may occur via inhibiting NF-kappaB activation independent of IkappaBalpha during hepatic ischemia/reperfusion injury
G3V6E6
LTC4s increases following spared nerve injury, significant increase 3 days after nerve injury and continues at least for 14 days. LTC4s mRNA is expressed constitutively throughout the grey matter and increases after nerve injury in dorsal horn. This increase in LTC4s mRNA mainly occurrs in cells with small nuclei
mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase, 5-LO-activating protein, and LTC4 synthase, are significantly increased in the wall of human abdominal aortic aneurysm
-
significantly elevated immunoexpression of LTC4 synthase observed in perennial allergic rhinitis biopsies
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
drug development
medicine
molecular biology
analysis
-
although structural differences near the active site and along the C-terminal alpha-helix V suggest that the mouse and human enzymes may function differently in vivo, the mouse enzyme is a useful tool in pharmacological research and drug development
analysis
cell-free and cell-based assay systems based on in situ-generated LTA4 that allow studying LTC4S activity and investigating LTC4S inhibitors
analysis
although structural differences near the active site and along the C-terminal alpha-helix V suggest that the mouse and human enzymes may function differently in vivo, the mouse enzyme is a useful tool in pharmacological research and drug development
drug development
leukotrienes are an important therapeutic target in asthma and inflammatory diseases
drug development
although structural differences near the active site and along the C-terminal alpha-helix V suggest that the mouse and human enzymes may function differently in vivo, the mouse enzyme is a useful tool in pharmacological research and drug development
medicine
-
(-1072)GNA and (-444)ANC promoter polymorphisms of LTC4 synthase influence risk of transient ischemic attack and ischemic stroke, but not risk of ischemic heart disease/coronary atherosclerosis, asthma, or chronic obstructive pulmonary disease in a Danish population. The (-1072)A allele has a frequency of 0.07 while the (-444)C allele has a frequency of 0.29. The (-1072)A and (-444)C alleles are on different haplotypes, thus one polymorphism cannot tag the other. Genetically altered leukotriene C4 synthase activity may play a role in thrombi formation rather than the development of atherosclerosis
medicine
-
sodium nitroprusside inhibits leukotriene C4 synthase activity and dwonregulates the protein expression of the enzyme
-
medicine
-
resequencing the gene coding for leukotriene C4 synthase in an population with extreme risk of venous thromboembolism, ischemic stroke and myocardial infarction, among more than 1500 individuals, reveals 17 unknown mutations, of which four are likely to change protein function, i.e. 211G>A, with minor allele frequency, IVS3 + 1G>A, 374G>A and 451_453+10del. Age and sex adjusted odds ratios for venous thromboembolism are 2.0 for IVS3+1G>A heterozygotes versus wild-type, and 1.9 for any mutation heterozygote versus wild-type. Corresponding values are 2.0 and 1.5 for ischemic stroke, and 1.0 and 1.2 for myocardial infarction
medicine
-
mRNA levels for the three key enzymes/proteins in the biosynthesis of cysteinyl-leukotrienes, 5-lipoxygenase, 5-LO-activating protein, and LTC4 synthase, are significantly increased in the wall of human abdominal aortic aneurysm. Immunohistochemical staining reveals focal expression of 5-lipoxygenase, 5-LO-activating protein, and LTC4 synthase proteins in the media and adventitia, localized in areas rich in inflammatory cells, including macrophages, neutrophils, and mast cells. Challenge of abdominal aortic aneurysm wall tissue with exogenous LTD4 increases the release of matrix metalloproteinases 2 and 9, and selective inhibition of the CysLT1 receptor by montelukast blocks this effect
medicine
-
the C allele of the A-444C polymorphism is a risk factor for aspirin-induced urticaria in a Venezuelan population and may be a genetic marker for this phenotype. This single-nucleotide polymorphism is mainly associated with the cutaneous clinical pattern and with low skin response to histamine
