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Information on EC 2.3.3.8 - ATP citrate synthase and Organism(s) Homo sapiens and UniProt Accession P53396

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EC Tree
     2 Transferases
         2.3 Acyltransferases
             2.3.3 Acyl groups converted into alkyl groups on transfer
                2.3.3.8 ATP citrate synthase
IUBMB Comments
The enzyme can be dissociated into components, two of which are identical with EC 4.1.3.34 (citryl-CoA lyase) and EC 6.2.1.18 (citrate---CoA ligase).
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This record set is specific for:
Homo sapiens
UNIPROT: P53396
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
Synonyms
atp-citrate lyase, atp citrate lyase, citrate cleavage enzyme, atp:citrate lyase, adenosine triphosphate citrate lyase, atp citrate synthase, atp citrate (pro-s)-lyase, atp-citrate synthase alpha chain protein 2, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
ATP citrate lyase isoform 2
-
adenosine triphosphate citrate lyase
-
-
-
-
ATP citrate (pro-S)-lyase
-
-
-
-
ATP citrate lyase
-
-
ATP-citrate lyase
-
-
ATP-citric lyase
-
-
-
-
ATP:citrate lyase
-
-
-
-
ATP:citrate oxaloacetate lyase ((pro-3S)-CH2COO--> acetyl-CoA) (ATP-dephosphorylating)
-
-
-
-
ATP:citrate oxaloacetate-lyase (pro-3S-CH2COO->acetyl-CoA, ATP dephosphorylating)
-
-
-
-
ATP:citrate oxaloacetate-lyase CoA-acetylating and ATP-dephosphorylating
-
-
-
-
Citrate cleavage enzyme
-
-
-
-
citrate-ATP lyase
-
-
-
-
citric cleavage enzyme
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:oxaloacetate C-acetyltransferase [(pro-S)-carboxymethyl-forming, ADP-phosphorylating]
The enzyme can be dissociated into components, two of which are identical with EC 4.1.3.34 (citryl-CoA lyase) and EC 6.2.1.18 (citrate---CoA ligase).
CAS REGISTRY NUMBER
COMMENTARY hide
9027-95-6
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + citrate + CoA
ADP + phosphate + acetyl-CoA + oxaloacetate
show the reaction diagram
ADP + phosphate + acetyl-CoA + oxaloacetate
ATP + citrate + CoA
show the reaction diagram
-
-
-
-
?
ATP + citrate + CoA
acetyl-CoA + oxaloacetate + ADP + phosphate
show the reaction diagram
-
-
-
-
ir
ATP + citrate + CoA
ADP + phosphate + acetyl-CoA + oxaloacetate
show the reaction diagram
citrate + CoA + ATP
acetyl-CoA + oxaloacetate + ADP + phosphate
show the reaction diagram
-
-
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + citrate + CoA
ADP + phosphate + acetyl-CoA + oxaloacetate
show the reaction diagram
ADP + phosphate + acetyl-CoA + oxaloacetate
ATP + citrate + CoA
show the reaction diagram
-
-
-
-
?
