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Enzyme Nomenclature
Information on EC 4.1.3.1 - isocitrate lyase
for references in articles please use BRENDA:EC4.1.3.1
Word Map on EC 4.1.3.1
- 4.1.3.1
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interstrand
- malate
- lens
- eyes
-
crosslinks
-
collamer
-
fanconi
-
postoperative
- anemia
-
refract
-
intraocular
-
posterior
-
phakic
-
acuity
-
preoperative
-
chamber
-
tricarboxylic
-
uncorrected
- glyoxysomal
-
spherical
-
diopter
-
myopic
-
vault
- oxaloacetate
-
fancd2
-
fork
- mitomycin
- lymphocytopenia
- microbodies
- astigmatism
-
translesion
-
pupil
- psoralens
-
anaplerotic
-
lyases
-
incisions
-
monoubiquitination
-
lasik
-
cinahl
- sn-glycerol-3-phosphate
-
gaba-induced
-
keratomileusis
-
hyperopic
-
subcapsular
-
logmar
-
biomicroscopy
-
pupillary
-
monoadducts
- gelatinosa
-
replication-dependent
- drug development
- medicine
- molecular biology
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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
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EC NUMBER 
COMMENTARY 
4.1.3.1
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RECOMMENDED NAME
GeneOntology No.
isocitrate lyase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
isocitrate = succinate + glyoxylate
-
-
-
-
isocitrate = succinate + glyoxylate
kinetic mechanism is the same in microgravity and in standard g controls
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isocitrate = succinate + glyoxylate
common mechanism for catalysis with succinate: (1) an unfavorable prebinding isomerization of the active site Cys191-His193 pair to the thiolate-imidazolium form, a process that is favored in D2O, and (2) the transfer of a proton from succinate or 3-NP to Cys191
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isocitrate = succinate + glyoxylate
common mechanism for catalysis with succinate: (1) an unfavorable prebinding isomerization of the active site Cys191-His193 pair to the thiolate-imidazolium form, a process that is favored in D2O, and (2) the transfer of a proton from succinate or 3-NP to Cys191
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
condensation
-
-
-
-
elimination
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of an oxo-acid, C-C bond cleavage
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
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SYSTEMATIC NAME
IUBMB Comments
isocitrate glyoxylate-lyase (succinate-forming)
The isomer of isocitrate involved is (1R,2S)-1-hydroxypropane-1,2,3-tricarboxylate [3].
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CAS REGISTRY NUMBER
COMMENTARY
9045-78-7
-
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
wild-type: KT2442, mutant: KT217, poly(3-hydroxyalkanoate)-overproducing mutant in which aceA gene is knocked out
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-
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651648, 666423, 679472, 701127, 705492, 705567, 714444, 716722, 727039, 727045, 727341, 727419, 728701
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H37Rv, ATCC 25618, without functional ICL2 gene (aceA) because gene is split into two ORFs (aceAa and aceAb)
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
conserved residues in the subfamily 3 signature of ICL-Pa play important roles in catalysis and thermostability and are likely associated with the catalytic loop structural conformation. Three-dimensional structural homology modeling of ICL-Pa wild-type and mutants, structure comparisons, active site modeling, overview. Residue N214 plays an essential role in ICL-Pa catalytic activity
evolution
the enzyme belongs to the isocitrate lyase ICL subfamily 3, one of two eubacterial groups, it has a substitution of M504I compared to the cold-adapted ICLs, rendering is less thermostable, phylogenetic analysis, overview
evolution
the ICL family includes five subfamilies, and the 2-methylisocitrate lyase (MICL) family. The ICL from Pseudomonas aeruginosa (ICL-Pa) is identified in a different ICL node (subfamily 3) than other Pseudomonas ICL enzymes, phylogenetic analysis
evolution
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the enzyme belongs to the isocitrate lyase ICL subfamily 3, one of two eubacterial groups, it has a substitution of M504I compared to the cold-adapted ICLs, rendering is less thermostable, phylogenetic analysis, overview
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malfunction
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inhibiting the activity of this enzyme during experimental chronic lung infection of rats forces the infection into an acute state, which can then be treated with antibiotics. If antibiotics are not provided in combination with isocitrate lyase inhibitors, the resulting infection overwhelms the host, resulting in death. ICL mutant is hypervirulent, it does not establish a chronic infection but establishes an acute infection. ICL mutants are significantly more cytotoxic than other strains. Complementation of the mutant strain restores the wild-type phenotype
malfunction
-
a mutant deleted of the ICL gene (acuD) is fully virulent in a murine model
malfunction
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an ICL-deficient mutant is unable to utilize acetate, ethanol, citrate, glycerol, oleate, lactate, pyruvate, peptone, glutamate or alanine for growth, unlike the parental strain. ICL-deficient mutant is unable to utilize nonfermentable carbon sources and has reduced virulence in mice
malfunction
-