medicine
aspirin desensitization may provide effective therapy for aspirin-exacerbated respiratory disease, at least in part, through mitigation of STAT6 expression, thereby downregulating LTC4S pathways
medicine
(-1072)GNA and (-444)ANC promoter polymorphisms of LTC4 synthase influence risk of transient ischemic attack and ischemic stroke, but not risk of ischemic heart disease/coronary atherosclerosis, asthma, or chronic obstructive pulmonary disease in a Danish population. The (-1072)A allele has a frequency of 0.07 while the (-444)C allele has a frequency of 0.29. The (-1072)A and (-444)C alleles are on different haplotypes, thus one polymorphism cannot tag the other. Genetically altered leukotriene C4 synthase activity may play a role in thrombi formation rather than the development of atherosclerosis
medicine
-
sodium nitroprusside inhibits leukotriene C4 synthase activity and dwonregulates the protein expression of the enzyme
medicine
damaged or inflamed bronchial epithelium may synthesize leukotrienes that contribute directly to bronchoconstriction and leucocytosis in airway inflammation, LTC4 synthase is constitutively expressed in primary bronchial epithelial cells and in the 16-HBE 14o-cell line
medicine
aspirin induced urticaria aggregates in families inheriting the LTC4S -444C allele
molecular biology
the third hydrophobic region, containing a putative transmembrane helix, acts as a nuclear envelope localization signal and is involved in the homooligomerization of LTC4S
molecular biology
TNF-alpha exposure downregulates the LTC4 synthase gene expression in monocytes/macrophages via a transcriptional mechanism
molecular biology
TNF-alpha exposure downregulates the LTC4 synthase gene expression in monocytes/macrophages via a transcriptional mechanism
molecular biology
transient transfection into human monocytic leukemia (THP-1), rat basophilic leukemia (RBL-1), and human embryonic kidney (HEK293/T) epithelial cells show that eGFP was expressed by cells which express leukotriene C4 synthase (RBL-1 and THP-1) but not by the leukotriene C4 synthase negative HEK293/T cells
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sala, A.; Garcia, M.; Zarini, S.; Rossi, J.C.; Folco, G.; Durand, T.
14,15-dehydroleukotriene A4: a specific substrate for leukotriene C4 synthase
Biochem. J.
328
225-229
1997
Homo sapiens
-
brenda
Penrose, J.F.
LTC4 synthase: Enzymology, biochemistry, and molecular characterization
Clin. Rev. Allergy Immunol.
17
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1999
Homo sapiens
brenda
Penrose, J.F.; Austen, K.F.
The biochemical, molecular, and genomic aspects of leukotriene C4 synthase
Proc. Assoc. Am. Phys.
111
537-546
1999
Cavia porcellus, Homo sapiens, Mus musculus
-
brenda
Hevko, J.M.; Murphy, R.C.
Formation of murine macrophage-derived 5-oxo-7-glutathionyl-8,11,14-eicosatrienoic acid (FOG7) is catalyzed by leukotriene C4 synthase
J. Biol. Chem.
277
7037-7043
2002
Mus musculus
brenda
Sjostrom, M.; Jakobsson, P.J.; Juremalm, M.; Ahmed, A.; Nilsson, G.; Macchia, L.; Haeggstrom, J.Z.
Human mast cells express two leukotriene C4 synthase isoenzymes and the CysLT1 receptor
Biochim. Biophys. Acta
1583
53-62
2002
Homo sapiens
brenda
Gupta, N.; Gresser, M.J.; Ford-Hutchinson, A.W.
Kinetic mechanism of glutathione conjugation to leukotriene A4 by leukotriene C4 synthase
Biochim. Biophys. Acta
1391
157-168
1998
Homo sapiens
brenda
Söderström, M.; Hammarström, S.; Mannervik, B.
Leukotriene C synthase in mouse mastocytoma cells. An enzyme distinct from cytosolic and microsomal glutathione transferases
Biochem. J.
250
713-718
1988
Mus musculus
brenda
Christmas, P.; Weber, B.M.; McKee, M.; Brown, D.; Soberman, R.J.
Membrane localization and topology of leukotriene C4 synthase
J. Biol. Chem.
277
28902-28908
2002
Homo sapiens
brenda
Nicholson, D.W.; Ali, A.; Vaillancourt, J.P.; Calaycay, J.R.; Mumford, R.A.; Zamboni, R.J.; Ford-Hutchinson, A.W.
Purification to homogeneity and the N-terminal sequence of human leukotriene C4 synthase: a homodimeric glutathione S-transferase composed of 18-kDa subunits
Proc. Natl. Acad. Sci. USA
90
2015-2019
1993
Homo sapiens
brenda
Nicholson, D.W.; Ali, A.; Klemba, M.W.; Munday, N.A.; Zamboni, R.J.; Ford-Hutchinson, A.W.