ATP + citrate + CoA
acetyl-CoA + oxaloacetate + ADP + phosphate
show the reaction diagram
-
-
-
-
ir
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
required
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,3,8-trihydroxy-2-(3-methoxyphenyl)-6-methylanthracene-9,10-dione
-
-
1,3,8-trihydroxy-2-(4-methoxyphenyl)-6-methylanthracene-9,10-dione
-
-
1,3,8-trihydroxy-2-iodo-6-methylanthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)anthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-(3-methylphenyl)anthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-(pyridin-3-yl)anthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-phenylanthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-[(morpholin-4-yl)methyl]anthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-[(piperidin-1-yl)methyl]anthracene-9,10-dione
-
-
1,3,8-trihydroxy-6-methyl-2-[[methyl(phenyl)amino]methyl]anthracene-9,10-dione
-
-
1,3-dibromo-2,4,5-trihydroxy-7-methylanthracene-9,10-dione
-
-
1-chloro-2,4,5-trihydroxy-7-methylanthracene-9,10-dione
-
-
2,4,5-trihydroxy-7-methyl-1,3-di(pyridin-3-yl)anthracene-9,10-dione
-
-
2-chloro-1,3,8-trihydroxy-6-methylanthracen-9(10H)-one
-
-
2-chloro-1,3,8-trihydroxy-6-methylanthracene-9,10-dione
-
-
3-(1,3-benzoxazol-5-yl)-5,7-dihydroxy-9-methyl-3,4-dihydro-2H-anthra[2,3-e][1,3]oxazine-6,11-dione
-
-
4-chloro-1,3,8-trihydroxy-6-methylanthracen-9(10H)-one
-
-
4-[[(2-hexyl-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-3-yl)oxy]methyl]-5-methylfuran-2-carboxylic acid
0.01 mM, 95% inhibition. 0.1 mM, 100% inhibition
-
4-[[(3,4-dibenzyl-2-oxo-2H-1-benzopyran-7-yl)oxy]methyl]-5-methylfuran-2-carboxylic acid
0.01 mM, 3% inhibition. 0.1 mM, 64% inhibition
-
4-[[(3,4-dibenzyl-6-methyl-2-oxo-2H-1-benzopyran-7-yl)oxy]methyl]-5-methylfuran-2-carboxylic acid
0.01 mM, 32% inhibition. 0.1 mM, 84% inhibition
-
4-[[(6-hexyl-2-oxo-4-phenyl-2H-1-benzopyran-7-yl)oxy]methyl]-5-methylfuran-2-carboxylic acid
0.01 mM, 53% inhibition. 0.1 mM, 92% inhibition
-
4S-hydroxycitrate
-
5,7-dihydroxy-9-methyl-3-phenyl-3,4-dihydro-2H-anthra[2,3-e][1,3]oxazine-6,11-dione
-
5-methyl-4-[[(2-oxo-4-phenyl-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM,32% inhibition. 0.1 mM, 84% inhibition
-
5-methyl-4-[[(2-oxo-4-phenyl-6-propyl-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM, 97% inhibition. 0.1 mM, 97% inhibition
-
5-methyl-4-[[(4-methyl-2-oxo-3-phenyl-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM, 45% inhibition. 0.1 mM, 101% inhibition
-
5-methyl-4-[[(4-methyl-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-3-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM, 17% inhibition. 0.1 mM, 90% inhibition
-
5-[(2,3-dimethylbenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
0.01 mM, 11% inhibition. 0.1 mM, 43% inhibition
-
5-[(4-fluoro-2-methylbenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
0.01 mM, 3% inhibition. 0.1 mM, 9% inhibition
-
5-[(4-fluorobenzene-1-sulfonyl)amino]-2-phenyl-1-benzofuran-3-carboxylic acid
0.01 mM, 19% inhibition. 0.1 mM, 70% inhibition
-
5-[(4-methyl-3-nitrobenzene-1-sulfonyl)amino]-2-phenyl-1-benzofuran-3-carboxylic acid
0.01 mM,21% inhibition. 0.1 mM, 89% inhibition
-
5-[(4-methylbenzene-1-sulfonyl)amino]-2-phenyl-1-benzofuran-3-carboxylic acid
0.01 mM, 23% inhibition. 0.1 mM, 93% inhibition
-
5-[(benzenesulfonyl)amino]-2-phenyl-1-benzofuran-3-carboxylic acid
0.01 mM, 11% inhibition. 0.1 mM, 56% inhibition
-
5-[[(3,4-dibenzyl-2-oxo-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM, 9% inhibition. 0.1 mM, 49% inhibition
-
5-[[(4-methyl-6-oxo-7,8,9,10-tetrahydro-6H-dibenzo[b,d]pyran-3-yl)oxy]methyl]furan-2-carboxylic acid
0.01 mM, 18% inhibition. 0.1 mM, 88% inhibition
-
6,7-dibenzyl-2-methyl-5-[(4-methylbenzene-1-sulfonyl)amino]-1-benzofuran-3-carboxylic acid
0.01 mM, 12% inhibition. 0.1 mM, 42% inhibition
-
6,7-dibenzyl-5-[(4-ethylbenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