ICL1 mutant fails to grow on acetate or fatty acids, but is able to germinate and develop appressoria and is capable of degrading lipid bodies as well as the wild-type strain. Conidia from the ICL1-deficient mutant inoculated onto cucumber leaves and cotyledons form a reduced number of lesions on leaves, and especially on cotyledons, but nevertheless remain pathogenic. In invasive experiments such as the inoculation of conidia into wound sites, no defect is observed in the ICL1 mutant, while in penetration assays on cucumber cotyledons the mutant is unable to develop penetrating hyphae
malfunction
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an ICL1 mutant shows the same number of subarachnoidal yeast cells as the wild-type after 10 days in immunosuppressed rabbits. In an inhalation model of murine cryptococcosis, no differences in survival between an ICL1 mutant and the wild-type
malfunction
-
deletion of the ICL1 gene causes a reduction in appressorium formation, conidiogenesis and cuticle penetration, and an overall decrease in damage to leaves of rice and barley
malfunction
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single ICL mutations have no dramatic effect on the growth. ICL mutant has a reduced ability to sustain the infection. An ICL/AceA double mutant is unable to grow on carbon source. The double mutant inoculated into mice is eliminated from lungs and spleen and is unable to induce splenomegaly or alterations in lungs
malfunction
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ICL (aceA) mutant displays reduced virulence on alfalfa seedlings and a reduction in histopathology in rat lungs
malfunction
-
population of an ICL-deficient strain increases in macrophages after 12 h but then decline significantly
malfunction
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mutations in the sole ICL gene (aceA) prevent growth on acetate but do not affect pathogenesis in a mouse model
malfunction
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nutrient-starved bacilli lacking the glyoxylate shunt enzyme isocitrate lyase fail to reduce their intracellular ATP level and die, thus establishing a link between ATP control and intermediary metabolism. ICL loss-of-function mutant dies in the Loebel model. Viability is fully restored when the mutant strain is complemented with a wild-type copy of ICL
malfunction
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an aceA mutant displays enhanced biofilm formation during anaerobic growth. Expression of PcrV, of PopN (a regulator of the T3SS translocation process), ExoS (a T3 effector protein), and ExsD (a T3S regulator) is greatly reduced in the aceA mutant. Expression of aceA from a plasmid in trans can restore PcrV expression and ICL activity in the aceA mutant
malfunction
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enzyme-deficient cells undergo a progressive depletion of TCA cycle intermediates and accumulation of propionyl-CoA when metabolizing fatty acid substrates, phenotype, overview. Enzyme-deficient cells are unable to metabolize both even- and odd-chain fatty acids because of the dead-end depletion of TCA cycle intermediates by a constitutively active, but broken, methylcitrate cycle. Addition of cobalamin is sufficient to selectively protect ICL-deficient cells from the bactericidal effects of acetate and propionate, and this attenuation is accompanied by a dose-dependent restoration of TCA cycle activity and propionyl-CoA levels
malfunction
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nutrient-starved bacilli lacking the glyoxylate shunt enzyme isocitrate lyase fail to reduce their intracellular ATP level and die, thus establishing a link between ATP control and intermediary metabolism. ICL loss-of-function mutant dies in the Loebel model. Viability is fully restored when the mutant strain is complemented with a wild-type copy of ICL
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metabolism
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participation of isoforms in metabolic regulation of the glyoxylate cycle, organic acid metabolism during photorespiration in leaves and acidosis in corn seeds
metabolism
-
ICL overexpression and malonate addition has a significant impact on metabolism and on organic acid production profiles. Increased ICL expression does not result in an increased glyoxylate bypass flux, there is a global response with respect to gene expression, leading to an increased flux through the oxidative part of the TCA cycle. Instead of an increased production of succinate and malate, a major increase in fumarate production is observed. In the strain with overexpression of ICL the organic acid production shifts from fumarate towards malate production when malonate is added to the cultivation medium
metabolism
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isocitrate lyase is a key enzyme in the glyoxylate cycle
metabolism
-
first enzyme of the glyoxylate shunt, which allows for the anaplerosis of citric acid cycle intermediates under nutrient limiting conditions
metabolism
-
the enzyme is important in the glyoxylate shunt pathway, which is strongly induced in Pseudomonas aeruginosa during anaerobic growth and during growth on C2-sources, such as acetate or fatty acids, as the sole carbon source, overview
metabolism
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ICL overexpression and malonate addition has a significant impact on metabolism and on organic acid production profiles. Increased ICL expression does not result in an increased glyoxylate bypass flux, there is a global response with respect to gene expression, leading to an increased flux through the oxidative part of the TCA cycle. Instead of an increased production of succinate and malate, a major increase in fumarate production is observed. In the strain with overexpression of ICL the organic acid production shifts from fumarate towards malate production when malonate is added to the cultivation medium