Human leukotriene C4 synthase expression in dimethyl sulfoxide-differentiated U937 cells
J. Biol. Chem.
267
17849-17857
1992
Homo sapiens, Rattus norvegicus
brenda
Abe, M.; Hugli, T.E.
Characterization of leukotriene C4 synthetase in mouse peritoneal exudate cells
Biochim. Biophys. Acta
959
386-398
1988
Mus musculus
brenda
Soederstroem, M.; Morgenstern, R.; Hammarstroem, S.
Protein-protein interaction affinity chromatography of leukotriene C4 synthase
Protein Expr. Purif.
6
352-356
1995
Homo sapiens, Mus musculus
brenda
Izumi, T.; Honda, Z.; Ohishi, N.; Kitamura, S.; Tsuchida, S.; Sato, K.; Shimizu, T.; Seyama, Y.
Solubilization and partial purification of leukotriene C4 synthase from guinea-pig lung: a microsomal enzyme with high specificity towards 5,6-epoxide leukotriene A4
Biochim. Biophys. Acta
959
305-315
1988
Cavia porcellus, Rattus norvegicus
brenda
Goppelt-Struebe, M.
Two step purification of human and murine leukotriene C4 synthase
Biochim. Biophys. Acta
1256
257-261
1995
Homo sapiens, Mus musculus
brenda
Söderström, M.; Mannervik, B.; Garkov, V.; Hammarström, S.
On the nature of leukotriene C4 synthase in human platelets
Arch. Biochem. Biophys.
294
70-74
1992
Homo sapiens
brenda
Lam, B.K.; Frank Austen, K.
Leukotriene C4 synthase: a pivotal enzyme in cellular biosynthesis of the cysteinyl leukotrienes
Prostaglandins Other Lipid Mediat.
68-69
511-520
2002
Cavia porcellus, Homo sapiens, Mus musculus, Rattus norvegicus
brenda
Yoshimoto, T.; Soberman, R.J.; Lewis, R.A.; Austen, K.F.
Isolation and characterization of leukotriene C4 synthetase of rat basophilic leukemia cells
Proc. Natl. Acad. Sci. USA
82
8399-8403
1985
Rattus norvegicus
brenda
Tornhamre, S.; Sjolinder, M.; Lindberg, A.; Ericsson, I.; Nasman-Glaser, B.; Griffiths, W.J.; Lindgren, J.A.
Demonstration of leukotriene-C4 synthase in platelets and species distribution of the enzyme activity
Eur. J. Biochem.
251
227-235
1998
Bos taurus, Oryctolagus cuniculus, Equus caballus, Ovis aries, Homo sapiens, no activity in Sus scrofa, Rattus norvegicus
brenda
Wu, C.
Conversion of leukotrienes A4 to C4 in cell-free systems
Biochem. Biophys. Res. Commun.
134
85-92
1986
Cavia porcellus, Homo sapiens, Rattus norvegicus
brenda
Penrose, J.F.; Gagnon, L.; Goppelt-Struebe, M.; Myers, P.; Lam, B.K.; Jack, R.M.; Austen, K.F.; Soberman, R.J.
Purification of human leukotriene C4 synthase
Proc. Natl. Acad. Sci. USA
89
11603-11606
1992
Homo sapiens
brenda
Nicholson, D.W.; Klemba, M.W.; Rasper, D.M.; Metters, K.M.; Zamboni, R.J.
Purification of human leukotriene C4 synthase from dimethylsulfoxide-differentiated U937 cells
Eur. J. Biochem.
209
725-734
1992
Homo sapiens
brenda
Soberman, R.J.; Yoshimoto, T.
Leukotriene C4 synthase from rat basophilic leukemia cell microsomes
Methods Enzymol.
163
353-357
1988
Rattus norvegicus
brenda
Soberman, R.J.
Purification and properties of leukotriene C4 synthase from guinea pig lung microsomes
Methods Enzymol.
187
335-337
1990
Cavia porcellus
brenda
Söderström, M.; Mannervik, B.; Mammarström, S.
Leukotriene C4 synthase: characterization in mouse mastocytoma cells
Methods Enzymol.
187
306-312
1990
Mus musculus
brenda
Lam, B.K.; Penrose, J.F.; Rokach, J.; Xu, K.; Baldasaro, M.H.; Austen, K.F.