0.01 mM, 42% inhibition. 0.1 mM, 97% inhibition
-
6,7-dibenzyl-5-[(4-fluorobenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
0.01 mM, 28% inhibition. 0.1 mM, 95% inhibition
-
6,7-dibenzyl-5-[(4-tert-butylbenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
0.01 mM, 16% inhibition. 0.1 mM, 59% inhibition
-
bempedoic acid
Hydroxycitrate
-
methyl 3-chloro-5-(N-(4,6-difluoro-[1,1'-biphenyl]-3-yl)sulfamoyl)-4-hydroxybenzoate
SB-204990
in addition to lowering lipids by inhibiting ACLY, the chemical inhibitor SB-204990 also displays tumor suppressive effects
Tartrate
(+)-2,2-difluorocitrate
-
-
(-)-2,2-difluorocitrate
-
-
(-)-Hydroxycitrate
-
potent inhibitor
(1S,2S)-1,2-dihydroxypropane-1,2,3-tricarboxylic acid
-
50% inhibition at 0.00015 mM
(2E)-3-phenylprop-2-en-1-yl 2-[[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]amino]benzoate
-
50% inhibition at 0.00034 mM
(2R)-2-[(2S)-8-(3,5-dichlorophenyl)-2-hydroxyoctyl]-2-hydroxysuccinic acid
-
50% inhibition at 0.0021 mM
3,5-dichloro-2-hydroxy-N-(4-methoxybiphenyl-3-yl)benzenesulfonamide
-
50% inhibition of enzyme at 0.00013 mM, 50% inhibition of total lipid synthesis in HepG-2 cells at 0.008 mM, no cytotoxicity up to 0.05 mM
3,5-dichloro-N-(2,4,6-triphenyl-phenyl)-2-hydroxybenzenesulfonamide
-
50% inhibition at 0.00019 mM
3,5-dichloro-N-(3,5-di-tert-butylphenyl)-2-hydroxybenzenesulfonamide
-
50% inhibition at 0.0011 mM
5-methyl-2-(1-methylethyl)cyclohexyl 2-[[(3,5-dichloro-2-hydroxyphenyl)sulfonyl]amino]benzoate
-
50% inhibition at 0.00037 mM
BMS-303141
-
-
diethyldicarbonate
-
the addition of 0.5 mM ATP in the preincubation reaction mixture provided complete protection of enzyme activity from inactivation by diethyldicarbonate
Hydroxycitrate
radicicol
-
noncompetitive inhibitor
SB-201076
-
-
SB-204990
-
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
antizyme
-
antizyme 1 and 2 activate the enzyme through protein-protein interaction
-
D-fructose 1,6-diphosphate
-
activates
D-fructose 2,6-diphosphate
-
activates
D-fructose 6-phosphate
-
potent activator of the unphosphorylated recombinant enzyme, half-maximal activation at 0.16 mM
D-glucose 1-phosphate
-
activates
D-glucose 6-phosphate
-
activates
D-ribulose 5-phosphate
-
activates
D-xylulose 5-phosphate
-
activates
phosphoenolpyruvate
-
activates
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0308
citrate
pH and temperature not specified in the publication
0.047 - 41
ATP
0.0738 - 1.3
citrate
0.004 - 2.59
CoA
additional information
additional information
-
Km-value for phosphorylated enzyme forms
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
19
ATP
-
wild type enzyme, average value, in 50 mM Tris, 10 mM MgCl2, and 2 mM dithiothreitol (pH 8.0), at 22°C
230
citrate
-
wild type enzyme, average value, in 50 mM Tris, 10 mM MgCl2, and 2 mM dithiothreitol (pH 8.0), at 22°C
240
CoA
-
wild type enzyme, average value, in 50 mM Tris, 10 mM MgCl2, and 2 mM dithiothreitol (pH 8.0), at 22°C
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.137
ADP
pH and temperature not specified in the publication
0.00015
Hydroxycitrate
-
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0212
1,3,8-trihydroxy-2-(3-methoxyphenyl)-6-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0188
1,3,8-trihydroxy-2-(4-methoxyphenyl)-6-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0075
1,3,8-trihydroxy-2-iodo-6-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0133
1,3,8-trihydroxy-6-methyl-2-(1-methyl-1H-pyrazol-4-yl)anthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.03
1,3,8-trihydroxy-6-methyl-2-(3-methylphenyl)anthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0211
1,3,8-trihydroxy-6-methyl-2-(pyridin-3-yl)anthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0029
1,3-dibromo-2,4,5-trihydroxy-7-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0096
1-chloro-2,4,5-trihydroxy-7-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0235
