Information on EC 2.3.3.1 - citrate (Si)-synthase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY
2.3.3.1
-
RECOMMENDED NAME
GeneOntology No.
citrate (Si)-synthase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
acetyl-CoA + H2O + oxaloacetate = citrate + CoA
show the reaction diagram
The stereospecificity of this enzyme is opposite to that of EC 2.3.3.4, citrate (Re)-synthase, which is found in some anaerobes
-
-
-
acetyl-CoA + H2O + oxaloacetate = citrate + CoA
show the reaction diagram
active site His320; mechanism
-
acetyl-CoA + H2O + oxaloacetate = citrate + CoA
show the reaction diagram
high-level ab initio quantum mechanical/molecular mechanical modelling of citryl-CoA formation in citrate synthase reveals that an arginine residue acts as the proton donor
-
REACTION TYPE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
addition
-
-
-
-
PATHWAY
KEGG Link
MetaCyc Link
Biosynthesis of secondary metabolites
-
Citrate cycle (TCA cycle)
-
ethylene biosynthesis V
-
glutamine biosynthesis III
-
Glyoxylate and dicarboxylate metabolism
-
glyoxylate cycle
-
itaconate biosynthesis
-
Metabolic pathways
-
methylaspartate cycle
-
Microbial metabolism in diverse environments
-
mixed acid fermentation
-
respiration (anaerobic)
-
TCA cycle I (prokaryotic)
-
TCA cycle II (plants and fungi)
-
TCA cycle III (helicobacter)
-
TCA cycle IV (2-oxoglutarate decarboxylase)
-
TCA cycle V (2-oxoglutarate:ferredoxin oxidoreductase)
-
TCA cycle VI (obligate autotrophs)
-
TCA cycle VII (acetate-producers)
-
TCA cycle VIII (metazoan)
-
SYSTEMATIC NAME
IUBMB Comments
acetyl-CoA:oxaloacetate C-acetyltransferase [thioester-hydrolysing, (pro-S)-carboxymethyl forming]
The stereospecificity of this enzyme is opposite to that of EC 2.3.3.3, citrate (Re)-synthase, which is found in some anaerobes. Citrate synthase for which the stereospecificity with respect to C2 of oxaloacetate has not been established are included in EC 2.3.3.16, citrate synthase.
SYNONYMS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
(R)-citric synthase
-
-
-
-
citrate oxaloacetate-lyase ((pro-3S)-CH2COO---> acetyl-CoA)
-
-
-
-
citrate synthase
-
-
citrate synthase
-
-
citrate synthase isoform a
O75390
-
citrate synthase isoform b
-
-
EC 4.1.3.7
-
formerly
CAS REGISTRY NUMBER
COMMENTARY
9027-96-7
-
ORGANISM
COMMENTARY
LITERATURE
SEQUENCE CODE
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
strain ATCC 14123
-
-
Manually annotated by BRENDA team
adult male
-
-
Manually annotated by BRENDA team
male Wistar rats
-
-
Manually annotated by BRENDA team
Wistar-Furth, citrate synthase deficient strain, 28% decreased activity compared to wild-type
-
-
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
malfunction
-
citrate synthase activity reduction leads to a strong L-lysine accumulation
metabolism
-
the enzyme is required for both tricarboxylic acid and glyoxylic acid cycle activity
metabolism
-
citrate synthase is a key enzyme of the citric acid cycle that provides energy for cellular function. Additionally, the enzyme plays a critical role in providing citrate derived acetyl-CoA for lipogenesis and cholesterologenesis
physiological function
-
the citrate synthase gene is a direct retinoic acid receptor-related orphan receptor alpha target and one mechanism by which retinoic acid receptor-related orphan receptor alpha regulates lipid metabolism is via regulation of citrate synthase expression
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + H2O + oxaloacetate
citrate + CoA
show the reaction diagram
-
-
-
-
?
acetyl-CoA + H2O + oxaloacetate
citrate + CoA
show the reaction diagram
-
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
-
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
intermediate citryl-CoA
-
r
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
entry step to tricarboxylic acid cycle, key enzyme of tricarboxylic acid cycle
-
?
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
-
-
?
acetyl-CoA + oxaloacetate + H2O
citrate + CoA
show the reaction diagram
-
entry step to tricarboxylic acid cycle, key enzyme of tricarboxylic acid cycle
-
?