Molecular cloning, expression and characterization of mouse leukotriene C4 synthase
Eur. J. Biochem.
238
606-612
1996
Homo sapiens, Mus musculus
brenda
Bach, M.K.; Brashler, J.R.; Morton, D.R.
Solubilization and characterization of the leukotriene C4 synthetase of rat basophil leukemia cells: a novel, particulate glutathione S-transferase
Arch. Biochem. Biophys.
230
455-465
1984
Rattus norvegicus
brenda
Petric, R.; Nicholson, D.W.; Ford-Hutchinson, A.W.
Renal leukotriene C4 synthase: characterization, partial purification and alterations in experimental glomerulonephritis
Biochim. Biophys. Acta
1254
207-215
1995
Rattus norvegicus
brenda
Schroder, O.; Sjostrom, M.; Qiu, H.; Stein, J.; Jakobsson, P.J.; Haeggstrom, J.Z.
Molecular and catalytic properties of three rat leukotriene C4 synthase homologs
Biochem. Biophys. Res. Commun.
312
271-276
2003
Rattus norvegicus (Q925U2)
brenda
Svartz, J.; Blomgran, R.; Hammarstrom, S.; Soderstrom, M.
Leukotriene C4 synthase homo-oligomers detected in living cells by bioluminescence resonance energy transfer
Biochim. Biophys. Acta
1633
90-95
2003
Homo sapiens (Q16873), Homo sapiens
brenda
Schroder, O.; Sjostrom, M.; Qiu, H.; Jakobsson, P.J.; Haeggstrom, J.Z.
Microsomal glutathione S-transferases: selective up-regulation of leukotriene C4 synthase during lipopolysaccharide-induced pyresis
Cell. Mol. Life Sci.
62
87-94
2005
Rattus norvegicus
brenda
Yoshikawa, K.; Matsui, E.; Kaneko, H.; Fukao, T.; Inoue, R.; Teramoto, T.; Shinoda, S.; Fukutomi, O.; Aoki, M.; Kasahara, K.; Kondo, N.
A novel single-nucleotide substitution, Glu 4 Lys, in the leukotriene C4 synthase gene associated with allergic diseases
Int. J. Mol. Med.
16
827-831
2005
Homo sapiens (Q16873), Homo sapiens
brenda
Zaitsu, M.; Hamasaki, Y.; Matsuo, M.; Ichimaru, T.; Fujita, I.; Ishii, E.
Leukotriene synthesis is increased by transcriptional up-regulation of 5-lipoxygenase, leukotriene A4 hydrolase, and leukotriene C4 synthase in asthmatic children
J. Asthma
40
147-154
2003
Homo sapiens (Q16873), Homo sapiens
brenda
Abe, M.; Shibata, K.; Urata, H.; Sakata, N.; Katsuragi, T.
Induction of leukotriene C4 synthase after the differentiation of rat basophilic leukemia cells with retinoic acid and a low dose of actinomycin D and its suppression with methylprednisolone
J. Cell. Physiol.
196
154-164
2003
Rattus norvegicus
brenda
Mansour, M.; Tornhamre, S.
Inhibition of 5-lipoxygenase and leukotriene C4 synthase in human blood cells by thymoquinone
J. Enzyme Inhib. Med. Chem.
19
431-436
2004
Homo sapiens (Q16873), Homo sapiens
brenda
Shimada, A.; Satoh, M.; Chiba, Y.; Saitoh, Y.; Kawamura, N.; Keino, H.; Hosokawa, M.; Shimizu, T.
Highly selective localization of leukotriene C4 synthase in hypothalamic and extrahypothalamic vasopressin systems of mouse brain
Neuroscience
131
683-689
2005
Mus musculus (Q60860), Mus musculus
brenda
Mandal, A.K.; Skoch, J.; Bacskai, B.J.; Hyman, B.T.; Christmas, P.; Miller, D.; Yamin, T.t.D.; Xu, S.; Wisniewski, D.; Evans, J.F.; Soberman, R.J.
The membrane organization of leukotriene synthesis
Proc. Natl. Acad. Sci. USA
101
6587-6592
2004
Homo sapiens (Q16873)
brenda
Lam, B.K.
Leukotriene C4 synthase
Prostaglandins Leukot. Essent. Fatty Acids
69
111-116
2003
Homo sapiens (Q16873)
brenda
Schmidt-Krey, I.; Kanaoka, Y.; Mills, D.J.; Irikura, D.; Haase, W.; Lam, B.K.; Austen, K.F.; Kuehlbrandt, W.