2,4,5-trihydroxy-7-methyl-1,3-di(pyridin-3-yl)anthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.000283
2-chloro-1,3,8-trihydroxy-6-methylanthracen-9(10H)-one
Homo sapiens
pH 8.0, 30°C
-
0.0126
2-chloro-1,3,8-trihydroxy-6-methylanthracene-9,10-dione
Homo sapiens
pH 8.0, 30°C
-
0.0038
4-chloro-1,3,8-trihydroxy-6-methylanthracen-9(10H)-one
Homo sapiens
pH 8.0, 30°C
-
0.0041
5-methyl-4-[[(2-oxo-4-phenyl-6-propyl-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
Homo sapiens
pH 8.0, temperature not specified in the publication
-
0.0119
5-methyl-4-[[(4-methyl-2-oxo-3-phenyl-2H-1-benzopyran-7-yl)oxy]methyl]furan-2-carboxylic acid
Homo sapiens
pH 8.0, temperature not specified in the publication
-
0.0138
6,7-dibenzyl-5-[(4-ethylbenzene-1-sulfonyl)amino]-2-methyl-1-benzofuran-3-carboxylic acid
Homo sapiens
pH 8.0, temperature not specified in the publication
-
0.000377 - 0.000442
BMS-303141
0.00094
BMS-303141
Homo sapiens
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
2
-
recombinant enzyme
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.5
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
assay at
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
strong expression
Manually annotated by BRENDA team
normal and osteoarthritis human knee chondrocytes and cartilages
Manually annotated by BRENDA team
strong expression
Manually annotated by BRENDA team
normal and osteoarthritis human knee chondrocytes
Manually annotated by BRENDA team
ACLY deficiency in hepatocytes protects from hepatic steatosis and dyslipidemia
Manually annotated by BRENDA team
strong expression
Manually annotated by BRENDA team
primary skeletal muscle-derived myoblast
Manually annotated by BRENDA team
-
low expression
Manually annotated by BRENDA team
-
low expression
Manually annotated by BRENDA team
-
low expression
Manually annotated by BRENDA team
-
low expression
Manually annotated by BRENDA team
-
high expression
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
structural studies unmask a fundamental evolutionary relationship that links citrate synthase, the first enzyme of the oxidative Krebs cycle, to an ancestral tetrameric citryl-CoA lyase module that operates in the reverse Krebs cycle. This molecular transition marked a key step in the evolution of metabolism on Earth
malfunction
metabolism
physiological function
ATP citrate lyase plays a key role in regulating mitochondrial function, as well as glucose and lipid metabolism in skeletal muscle. The enzyme increases myoblast and satellite cell differentiation in vitro. It increases MYOD expression by acetyl-H3(K9/14/27) enrichment at the MYOD promoter. It acts downstream of IGF-1 to stimulate myogenesis. IT improves muscle regeneration following cardiotoxin-induced injury
malfunction
metabolism
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
ACLY_HUMAN
1101
0
120839
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
120608
x * 120608, calculated, identified by mass spectrometry
110000
-
4 * 110000, SDS-PAGE
120000
-
x * 120000, SDS-PAGE
125000
x * 125000, SDS-PAGE
480000
-
velocity sedimentation
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 120608, calculated, identified by mass spectrometry
homotetramer
tetramer
homotetramer
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
acetylation
phosphoprotein
ubiquitination
the enzyme is degraded by ubiquitinylation
phosphoprotein
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
full structure of human ACLY homotetramer in ternary complex with the inhibitor and ADP with an overall resolution of 3.67 A
in complex with citrate or tartrate, hanging drop vapor diffusion method, using either 12.5% (w/v) PEG 3350, 100 mM sodium tartrate, 100 mM Tris-HCl (pH 7.0) for the native protein or 10% PEG 3350, 75 mM potassium citrate, 100 mM Tris-HCl (pH 7.0) for the selenomethionyl protein