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metabolism
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isocitrate lyase is a key enzyme in the glyoxylate cycle
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physiological function
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isocitrate lyase is a persistence factor. ICL is not required for survival within unactivated murine macrophage cells
physiological function
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the glyoxylate cycle mediated by ICL is unnecessary for virulence
physiological function
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ICL1 contributes to virulence but is not essential for systemic infection. Role for the beta-oxidation pathway in virulence
physiological function
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lack of correlation between ICL gene expression and biological function
physiological function
-
important role for ICL in fungal virulence on plants. The ICL1 gene is expressed during its infection of Brassica napus cotyledons and inactivation of this locus causes low germination rates of pycnidiospores, reducing the pathogenicity of the fungus on cotyledons as well as limiting its hyphal growth on canola
physiological function
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ICL is essential for full virulence in the organism
physiological function
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two functional ICLs. ICL has a pivotal role in bacterial persistence in the host. ICL activity is essential for survival in the host. ICL and to a lesser extent AceA are required for the growth on propionate and on odd-chain fatty acids as a carbon source. The organism possesses dual ICL/MICL activity and can support growth on acetate and propionate
physiological function
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ICL is essential for long-term survival and proliferation in macrophages
physiological function
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ICL is required for persistence during chronic infection, but not for acute lethal infection in mice
physiological function
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ICL gene is required for non-growing survival in the Loebel model (nutrient deprivation in oxygen-rich medium)
physiological function
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involved in a novel pathway for pyruvate dissimilation (GAS pathway: utilizes the glyoxylate shunt, anaplerotic fixation of carbon from CO2 and succinyl CoA synthetase for the generation of succinyl CoA)
physiological function
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involved in a novel pathway for pyruvate dissimilation (GAS pathway: utilizes the glyoxylate shunt, anaplerotic fixation of carbon from CO2 and succinyl CoA synthetase for the generation of succinyl CoA)
physiological function
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the enzyme catalyzes the first committed step in the glyoxylate cycle, it is essential in Mycobacterium tuberculosis for cell survival during chronic infection
physiological function
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isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. The enzyme is important during steady stage growth when it converts isocitrate to succinate and glyoxylate
physiological function
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the enzyme regulates the type III secretion system, T3SS, overview. Expression of the T3SS in oxygen-limited growth conditions is strongly dependent on the glyoxylate shunt enzyme, isocitrate lyase, which probably affects the RetS/LadS signalling pathways. ICL-dependent regulation of the T3SS does not alter the expression level of the master transcriptional regulator, ExsA, but affects expression of the T3 structural proteins, effectors and regulators, ExsC, ExsD and ExsE
physiological function
-
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases required for growth on even and odd chain fatty acids
physiological function
isocitrate lyase plays an important role in the ability of Pseudomonas aeruginosa to grow on fatty acids, acetate, acyclic terpenes, and amino acids
physiological function
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the enzyme catalyzes the first committed step in the glyoxylate cycle, it is essential in Mycobacterium tuberculosis for cell survival during chronic infection
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physiological function
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ICL gene is required for non-growing survival in the Loebel model (nutrient deprivation in oxygen-rich medium); involved in a novel pathway for pyruvate dissimilation (GAS pathway: utilizes the glyoxylate shunt, anaplerotic fixation of carbon from CO2 and succinyl CoA synthetase for the generation of succinyl CoA)
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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
(1S,2S)-1-hydroxypropane-1,2,3-tricarboxylate
succinate + glyoxylate
-
reversible aldol cleavage
glyoxylate shunt
-
r
(2R)-ethyl-(3S)-methyl malate
2-oxobutanoate + propanoate
-
-
-
?
(2R)-isobutyl-(3S)-methyl malate
4-methyl-2-oxopentanoate + propanoate
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-
-
?
(2R)-propyl-(3S)-methyl malate
4-methyl-2-oxopentanoate + propanoate
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-
-
?
isocitrate + phenylhydrazine
? + glyoxylate phenylhydrazone
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-
-
?
(2R,3S:2S,3R)-2-methyl-isocitrate
succinate + pyruvate
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-
-
?
isocitrate
?