Human leukotriene C4 synthase at 4.5.ANG. resolution in projection
Structure
12
2009-2014
2004
Homo sapiens (Q16873)
brenda
Serio, K.J.; Luo, C.; Luo, L.; Mao, J.T.
TNF-alpha downregulates the leukotriene C4 synthase gene in mononuclear phagocytes
Am. J. Physiol.
292
L215-L222
2007
Homo sapiens (Q16873), Homo sapiens
brenda
Serio, K.J.; Luo, C.; Luo, L.; Mao, J.T.
TNF-alpha downregulates the leukotriene C4 synthase gene in mononuclear phagocytes
Am. J. Physiol. Lung Cell Mol. Physiol.
292
L215-L222
2007
Mus musculus (Q60860), Mus musculus
brenda
Strid, T.; Soederstroem, M.; Hammarstroem, S.
Leukotriene C4 synthase promoter driven expression of GFP reveals cell specificity
Biochem. Biophys. Res. Commun.
366
80-85
2008
Mus musculus (Q60860), Mus musculus
brenda
Yang, S.L.; Lou, Y.J.
Sodium nitroprusside decreased leukotriene C4 generation by inhibiting leukotriene C4 synthase expression and activity in hepatic ischemia-reperfusion injured rats
Biochem. Pharmacol.
73
724-735
2007
Rattus norvegicus, Rattus norvegicus Sprague-Dawley
brenda
Mastalerz, L.; Setkowicz, M.; Sanak, M.; Rybarczyk, H.; Szczeklik, A.
Familial aggregation of aspirin-induced urticaria and leukotriene C synthase allelic variant
Br. J. Dermatol.
154
256-260
2006
Homo sapiens (Q16873), Homo sapiens
brenda
Jame, A.J.; Lackie, P.M.; Cazaly, A.M.; Sayers, I.; Penrose, J.F.; Holgate, S.T.; Sampson, A.P.
Human bronchial epithelial cells express an active and inducible biosynthetic pathway for leukotrienes B4 and C4
Clin. Exp. Allergy
37
880-892
2007
Homo sapiens (Q16873), Homo sapiens
brenda
Svartz, J.; Hallin, E.; Shi, Y.; Soederstroem, M.; Hammarstroem, S.
Identification of regions of leukotriene C4 synthase which direct the enzyme to its nuclear envelope localization
J. Cell. Biochem.
98
1517-1527
2006
Homo sapiens (Q16873), Homo sapiens
brenda
Ago, H.; Kanaoka, Y.; Irikura, D.; Lam, B.K.; Shimamura, T.; Austen, K.F.; Miyano, M.
Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis
Nature
448
609-612
2007
Homo sapiens (Q16873), Homo sapiens
brenda
Martinez Molina, D.; Wetterholm, A.; Kohl, A.; McCarthy, A.A.; Niegowski, D.; Ohlson, E.; Hammarberg, T.; Eshaghi, S.; Haeggstroem, J.Z.; Nordlund, P.
Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase
Nature
448
613-616
2007
Homo sapiens (Q16873), Homo sapiens
brenda
Freiberg, J.J.; Tybjaerg-Hansen, A.; Sillesen, H.; Jensen, G.B.; Nordestgaard, B.G.
Promotor polymorphisms in leukotriene C4 synthase and risk of ischemic cerebrovascular disease
Arterioscler. Thromb. Vasc. Biol.
28
990-996
2008
Homo sapiens
brenda
Ma, K.; Zhang, Y.; Zhu, D.; Lou, Y.
Protective effects of asiatic acid against D-galactosamine/lipopolysaccharide-induced hepatotoxicity in hepatocytes and kupffer cells co-cultured system via redox-regulated leukotriene C4 synthase expression pathway
Eur. J. Pharmacol.
603
98-107
2009
Rattus norvegicus
brenda
Sveinbjoernsson, B.; Rasmuson, A.; Baryawno, N.; Wan, M.; Pettersen, I.; Ponthan, F.; Orrego, A.; Haeggstroem, J.Z.; Johnsen, J.I.; Kogner, P.
Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy
FASEB J.
22
3525-3536
2008
Homo sapiens
brenda
Wetterholm, A.; Martinez Molina, D.; Nordlund, P.; Eshaghi, S.; Haeggstroem, J.Z.