tartrate and ADP-Mg2+ bound N-terminal portion of the enzyme containing residues 1-817, hanging drop vapor diffusion method, using 12.5% (w/v) polyethylene glycol 3350, 125 mM sodium tartrate, 100 mM Tris-HCl (pH 8.2)
vapour diffusion crystallization
vapour diffusion in hanging drops. The protein is modified by introducing cleavage sites for Tobacco etch virus protease on either side of a disordered linker. The protein crystallized consists of residues 2-425-ENLYFQ and S-488-810 of human ATP-citrate lyase. When co-crystals are grown with ATP and magnesium ions as well as either the inhibitor (2S,3S)-2-hydroxycitrate or citrate, Mg2+-ADP is bound and His760 is phosphorylated
in the presence of tartrate, ATP and magnesium ions
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D1026N
mutant enzyme has 2% activity compared to wild-type enzyme
H975A
mutant enzyme has 25% activity compared to wild-type enzyme
H760A
-
the turnover number of the mutant is similar to that of wild type in the absence of citrate and CoA, yet significantly less than that of wild type enzyme in the presence of both citrate and CoA
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
30
-
4 h, stable
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
activity is stabilized by acetylation
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 1 year, stable
-
-20°C, pH 8 stable for 4 months
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
immobilized metal-ion affinity chromatography
Ni-NTA agarose column chromatography, Q-Sepharose column chromatography and DEAE-Sephacel gel filtration
ammonium sulfate precipitation, ion exchange chromatography (DEAE), gel filtration
-
glutathione Sepharose bead chromatography
-
recombinant enzyme
-
Superose 12 gel filtration
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21(DE3) cells
expression in Escherichia coli
expressed in 293-F cells
-
expressed in Baculovirus Bac-N-Blue expression system
-
expressed in Escherichia coli DH5alpha cells
-
expressed in Sf9 cells using a a baculovirus expression system
-
expression in Escherichia coli
-
myc-tagged version expressed in different cell lines
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
highly induced in the kidney of overweight or obese patients with chronic kidney disease. Induction is associated with increased ectopic lipid accumulation, glomerulosclerosis, and albuminuria. Acetyl-CoA is the substrate for de novo lipogenesis as well as for histone acetylation. By raising acetyl-CoA concentration ATP-citrate lyase promotes H3K9/14 and H3K27 hyperacetylation leading to up-regulation of several rate-limiting lipogenic enzymes and fibrogenic factors. On the other hand, the excess acetyl-CoA generated as a result of ATP-citrate lyase induction provides the substrate for these lipogenic enzymes to drive de novo lipogenesis leading to ectopic lipid accumulation, a detrimental event toward renal injury
in mesangial cells, the enzyme is synergistically induced by high glucose, palmitate, and TNF-alpha via NF-kapaB and PKA pathways
low molecular weight cyclin E upregulates enzymatic activity, subsequently increasing lipid droplet formation, thereby providing cells with essential building blocks to support growth
overexpressed in many cancers. ACLY transcription is promoted by SREBP1
the enzyme is overexpressed in cancer cells
enzyme mRNA and protein levels markedly (about 2.5fold) and quickly increase in activated macrophages. Tumour necrosis factor alpha and interferon gamma upregulate enzyme gene expression
-
sterol regulatory element binding protein-1 up-regulates the enzyme at mRNA level via Akt signaling
-
there are about 3fold increased levels of the enzyme in glioblastoma pseudopodia compared to unmigrated cells
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
medicine
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hoffmann, G.E.; Andres, H.; Weiss, L.; Kreisel, C.; Sander, R.