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assimilation of one-carbon compounds in the icl+ serine pathway
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-
-
isocitrate
glyoxylate + succinate
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blue-native SDS-PAGE
coupling glyoxylate formation to lactate dehydrogenase type II activity (10 U) in presence of NAD+
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?
isocitrate
succinate + glyoxylate
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pH 7.3, cell-free extracts, in presence of MgCl2 and 2,4-dinitrophenylhydrazine
analysis based on absorbance at 450 nm
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?
isocitrate
succinate + glyoxylate
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pH 7.3, cell-free extracts, in presence of MgCl2 and 2,4-dinitrophenylhydrazine
analysis based on absorbance at 450 nm
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?
isocitrate
succinate + glyoxylate
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first step in glyoxylate-bypass pathway
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?
isocitrate
succinate + glyoxylate
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regulatory enzyme playing a crucial role in fungal growth
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?
isocitrate
succinate + glyoxylate
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key enzyme of the glyoxylate cycle
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-
?
isocitrate
succinate + glyoxylate
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key enzyme of the glyoxylate cycle
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?
isocitrate
succinate + glyoxylate
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30°C, pH 7.5, HEPES containing phenylhydrazine HCl
absorbance of glyoxylate phenylhydrazone at 334 nm
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r
isocitrate
succinate + glyoxylate
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isotopic analysis, solvent kinetic isotope effects in the direction of isocitrate cleavage arise from the initial deprotonation of the C2 hydroxyl group of isocitrate or the protonation of the aci-acid of the succinate product of the isocitrate aldolcleavage by a solvent-derived proton, equilibrium perturbation in D2O, NMR spectroscopy and mass spectrometry, modeling, overview. The final equilibrium isotopic composition of reactants in D2O reveals dideuterated succinate, protiated glyoxylate, and monodeuterated isocitrate, with the transient appearance and disappearance of monodeuterated succinate
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-
r
isocitrate
succinate + glyoxylate
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rate-limiting enzyme of the citric acid cycle
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?
isocitrate
succinate + glyoxylate
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first enzyme of glyoxylate shunt
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?
additional information
?
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Lys-193, Cys-195, His-197 and His-356 are catalytic, active-site residues, while His-184 is involved in the assembly of the tetrameric enzyme
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additional information
?
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Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
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NATURAL SUBSTRATES
NATURAL PRODUCTS
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
(1S,2S)-1-hydroxypropane-1,2,3-tricarboxylate
succinate + glyoxylate
-
reversible aldol cleavage
glyoxylate shunt
-
r
additional information
?
-
-
Mycobacterium tuberculosis isocitrate lyases are catalytically bifunctional isocitrate and methylisocitrate lyases, EC 4.1.3.1 and EC 4.1.3.30, required for growth on even and odd chain fatty acids
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-
-
isocitrate
?
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assimilation of one-carbon compounds in the icl+ serine pathway
-
-
-
isocitrate
succinate + glyoxylate
-
first step in glyoxylate-bypass pathway
-
?
isocitrate
succinate + glyoxylate
-
regulatory enzyme playing a crucial role in fungal growth
-
?
isocitrate
succinate + glyoxylate
-
key enzyme of the glyoxylate cycle
-
-
?
isocitrate
succinate + glyoxylate
-
key enzyme of the glyoxylate cycle
-
-
?
isocitrate
succinate + glyoxylate
-
rate-limiting enzyme of the citric acid cycle
-
?
isocitrate
succinate + glyoxylate
-
first enzyme of glyoxylate shunt
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ba2+
Cd2+
-