High-level expression, purification, and crystallization of recombinant rat leukotriene C4 synthase from the yeast Pichia pastoris
Protein Expr. Purif.
60
1-6
2008
Rattus norvegicus
brenda
Bevan, S.; Dichgans, M.; Wiechmann, H.E.; Gschwendtner, A.; Meitinger, T.; Markus, H.S.
Genetic variation in members of the leukotriene biosynthesis pathway confer an increased risk of ischemic stroke: a replication study in two independent populations
Stroke
39
1109-1114
2008
Homo sapiens
brenda
Ma, K.F.; Yang, H.Y.; Chen, Z.; Qi, L.Y.; Zhu, D.Y.; Lou, Y.J.
Enhanced expressions and activations of leukotriene C4 synthesis enzymes in D-galactosamine/lipopolysaccharide-induced rat fulminant hepatic failure model
World J. Gastroenterol.
14
2748-2756
2008
Rattus norvegicus
brenda
Strid, T.; Svartz, J.; Franck, N.; Hallin, E.; Ingelsson, B.; Soederstroem, M.; Hammarstroem, S.
Distinct parts of leukotriene C(4) synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein
Biochem. Biophys. Res. Commun.
381
518-522
2009
Homo sapiens (Q16873)
brenda
Westergren, V.S.; Wilson, S.J.; Penrose, J.F.; Howarth, P.H.; Sampson, A.P.
Nasal mucosal expression of the leukotriene and prostanoid pathways in seasonal and perennial allergic rhinitis
Clin. Exp. Allergy
39
820-828
2009
Homo sapiens (Q16873)
brenda
Okubo, M.; Yamanaka, H.; Kobayashi, K.; Noguchi, K.
Leukotriene synthases and the receptors induced by peripheral nerve injury in the spinal cord contribute to the generation of neuropathic pain
Glia
58
599-610
2010
Rattus norvegicus (Q925U2)
brenda
Steinke, J.W.; Culp, J.A.; Kropf, E.; Borish, L.
Modulation by aspirin of nuclear phospho-signal transducer and activator of transcription 6 expression: Possible role in therapeutic benefit associated with aspirin desensitization
J. Allergy Clin. Immunol.
124
724-730
2009
Homo sapiens (Q16873)
brenda
Newcomer, M.E.; Gilbert, N.C.
Location, location, location: compartmentalization of early events in leukotriene biosynthesis
J. Biol. Chem.
285
25109-25114
2010
Homo sapiens (Q16873)
brenda
Sanchez-Borges, M.; Acevedo, N.; Vergara, C.; Jimenez, S.; Zabner-Oziel, P.; Monzon, A.; Caraballo, L.
The A-444C polymorphism in the leukotriene C4 synthase gene is associated with aspirin-induced urticaria
J. Investig. Allergol. Clin. Immunol.
19
375-382
2009
Homo sapiens
brenda
Freiberg, J.J.; Dahl, M.; Tybjaerg-Hansen, A.; Grande, P.; Nordestgaard, B.G.
Leukotriene C4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals
J. Mol. Cell. Cardiol.
46
579-586
2009
Homo sapiens (Q16873), Homo sapiens
brenda
Zhao, G.; Johnson, M.C.; Schnell, J.R.; Kanaoka, Y.; Haase, W.; Irikura, D.; Lam, B.K.; Schmidt-Krey, I.
Two-dimensional crystallization conditions of human leukotriene C4 synthase requiring adjustment of a particularly large combination of specific parameters
J. Struct. Biol.
169
450-454
2010
Homo sapiens
brenda
Esser, J.; Gehrmann, U.; Salvado, M.D.; Wetterholm, A.; Haeggstroem, J.Z.; Samuelsson, B.; Gabrielsson, S.; Scheynius, A.; Radmark, O.
Zymosan suppresses leukotriene C4 synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors
FASEB J.
25
1417-1427
2011
Homo sapiens
brenda
Rinaldo-Matthis, A.; Wetterholm, A.; Martinez Molina, D.; Holm, J.; Niegowski, D.; Ohlson, E.; Nordlund, P.; Morgenstern, R.; Haeggstroem, J.Z.