Properties and organ distribution of ATP citrate (pro-3S)-lyase
Biochim. Biophys. Acta
620
151-158
1980
Gallus gallus, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Tosukhowong, P.; Borvonpadungkitti, S.; Prasongwatana, V.; Tungsanga, K.; Jutuporn, S.; Dissayabutr, T.; Reungjui, S.; Sriboonlue, P.
Urinary citrate excretion in patients with renal stone: roles of leucocyte ATP citrate lyase activity and potassium salts therapy
Clin. Chim. Acta
325
71-78
2002
Homo sapiens
Manually annotated by BRENDA team
Ki, S.W.; Ishigami, K.; Kitahara, T.; Kasahara, K.; Yoshida, M.; Horinouchi, S.
Radicicol binds and inhibits mammalian ATP citrate lyase
J. Biol. Chem.
275
39231-39236
2000
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Potapova, I.A.; El-Maghrabi, M.R.; Doronin, S.V.; Benjamin, W.B.
Phosphorylation of recombinant human ATP:citrate lyase by cAMP-dependent protein kinase abolishes homotropic allosteric regulation of the enzyme by citrate and increases the enzyme activity. Allosteric activation of ATP:citrate lyase by phosphorylated sugars
Biochemistry
39
1169-1179
2000
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Tosukhowong, P.; Tungsanga, K.; Phongudom, S.; Sriboonlue, P.
Effects of potassium-magnesium citrate supplementation on cytosolic ATP citrate lyase and mitochondrial aconitase activity in leukocytes: a window on renal citrate metabolism
Int. J. Urol.
12
140-144
2005
Homo sapiens
Manually annotated by BRENDA team
Michno, A.; Skibowska, A.; Raszeja-Specht, A.; Cwikowska, J.; Szutowicz, A.
The role of adenosine triphosphate citrate lyase in the metabolism of acetyl coenzyme a and function of blood platelets in diabetes mellitus
Metabolism
53
66-72
2004
Homo sapiens
Manually annotated by BRENDA team
Li, J.J.; Wang, H.; Tino, J.A.; Robl, J.A.; Herpin, T.F.; Lawrence, R.M.; Biller, S.; Jamil, H.; Ponticiello, R.; Chen, L.; Chu, C.H.; Flynn, N.; Cheng, D.; Zhao, R.; Chen, B.; Schnur, D.; Obermeier, M.T.; Sasseville, V.; Padmanabha, R.; Pike, K.; Harrity, T.
2-Hydroxy-N-arylbenzenesulfonamides as ATP-citrate lyase inhibitors
Bioorg. Med. Chem. Lett.
17
3208-3211
2007
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Hatzivassiliou, G.; Zhao, F.; Bauer, D.E.; Andreadis, C.; Shaw, A.N.; Dhanak, D.; Hingorani, S.R.; Tuveson, D.A.; Thompson, C.B.
ATP citrate lyase inhibition can suppress tumor cell growth
Cancer Cell
8
311-321
2005
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Migita, T.; Narita, T.; Nomura, K.; Miyagi, E.; Inazuka, F.; Matsuura, M.; Ushijima, M.; Mashima, T.; Seimiya, H.; Satoh, Y.; Okumura, S.; Nakagawa, K.; Ishikawa, Y.
ATP citrate lyase: activation and therapeutic implications in non-small cell lung cancer
Cancer Res.
68
8547-8554
2008
Homo sapiens
Manually annotated by BRENDA team
Beckner, M.E.; Fellows-Mayle, W.; Zhang, Z.; Agostino, N.R.; Kant, J.A.; Day, B.W.; Pollack, I.F.
Identification of ATP citrate lyase as a positive regulator of glycolytic function in glioblastomas
Int. J. Cancer
126
2282-2295
2009
Homo sapiens, Homo sapiens (P53396)
Manually annotated by BRENDA team
Ma, Z.; Chu, C.; Cheng, D.