5 mM, 90% inhibition of Mg2+-activated enzyme, interaction with catalytic domain induces partial unfolding (revealed by thermal denaturation, far-UV circular dichroism, fluorescence spectra, and glutaraldehyde crosslinking)
Co2+
Fe2+
Mg2+
Mn2+
Ni2+
Sr2+
Zn2+
-
5 mM, 90% inhibition of Mg2+-activated enzyme, interaction with catalytic domain induces partial unfolding (revealed by thermal denaturation, far-UV circular dichroism, ANS fluorescence spectra, and glutaraldehyde crosslinking)
additional information
-
no significant change in enzyme activity after incubation with Co2+, Pb2+, Fe2+, Cu2+, Cd2+, Na+, K+, Cl-
Co2+
-
Co2+ 12% as effective as Mg2+; no activity in absence of exogenous cation
Co2+
-
Co2+ 18% as effective as Mg2+; no activity in absence of exogenous cation
Co2+
-
Co2+ 17% as effective as Mg2+; no activity in absence of exogenous cation
Co2+
-
Co2+ 29% as effective as Mg2+; no activity in absence of exogenous cation
Fe2+
-
no activity in absence of exogenous cation, Fe2+ 7% as effective as Mg2+
Mg2+
-
requirement, optimal concentration: 2 mM, Km value: 0.092 at pH 7
Mg2+
-
Icl enzyme: most effective cation, optimal concentration: 5 mM
Mg2+
-
5 mM, essential for catalytic activity, 100% activity, binds and stabilizes non-catalytic alpha/beta barrel core without structural alterations (revealed by thermal, urea and GdnHCL denaturation and far-UV CD)
Mg2+
-
reactivation after thermal inactivation, Mg2+-isocitrate complex is true substrate, 2 Mg2+-binding sites: catalytic and activator site
Mn2+
-
Mn2+ 14% as effective as Mg2+; no activity in absence of exogenous cation
Mn2+
-
Mn2+ 31% as effective as Mg2+; no activity in absence of exogenous cation
Mn2+
-
Mn2+ 54% as effective as Mg2+; no activity in absence of exogenous cation
Mn2+
-
Mn2+ 27% as effective as Mg2+; no activity in absence of exogenous cation
Mn2+
-
Mn2+ 24% as effective as Mg2+; no activity in absence of exogenous cation
Mn2+
-
Icl enzyme: can replace Mg2+, yielding 39% of the activity obtained with Mg2+
Mn2+
-
5 mM, 45% activity, binds and stabilizes non-catalytic alpha/beta barrel core without structural alterations (revealed by thermal, urea and GdnHCL denaturation and far-UV CD)
Ni2+
-
no activity in absence of exogenous cation, Ni2+ 7% as effective as Mg2+
Sr2+
-
no activity in absence of exogenous cation, Sr2+ 3% as effective as Mg2+
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INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(1R,2R,6E)-8-(2,5-dihydroxyphenyl)-2-hydroxy-6-methyl-1-[[(1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]methyl]oct-6-en-1-yl hydrogen sulfate
-
-
(1S,4bS,10aR,12aS)-10a-[(acetyloxy)methyl]-1-formyl-4b,7,7,12a-tetramethyl-1,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrochrysene-2-carboxylic acid
-
scarlarane sesterterpene, isolated from Smenospongia sp.
(2E,6E)-9-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydro-2H-chromen-2-yl]-2,6-dimethylnona-2,6-dienal
-
-
(2E,7E)-10-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydro-2H-chromen-2-yl]-3,7-dimethyl-2-(2-methylprop-1-en-1-yl)deca-2,7-dienal
-
-
(2R)-2-[(3E,7E)-9-(hydroxymethyl)-4,8,11-trimethyldodeca-3,7,10-trien-1-yl]-2,8-dimethyl-3,4-dihydro-2H-chromen-6-ol
-
-
(4R,5R)-4-[(2E)-5-[(2R)-6-hydroxy-2,8-dimethyl-3,4-dihydro-2H-chromen-2-yl]-2-methylpent-2-en-1-yl]-2-methyl-5-(2-methylprop-1-en-1-yl)cyclopent-2-en-1-one
-
-
(4S,5bR,11aS,13aS,13bR)-4-hydroxy-5b,8,8,11a,13a-pentamethyl-1,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a,13b-octadecahydrochryseno[1,2-c]furan-1-yl acetate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
(4S,5bS,11aR,13aS,13bR)-11a-formyl-4-hydroxy-5b,8,8,13a-tetramethyl-1,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a,13b-octadecahydrochryseno[1,2-c]furan-1-yl acetate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
(4S,5bS,11aR,13aS,13bR)-11a-[(acetyloxy)methyl]-5b,8,8,13a-tetramethyl-1,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a,13b-octadecahydrochryseno[1,2-c]furan-1,4-diyl diacetate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
(5bS,11aR,13aS,13bR)-11a-(hydroxymethyl)-5b,8,8,13a-tetramethyl-3-oxo-1,3,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a,13b-octadecahydrochryseno[1,2-c]furan-1-yl acetate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
(5E)-5-[(2R,6E,10E)-13-furan-3-yl-2,6,10-trimethyltrideca-6,10-dien-1-ylidene]-4-hydroxy-3-methylfuran-2(5H)-one
-
linear furanosesterterpene, isolated from Smenospongia sp.
(5Z)-4-(3,5-dibromo-4-hydroxyphenyl)-3-[(S)-(3,5-dibromo-4-methoxyphenyl)(hydroxy)methyl]-5-(4-methoxybenzylidene)furan-2(5H)-one
i.e. cadiolide H, purified from the ascidian Synoicum sp.
(5Z)-4-(3-bromo-4-hydroxyphenyl)-3-(3,5-dibromo-4-hydroxybenzoyl)-5-(3,5-dibromo-4-hydroxybenzylidene)furan-2(5H)-one
i.e. cadiolide E, purified from the ascidian Synoicum sp.