METALS and IONS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
additional information
-
no activation by metal ions
INHIBITORS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
2-oxoglutarate
-
no inhibition
amphetamine
-
valproate reverses and lithium prevents the enzyme inhibition
ATP
-
noncompetitive against acetyl-CoA
Ouabain
-
activity was inhibited immediately after the administration of ouabain in the prefrontal cortex at the doses of 0.01 mM and 0.1 mM
SDS
-
strong inhibition
ACTIVATING COMPOUND
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
KM VALUE [mM] Maximum
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.005
-
acetyl-CoA
-
wild-type
0.01
-
acetyl-CoA
-
-
0.018
-
acetyl-CoA
-
-
0.089
-
acetyl-CoA
-
mutant H320G
0.41
-
acetyl-CoA
-
-
10
-
acetyl-CoA
-
-
0.005
-
oxaloacetate
-
-
0.0059
-
oxaloacetate
-
wild-type
0.019
-
oxaloacetate
-
-
0.027
-
oxaloacetate
-
-
0.043
-
oxaloacetate
-
mutant H320G
5
-
oxaloacetate
-
-
TURNOVER NUMBER [1/s]
TURNOVER NUMBER MAXIMUM[1/s]
SUBSTRATE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
IMAGE
0.275
-
oxaloacetate
-
mutant H320G
167
-
oxaloacetate
-
wild-type
SPECIFIC ACTIVITY [µmol/min/mg]
SPECIFIC ACTIVITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
0.076
-
-
citrate synthase deficient strain
24
-
-
purified enzyme
108
-
-
purified enzyme
additional information
-
-
-
additional information
-
-
activity in trained and untrained skeletal muscle, highest in acutely trained muscle due to mitochondrial membrane breakdown, mechanism
pH OPTIMUM
pH MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
7.4
-
-
enzyme assay at
7.9
-
-
enzyme assay at
8
-
-
enzyme assay at
additional information
-
-
pI: 5.4
TEMPERATURE OPTIMUM
TEMPERATURE OPTIMUM MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
30
-
-
enzyme assay at
SOURCE TISSUE
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
SOURCE
-
highest at 4-cell stage
Manually annotated by BRENDA team
-
ventricular tissue with greater activity than right atrium
Manually annotated by BRENDA team
-
left free wall shows higher activity than that at the apex
Manually annotated by BRENDA team
-
cancer and normal tissue
Manually annotated by BRENDA team
-
activity of citrate synthase is significantly higher compared with adjacent nonneoplastic tissue
Manually annotated by BRENDA team
-
of female rats. Deep region closest have the highest citrate synthase activity
Manually annotated by BRENDA team
-
trained and untrained
Manually annotated by BRENDA team
-
a significant increase in maximal activity (63%) and expression (80%) of citrate synthase is observed in stimulated soleus muscles, isolated 1 h after electrical stimulation as compared to controls
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
encoded by nuclear DNA, precursor is synthesized in the cytosol, import into mitochondrion
Manually annotated by BRENDA team
-
mitochondrial adaptation
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
Bacillus subtilis (strain 168)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Pyrobaculum aerophilum (strain ATCC 51768 / IM2 / DSM 7523 / JCM 9630 / NBRC 100827)
Pyrococcus furiosus (strain ATCC 43587 / DSM 3638 / JCM 8422 / Vc1)
Sulfolobus solfataricus (strain ATCC 35092 / DSM 1617 / JCM 11322 / P2)
Sulfolobus tokodaii (strain DSM 16993 / JCM 10545 / NBRC 100140 / 7)
Sulfolobus tokodaii (strain DSM 16993 / JCM 10545 / NBRC 100140 / 7)
Thermoplasma acidophilum (strain ATCC 25905 / DSM 1728 / JCM 9062 / NBRC 15155 / AMRC-C165)
Thermoplasma acidophilum (strain ATCC 25905 / DSM 1728 / JCM 9062 / NBRC 15155 / AMRC-C165)
Thermoplasma acidophilum (strain ATCC 25905 / DSM 1728 / JCM 9062 / NBRC 15155 / AMRC-C165)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)
Vibrio vulnificus (strain CMCP6)
MOLECULAR WEIGHT
MOLECULAR WEIGHT MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
70000
-
-
gel filtration
104000
-
-
gel filtration
250000
-
-
gel filtration
additional information
-
-
amino acid sequence
SUBUNITS
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
?