A novel direct homogeneous assay for ATP citrate lyase
J. Lipid Res.
50
2131-2135
2009
Homo sapiens
Manually annotated by BRENDA team
Wellen, K.; Hatzivassiliou, G.; Sachdeva, U.; Bui, T.; Cross, J.; Thompson, C.
ATP-citrate lyase links cellular metabolism to histone acetylation
Science
324
1076-1080
2009
Homo sapiens
Manually annotated by BRENDA team
Sun, T.; Hayakawa, K.; Fraser, M.E.
ADP-Mg2+ bound to the ATP-grasp domain of ATP-citrate lyase
Acta Crystallogr. Sect. F
67
1168-1172
2011
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Chypre, M.; Zaidi, N.; Smans, K.
ATP-citrate lyase: a mini-review
Biochem. Biophys. Res. Commun.
422
1-4
2012
Homo sapiens, Mus musculus
Manually annotated by BRENDA team
Fan, F.; Williams, H.J.; Boyer, J.G.; Graham, T.L.; Zhao, H.; Lehr, R.; Qi, H.; Schwartz, B.; Raushel, F.M.; Meek, T.D.
On the catalytic mechanism of human ATP citrate lyase
Biochemistry
51
5198-5211
2012
Homo sapiens
Manually annotated by BRENDA team
Sun, T.; Hayakawa, K.; Bateman, K.S.; Fraser, M.E.
Identification of the citrate-binding site of human ATP-citrate lyase using X-ray crystallography
J. Biol. Chem.
285
27418-27428
2010
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Zaidi, N.; Royaux, I.; Swinnen, J.V.; Smans, K.
ATP citrate lyase knockdown induces growth arrest and apoptosis through different cell- and environment-dependent mechanisms
Mol. Cancer Ther.
11
1925-1935
2012
Homo sapiens
Manually annotated by BRENDA team
Infantino, V.; Iacobazzi, V.; Palmieri, F.; Menga, A.
ATP-citrate lyase is essential for macrophage inflammatory response
Biochem. Biophys. Res. Commun.
440
105-111
2013
Homo sapiens
Manually annotated by BRENDA team
Tajima, A.; Murai, N.; Murakami, Y.; Iwamoto, T.; Migita, T.; Matsufuji, S.
Polyamine regulating protein antizyme binds to ATP citrate lyase to accelerate acetyl-CoA production in cancer cells
Biochem. Biophys. Res. Commun.
471
646-651
2016
Homo sapiens
Manually annotated by BRENDA team
Lee, J.H.; Jang, H.; Lee, S.M.; Lee, J.E.; Choi, J.; Kim, T.W.; Cho, E.J.; Youn, H.D.
ATP-citrate lyase regulates cellular senescence via an AMPK- and p53-dependent pathway
FEBS J.
282
361-371
2015
Homo sapiens
Manually annotated by BRENDA team
Hu, J.; Komakula, A.; Fraser, M.E.
Binding of hydroxycitrate to human ATP-citrate lyase
Acta Crystallogr. Sect. D
73
660-671
2017
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Jernigan, F.E.; Hanai, J.I.; Sukhatme, V.P.; Sun, L.
Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening
Bioorg. Med. Chem. Lett.
27
929-935
2017
Homo sapiens (P53396)
Manually annotated by BRENDA team
Icard, P.; Wu, Z.; Fournel, L.; Coquerel, A.; Lincet, H.; Alifano, M.
ATP citrate lyase A central metabolic enzyme in cancer
Cancer Lett.
471
125-134
2020
Homo sapiens (P53396)
Manually annotated by BRENDA team
Lucenay, K.S.; Doostan, I.; Karakas, C.; Bui, T.; Ding, Z.; Mills, G.B.; Hunt, K.K.; Keyomarsi, K.
Cyclin E associates with the lipogenic enzyme ATP-citrate lyase to enable malignant growth of breast cancer cells
Cancer Res.