(5Z)-5-(3-bromo-4-hydroxybenzylidene)-4-(3-bromo-4-hydroxyphenyl)-3-[(S)-(3,5-dibromo-4-methoxyphenyl)(hydroxy)methyl]furan-2(5H)-one
i.e. cadiolide G, purified from the ascidian Synoicum sp.
(5Z)-5-[(2R,5Z,9Z)-13-furan-3-yl-2,6,10-trimethyltrideca-5,9-dien-1-ylidene]-4-hydroxy-3-methylfuran-2(5H)-one
-
linear furanosesterterpene, isolated from Smenospongia sp.
1-carboxy-6-hydroxy-3,4-dihydro-beta-carboline
-
weak inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
1-cyclopropyl-6-fluoro-7-[4-(3-nitropropanoyl)piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
-
-
1-cyclopropyl-7-(3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl)-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
-
-
1-cyclopropyl-7-[3,5-dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
-
a fluoroquinolone derivative and structural analogue of succinate
1-ethyl-6,8-difluoro-7-[3-methyl-4-(3-nitropropanoyl)piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
-
-
1-ethyl-6-fluoro-7-[4-(3-nitropropanoyl)piperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
-
-
12-deacetoxy-23-acetoxy-19-O-acetylscalarin
-
cytotoxic, isolated from Smenospongia sp.
12-deacetoxy-23-hydroxyheteronemin
-
cytotoxic, isolated from Smenospongia sp.
2,2',3-tribromo-3',4,4',5-tetrahydroxy-6'-hydroxymethyldiphenylmethane
-
-
2-[(2E,7R,8R)-7,8-dihydroxy-3-methyl-9-[(1S,4aS,8aS)-2,5,5,8a-tetramethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]non-2-en-1-yl]benzene-1,4-diol
-
-
3-bromo-4-(2,3-dibromo-4,5-dihydroxybenzyl)-5-methoxymethylpyrocatechol
-
-
3-nitro-1-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]propan-1-one
-
-
4-hydroxy-9-deoxoidiadione
-
cytotoxic, linear furanosesterterpene, isolated from Smenospongia sp.
5-hydroxy-1H-indole-3-carboxylic acid methyl ester
-
weak inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
5-hydroxyindole-3-carbaldehyde
-
moderate inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
ascorbate
-
enzyme is inhibited by an ascorbate plus Fe2+ system under aerobic conditions,16% residual activity at 2 mM ascorbate/0.02 mM Fe2+. Inactivation requires hydrogen peroxide, and can be prevented by catalase, EDTA, Mg2+, isocitrate, 20 mM glutathione, 20 mM dithiothreitol or 40 mM L-cysteine
dimethyl (2Z)-2-(3,5-dibromo-4-hydroxybenzoyl)-3-(3,5-dibromo-4-hydroxyphenyl)but-2-enedioate
i.e. synoilide A, purified from the ascidian Synoicum sp.
dimethyl (2Z)-2-(3-bromo-4-hydroxyphenyl)-3-(3,5-dibromo-4-hydroxybenzoyl)but-2-enedioate
i.e. synoilide B, purified from the ascidian Synoicum sp.
Fe2+
-
enzyme is inhibited by an ascorbate plus Fe2+ system under aerobic conditions,16% residual activity at 2 mM ascorbate/0.02 mM Fe2+. Inactivation requires hydrogen peroxide, and can be prevented by catalase, EDTA, Mg2+, isocitrate, 20 mM glutathione, 20 mM dithiothreitol or 40 mM L-cysteine
GSSG
-
ICL can be inactivated by glutathionylation and reactivated by glutaredoxin after reduced dithiothreitol treatment, whereas thioredoxin does not appear to regulate ICL activity
hyrtiosin A
-
moderate inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
hyrtiosin B
-
strong inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
methyl (1R,4bS,10aR,12aS)-10a-[(acetyloxy)methyl]-1-formyl-4b,7,7,12a-tetramethyl-1,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrochrysene-2-carboxylate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
methyl (1S,4bS,10aR,12aS)-10a-[(acetyloxy)methyl]-1-formyl-4b,7,7,12a-tetramethyl-1,4,4a,4b,5,6,6a,7,8,9,10,10a,10b,11,12,12a-hexadecahydrochrysene-2-carboxylate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
methyl 2-[bis(3,5-dibromo-4-hydroxyphenyl)methylidene]-4-(3,5-dibromo-4-hydroxyphenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate
i.e. cadiolide I, purified from the ascidian Synoicum sp.