-
x * 47000, SDS-PAGE
dimer
-
2 * 50000, SDS-PAGE
tetramer
-
2 * 45000 + 2 * 80000, alpha, beta, SDS-PAGE
dimer
-
2 * 40000, SDS-PAGE
additional information
-
molecular basis of subunit interactions
additional information
-
in presence of nardilysin, EC 3.4.24.61, citrate synthase co-immunoprecipitates with mitochondrial malate dehydrogenase. In addition, citrate synthase binds to immobilized nardilysin
additional information
P00889
detection of peptides within the enzyme which show strong binding with small heat shock proteins. Thermostabilization of thermosensitive citrate synthase by small heat shock proteins is achieved by stabilization of the C- and N-terminae in the protruding thermosensitive softspot, which is absent in the thermostable forms of the enzyme’s dimer
pH STABILITY
pH STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
TEMPERATURE STABILITY MAXIMUM
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
38
-
-
thermal inactivation: less than 12% of activity remains after 60 min
additional information
-
-
-
additional information
-
P00889
small heat shock proteins prevent aggregation of citrate synthase and bind to the N-terminal region which is absent in thermostable forms of citrate synthase
Purification/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
commercial preparation
-
Cloned/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
cDNA cloning and sequencing, mRNA expression pattern during embryonic development, DNA and amino acid sequence analysis
-
EGFP-fusion version expressed in HeLa cell
O75390
expressed in Hep-G2 cells
-
EXPRESSION
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
Al3+ increases the expression level of citrate synthase gene and enzyme activity
-
during sexual development, the expression of citrate synthase is significantly weak in the content of cleistothecia including ascospores
-
during sexual development, the expression of citrate synthase is quite strong in cleistothecial shells. Acetate shows a strong inductive effect on citA expression, which is subjected to carbon catabolite repression caused by glucose
-
during sexual development, the expression of citrate synthase is significantly weak in the content of cleistothecia including ascospores
Emericella nidulans FGSC A26
-
-
during sexual development, the expression of citrate synthase is quite strong in cleistothecial shells. Acetate shows a strong inductive effect on citA expression, which is subjected to carbon catabolite repression caused by glucose
Emericella nidulans FGSC A26
-
-
overexpression of retinoic acid receptor-related orphan receptor alpha (5fold), leads to a 94% increase in citrate synthase mRNA levels and enzyme activity in Hep-G2 cells
-
expression is regulated by catabolite control protein C (CcpC)
-
the mRNA expression of citrate synthase in liver is reduced by 42% in the staggerer mice (which possess a nonfunctional retinoic acid receptor-related orphan receptor alpha protein) relative to the wild type mice
-
AlCl3 treatment
-
in AlCl3 containing growth edium
-
acute administration of olanzapine inhibits citrate synthase activity in cerebellum and prefrontal cortex
-
oanzapine 3 mg/kg and fluoxetine 12.5 mg/kg in combination increase citrate synthase activity in prefrontal cortex, hippocampus and striatum. The chronic administration of olanzapine increases citrate synthase activity in prefrontal cortex, hippocampus and striatum and fluoxetine increases citrate synthase activity in striatum
-
ENGINEERING
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
H320G
-
effect of H320G substitution, solvent accessibility, and conformational changes on catalysis and activity
Renatured/COMMENTARY
ORGANISM
UNIPROT ACCESSION NO.
LITERATURE
only after removal of 6 M denaturing guanidinium chloride by dialysis, not by dilution, dithiothreitol-dependent
-
study on the mechanism of aggregation during refolding of enzyme and its prevention using cosolvent additives of the polyol series. No parallel correlation between the folding effect and the general stabilization is observed. Glycerol is most effective in enhancing the refolding yield of citrate synthase, and a complete recovery of enzymatic activity is observed at 7 M glycerol and 0.01 mg per ml protein. Kinetic experiments suggest that polyols act very early in the refolding process. Both the thermodynamic and the kinetic aspects are critical in the folding process
-
APPLICATION
ORGANISM
UNIPROT ACCESSION NO.
COMMENTARY
LITERATURE
analysis
-
cellular stress marker