76
2406-2418
2016
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Das, S.; Morvan, F.; Morozzi, G.; Jourde, B.; Minetti, G.C.; Kahle, P.; Rivet, H.; Brebbia, P.; Toussaint, G.; Glass, D.J.; Fornaro, M.
ATP citrate lyase regulates myofiber differentiation and increases regeneration by altering histone acetylation
Cell Rep.
21
3003-3011
2017
Homo sapiens (P53396), Mus musculus (Q91V92), Mus musculus
Manually annotated by BRENDA team
Koerner, S.K.; Hanai, J.I.; Bai, S.; Jernigan, F.E.; Oki, M.; Komaba, C.; Shuto, E.; Sukhatme, V.P.; Sun, L.
Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase
Eur. J. Med. Chem.
126
920-928
2017
Homo sapiens (P53396)
Manually annotated by BRENDA team
Chen, Y.; Deb, D.K.; Fu, X.; Yi, B.; Liang, Y.; Du, J.; He, L.; Li, Y.C.
ATP-citrate lyase is an epigenetic regulator to promote obesity-related kidney injury
FASEB J.
33
9602-9615
2019
Homo sapiens (P53396), Homo sapiens, Mus musculus (Q91V92)
Manually annotated by BRENDA team
Chen, L.Y.; Lotz, M.; Terkeltaub, R.; Liu-Bryan, R.
Modulation of matrix metabolism by ATP-citrate lyase in articular chondrocytes
J. Biol. Chem.
293
12259-12270
2018
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Bazilevsky, G.A.; Affronti, H.C.; Wei, X.; Campbell, S.L.; Wellen, K.E.; Marmorstein, R.
ATP-citrate lyase multimerization is required for coenzyme-A substrate binding and catalysis
J. Biol. Chem.
294
7259-7268
2019
Homo sapiens (P53396)
Manually annotated by BRENDA team
Khwairakpam, A.D.; Banik, K.; Girisa, S.; Shabnam, B.; Shakibaei, M.; Fan, L.; Arfuso, F.; Monisha, J.; Wang, H.; Mao, X.; Sethi, G.; Kunnumakkara, A.B.
The vital role of ATP citrate lyase in chronic diseases
J. Mol. Med.
98
71-95
2020
Homo sapiens (P53396)
Manually annotated by BRENDA team
Wei, X.; Schultz, K.; Bazilevsky, G.A.; Vogt, A.; Marmorstein, R.
Molecular basis for acetyl-CoA production by ATP-citrate lyase
Nat. Struct. Mol. Biol.
27
33-41
2020
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Wei, J.; Leit, S.; Kuai, J.; Therrien, E.; Rafi, S.; Harwood, H.J.; DeLaBarre, B.; Tong, L.
An allosteric mechanism for potent inhibition of human ATP-citrate lyase
Nature
568
566-570
2019
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Verschueren, K.H.G.; Blanchet, C.; Felix, J.; Dansercoer, A.; De Vos, D.; Bloch, Y.; Van Beeumen, J.; Svergun, D.; Gutsche, I.; Savvides, S.N.; Verstraete, K.
Structure of ATP citrate lyase and the origin of citrate synthase in the Krebs cycle
Nature
568
571-575
2019
Homo sapiens (P53396), Homo sapiens, Chlorobium limicola (Q9AQH6)
Manually annotated by BRENDA team
Feng, X.; Zhang, L.; Xu, S.; Shen, A.Z.
ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis An updated review
Prog. Lipid Res.
77
101006
2020
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team
Li, H.; Sartorelli, V.
ATP citrate lyase a new player linking skeletal muscle metabolism and epigenetics
Trends Endocrinol. Metab.
29
202-204
2018
Homo sapiens (P53396)
Manually annotated by BRENDA team
Granchi, C.
Discovery of allosteric inhibition of human ATP-citrate lyase
Trends Pharmacol. Sci.
40
364-366
2019
Homo sapiens (P53396), Homo sapiens
Manually annotated by BRENDA team