N'1-[(4-nitrophenyl)methylene]-2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydro-1-phthalazinyl]ethanohydrazide
-
is the most active compound
serotonin
-
moderate inhibition, isolated from marine sponge Hyrtios sp. (Thorectidae family)
sodium (2S)-5-furan-3-yl-2-[(1R)-1-hydroxy-2-[(1S,2R,4aR,8aR)-2-methyl-5-methylidenedecahydronaphthalen-1-yl]ethyl]pentyl sulfate
-
-
[(5bS,11aR,13aS)-5b,8,8,13a-tetramethyl-5,5a,5b,6,7,7a,8,9,10,11,11b,12,13,13a-tetradecahydrochryseno[1,2-c]furan-11a(4H)-yl]methanol
-
scarlarane sesterterpene, isolated from Smenospongia sp.
[(5bS,11aR,13aS)-5b,8,8,13a-tetramethyl-5,5a,5b,6,7,7a,8,9,10,11,11b,12,13,13a-tetradecahydrochryseno[1,2-c]furan-11a(4H)-yl]methyl acetate
-
scarlarane sesterterpene, isolated from Smenospongia sp.
[(5bS,11aR,13aS,13bR)-1-methoxy-5b,8,8,13a-tetramethyl-1,5,5a,5b,6,7,7a,8,9,10,11,11b,12,13,13a,13b-hexadecahydrochryseno[1,2-c]furan-11a(3H)-yl]methanol
-
scarlarane sesterterpene, isolated from Smenospongia sp.
2-(4-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 4-chloro-2-methoxybenzoate
-
-
2-(4-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 4-chloro-2-methoxybenzoate
-
-
2-(4-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 4-chloro-2-methoxybenzoate
-
-
2-(4-chloro-2-methoxyphenyl)-6-(trifluoromethyl)benzo[d]oxazole
-
-
2-(5-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 5-chloro-2-methoxybenzoate
-
-
2-(5-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 5-chloro-2-methoxybenzoate
-
-
2-(5-chloro-2-methoxybenzamido)-5-(trifluoromethyl)phenyl 5-chloro-2-methoxybenzoate
-
-
2-(5-chloro-2-methoxyphenyl)-6-(trifluoromethyl)benzo[d]oxazole
-
-
3-nitropropionate
-
no growth of Mycobacterium tuberculosis on fatty acids after addition of 3-nitropropionate
3-nitropropionate
-
0.1 mM, inhibition of bacterial growth on and metabolisation of proprionate as sole carbon in absence of Vitamin B12
3-nitropropionate
-
a succinate analogue. Inhibition by 3-nitropropionate proceeds through an unusual double slow-onset process featuring formation of a complex with a Ki of 0.0033 mM during the first minute, followed by formation of a final complex with a Ki* of 44 nM over the course of several min to hours
4,5-dichloro-2-(5-chloro-2-methoxybenzamido)phenyl 5-chloro-2-methoxybenzoate
-
-
4,5-dichloro-2-(5-chloro-2-methoxybenzamido)phenyl 5-chloro-2-methoxybenzoate
-
-
4,5-dichloro-2-(5-chloro-2-methoxybenzamido)phenyl 5-chloro-2-methoxybenzoate
-
-
4-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
4-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
4-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
4-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
4-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
4-chloro-N-(4,5-dichloro-2-hydroxyphenyl)-2-methoxybenzothioamide
-
-
5-chloro-2-(4-chloro-2-methoxybenzamido)phenyl 4-chloro-2-methoxybenzoate
-
-
5-chloro-2-(4-chloro-2-methoxybenzamido)phenyl 4-chloro-2-methoxybenzoate
-
-
5-chloro-2-(4-chloro-2-methoxybenzamido)phenyl 4-chloro-2-methoxybenzoate
-
-
5-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
5-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
5-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(2-hydroxy-4-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
5-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzamide
-
-
5-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(2-hydroxy-5-(trifluoromethyl)phenyl)-2-methoxybenzothioamide
-
-
5-chloro-N-(4,5-dichloro-2-hydroxyphenyl)-2-methoxybenzothioamide
-
-
H2O2
-
incubation with 0.1 mM H2O2 and 0.5mM GSH for 30 min results in a decrease of protein activity comparable with that obtained in the presence of GSSG. The addition of reduced dithiothreitol provides full reactivation of enzyme activity. Exposure to 1 mM H2O2 for 30 min results in an almost complete inactivation of the enzyme, whereas in the presence of a 10fold lower concentration of H2O2 (0.1 mM), ICL retains 20% of total activity after 30 min of incubation. GSH, reacting with sulfenic acid, can protect the protein from H2O2-mediated irreversible inactivation by glutathionylation
H2O2
-
inhibits enzyme activity with increased concentrations, no activity above 1.3 mM