Arginine 104 is a key catalytic residue in leukotriene C4 synthase
J. Biol. Chem.
285
40771-40776
2010
Homo sapiens (Q16873), Homo sapiens
brenda
Saino, H.; Ukita, Y.; Ago, H.; Irikura, D.; Nisawa, A.; Ueno, G.; Yamamoto, M.; Kanaoka, Y.; Lam, B.K.; Austen, K.F.; Miyano, M.
The catalytic architecture of leukotriene C4 synthase with two arginine residues
J. Biol. Chem.
286
16392-16401
2011
Homo sapiens (Q16873)
brenda
Freiberg, J.J.; Tybjaerg-Hansen, A.; Nordestgaard, B.G.
Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals
J. Thromb. Haemost.
8
1694-1701
2010
Homo sapiens
brenda
Di Gennaro, A.; Wagsaeter, D.; Maeyraenpaeae, M.I.; Gabrielsen, A.; Swedenborg, J.; Hamsten, A.; Samuelsson, B.; Eriksson, P.; Haeggstroem, J.Z.
Increased expression of leukotriene C4 synthase and predominant formation of cysteinyl-leukotrienes in human abdominal aortic aneurysm
Proc. Natl. Acad. Sci. USA
107
21093-21097
2010
Homo sapiens
brenda
Niegowski, D.; Kleinschmidt, T.; Olsson, U.; Ahmad, S.; Rinaldo-Matthis, A.; Haeggstroem, J.Z.
Crystal structures of leukotriene C4 synthase in complex with product analogs: implications for the enzyme mechanism
J. Biol. Chem.
289
5199-5207
2014
Homo sapiens (Q16873), Homo sapiens
brenda
MacDonald, C.A.; Bushnell, E.A.; Gauld, J.W.; Boyd, R.J.
The catalytic formation of leukotriene C4: a critical step in inflammatory processes
Phys. Chem. Chem. Phys.
16
16284-16289
2014
Homo sapiens
brenda
Niegowski, D.; Kleinschmidt, T.; Ahmad, S.; Qureshi, A.A.; Marback, M.; Rinaldo-Matthis, A.; Haeggstroem, J.Z.
Structure and inhibition of mouse leukotriene C4 synthase
PLoS ONE
9
e96763
2014
Mus musculus (Q60860), Mus musculus
brenda
Liening, S.; Scriba, G.K.; Rummler, S.; Weinigel, C.; Kleinschmidt, T.K.; Haeggstroem, J.Z.; Werz, O.; Garscha, U.
Development of smart cell-free and cell-based assay systems for investigation of leukotriene C4 synthase activity and evaluation of inhibitors
Biochim. Biophys. Acta
1861
1605-1613
2016
Homo sapiens (Q16873)
brenda
Hong, F.F.; Wang, Y.F.; Liu, H.; Yang, M.W.; Yang, S.L.
V-PYRRO/NO downregulates mRNA expression levels of leukotriene C4 synthase during hepatic ischemia reperfusion injury in rats via inhibition of the nuclear factor-kappaB activation pathway
Biomed. Rep.
4
112-116
2016
Rattus norvegicus (G3V6E6)
brenda
Ahmad, S.; Ytterberg, A.J.; Thulasingam, M.; Tholander, F.; Bergman, T.; Zubarev, R.; Wetterholm, A.; Rinaldo-Matthis, A.; Haeggstroem, J.Z.
Phosphorylation of leukotriene C4 synthase at serine 36 impairs catalytic activity
J. Biol. Chem.
291
18410-18418
2016
Homo sapiens (Q16873)
brenda
Kleinschmidt, T.K.; Haraldsson, M.; Basavarajappa, D.; Lundeberg, E.; Thulasingam, M.; Ekoff, M.; Fauland, A.; Lehmann, C.; Kahnt, A.S.; Lindbom, L.; Haeggstroem, J.Z.
Tandem benzophenone amino pyridines, potent and selective inhibitors of human leukotriene C4 synthase
J. Pharmacol. Exp. Ther.
355
108-116
2015
Homo sapiens (Q16873), Homo sapiens
brenda
Zhang, Z.; Lv, Z.; Wei, Z.; Li, C.; Shao, Y.; Zhang, W.; Zhao, X.; Xiong, J.
Microsomal glutathione transferase 2 modulates LTC4 synthesis and ROS production in Apostichopus japonicus
Mol. Immunol.
91
114-122
2017
Apostichopus japonicus (A0A219VGM9), Apostichopus japonicus
brenda
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