Itaconate
-
a succinate analogue lacking an acidic alpha-proton, the inhhibitor does not display slow-binding behavior
Itaconic acid
-
potent competitive inhibitor of ICL, 1 mg/ml reduces the activity to 42% of the uninhibited control. Inhibition of ICL enzymatic activity during chronic infection of rats forces the infection into an acute phase
Itaconic acid
-
itaconic acid specifically inhibits growth of wild-type cells on acetate and propionate, but not dextrose, in an ICL-dependent manner, and elicited metabolomic changes similar to those observed with ICL-deficient cells. Enzyme ICL inhibition by itaconic acid results in a specific decrease in intrabacterial pH from pH 7.3 to pH 6.4 in propionate-grown cells, not in acetate-grown cells
KCl
-
at pH-values above 8.6 inhibition, below pH 8.6 activation by KCl
p-chloromercuribenzoate
-
100% inhibition at 0.02 mM, reversible by 2-mercaptoethanol
additional information
-
6-hydroxy-3,4-dihydro-1-oxo-beta-carboline, isolated from marine sponge Hyrtios sp. (Thorectidae family), defined inactive as inhibitor since IC50 is higher than 0.989 mM at a concentration of 2 mg/ml
-
additional information
-
natural glyoxylate cycle inhibitors such 5-hydroxyindole-type alkaloids are potent inhibitors
-
additional information
cadiolide and synoilide ICL inhibitors (5Z)-4-(3-bromo-4-hydroxyphenyl)-3-(3,5-dibromo-4-hydroxybenzoyl)-5-(3,5-dibromo-4-hydroxybenzylidene)furan-2(5H)-one, (5Z)-5-(3-bromo-4-hydroxybenzylidene)-4-(3-bromo-4-hydroxyphenyl)-3-[(S)-(3,5-dibromo-4-methoxyphenyl)(hydroxy)methyl]furan-2(5H)-one, (5Z)-4-(3,5-dibromo-4-hydroxyphenyl)-3-[(S)-(3,5-dibromo-4-methoxyphenyl)(hydroxy)methyl]-5-(4-methoxybenzylidene)furan-2(5H)-one, methyl 2-[bis(3,5-dibromo-4-hydroxyphenyl)methylidene]-4-(3,5-dibromo-4-hydroxyphenyl)-5-oxo-2,5-dihydrofuran-3-carboxylate, dimethyl (2Z)-2-(3,5-dibromo-4-hydroxybenzoyl)-3-(3,5-dibromo-4-hydroxyphenyl)but-2-enedioate and dimethyl (2Z)-2-(3-bromo-4-hydroxyphenyl)-3-(3,5-dibromo-4-hydroxybenzoyl)but-2-enedioate have no inhibitory effects on Candida albicans strain SC5314 grown in glucose, but are inhibitory to strain SC5314 grown in acetate
-
additional information
-
degradation of the aceA mRNA, encoding the enzyme, by RNase E/G, that cleaves the aceA mRNA at a single-stranded AU-rich region in the 3' untranslated region. The level of aceA mRNA is approximately 3fold higher in the rneG knockout mutant strain compared to the wild-type strain
-
additional information
-
reversible loss of activity in isocitrate lyase from Haloferax volcanii when the enzyme is out of extract without a thiol, such as dithiothreitol
-
additional information
-
halisulfates from the tropical sponge Hippospongia sp. are able to inhibit ICL activity, appressorium formation and C2 utilization
-
additional information
-
design, synthesis, and in vitro antimycobacterial activities against human hepatic cells of a series of 2-methoxy-2'-hydroxybenzanilide derivatives and their thioxo analogues, overview
-
additional information
-
design, synthesis, and in vitro antimycobacterial activities against human hepatic cells of a series of 2-methoxy-2'-hydroxybenzanilide derivatives and their thioxo analogues, overview
-
additional information
-
some 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid hydrazones show 45-61% inhibition at 10 mM
-
additional information
-
extracts of Illicium verum and Zingiber officinale inhibit ICL
-
additional information
-
design, synthesis, inhibitory potencies against the enzyme, and in vitro antimycobacterial activities against human hepatic cells of a series of 2-methoxy-2'-hydroxybenzanilide derivatives and their thioxo analogues, overview
-
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
acetate
-
activity of the ICL promoter is significantly upregulated during growth on acetate
glutaredoxin 1
-
reactivation of GSSG-treated ICL in the presence of glutaredoxin 1 within 20 min
-
acetyl-CoA
more than 4fold increased enzyme activity in the presence of 150 microM acetyl-CoA
acetyl-CoA
increases the substrate binding affinities isocitrate and succinate, but had little effect on the affinity for glyoxylate
dithiothreitol