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Information on EC 6.2.1.16 - acetoacetate-CoA ligase and Organism(s) Mus musculus and UniProt Accession Q9D2R0
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6.2.1.16 acetoacetate-CoA ligaseIUBMB Comments
Also acts, more slowly, on L-3-hydroxybutanoate.
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Word Map
- 6.2.1.16
- ketone
- cholesterol
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lipogenesis
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body-utilizing
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lipogenic
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thiolase
- hmg-coa
- 3-hydroxybutyrate
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coa-transferase
- cholestyramine
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zoogloea
- ramigera
- srebp-2
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
acetoacetyl-coa synthetase, slaacs, acetoacetate-coa ligase, acetoacetyl coa synthetase, acetoacetyl-coa ligase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
Acetoacetate--CoA ligase
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Acetoacetyl CoA synthetase
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Acetoacetyl-CoA ligase
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Acetoacetyl-CoA synthase
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Acetoacetyl-CoA synthetase
Acetoacetyl-coenzyme A synthetase
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Synthetase, acetoacetyl coenzyme A
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Acetoacetyl-CoA synthetase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Acid-thiol ligation
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SYSTEMATIC NAME
IUBMB Comments
acetoacetate:CoA ligase (AMP-forming)
Also acts, more slowly, on L-3-hydroxybutanoate.
CAS REGISTRY NUMBER
COMMENTARY
39394-62-2
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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
additional information
?
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AACS promoter activity is controlled mainly by C/EBP? during adipogenesis
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?
ATP + acetoacetate + CoA
AMP + diphosphate + acetoacetyl-CoA
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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
additional information
?
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-
AACS promoter activity is controlled mainly by C/EBP? during adipogenesis
-
-
?
ATP + acetoacetate + CoA
AMP + diphosphate + acetoacetyl-CoA
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-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
additional information
no expression in cerebrum, cerebellum, skeletal muscle, spleen, heart, and lung, expression analysis, overview
additional information
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no expression in cerebrum, cerebellum, skeletal muscle, spleen, heart, and lung, expression analysis, overview
additional information
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expression analysis, no expression in skeletal muscle and spleen, overview
additional information
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AACS mRNA levels are dramatically increased in mice that are fed hypocholesterolemic agents
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
overexpression of recombinant mutants N500Q, N503Q, or N547Q, as well as of the wild-type enzyme, increases the ketone body-utilizing activity of HEK-293 cells, but that of N545Q does not. Overexpression of wild-type AACS, N500Q, or N503Q has no effect on legumain activity, but mutations N545Q and N547Q significantly reduce the activity compared to wild-type
metabolism
physiological function
malfunction
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knockdown of AACS inhibits differentiation of 3T3-L1 cells and suppresses expression of the adipocyte markers, peroxisome proliferator-activated receptor gamma and CCAAT/enhancer binding protein alpha
metabolism
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AACS is involved in the pathway of ketone body metabolism, overview
physiological function
additional information
metabolism
Legumain is involved in the cleavage of AACS in the kidney, suggesting that AACS is degraded by the lysosomal pathway
metabolism
acetoacetyl-CoA synthetase (AACS) is responsible for the synthesis of cholesterol and fatty acids. It is cleaved by legumain, a lysosomal asparaginyl endopeptidase. Asn547 is the specific cleavage site of AACS in mouse livers. The cleaved form of AACS (1-547) loses the ability to convert acetoacetate to acetoacetyl-CoA. Overexpression of the cleaved form of AACS (1-547) increases the protein expression of caveolin-1, the principal component of the caveolae. Cleavage of AACS by legumain is critical for the regulation of enzymatic activity and results in gain-of-function changes
physiological function
acetoacetyl-CoA synthetase (AACS) is a ketone body-utilizing enzyme and is responsible for the synthesis of cholesterol and fatty acids. Overexpression of wild-type AACS and AACS (1-547) increased the protein expression of caveolin-1, a scaffolding protein and the principal component of the caveolae, in the cytosol of liver cells. Enzyme AACS has a unique role in caveolae/lipid rafts
physiological function
in the cytosol, acetoacetate is converted to acetoacetyl-CoA by acetoacetyl-CoA synthetase (AACS) for the synthesis of cholesterol and fatty acids. Acetoacetyl-CoA synthetase is a ketone body-utilizing enzyme, which is responsible for the synthesis of cholesterol and fatty acids from ketone bodies in lipogenic tissues, such as the liver and adipocytes. Enzyme AACS is posttranslationally regulated, being cleaved at a specific site in the kidney
physiological function
hydrodynamics-based gene transduction shows that overexpression of AACS (1547) increases the protein expression of caveolin-1, the principal component of the caveolae. Cleavage of AACS by legumain is critical for the regulation of enzymatic activity and results in gain-of-function changes
physiological function
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AACS plays an important role in cholesterol homeostasis
physiological function
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the enzyme has a crucial role in the mechanism of 3T3-L1 differentiation
additional information
site-specific cleavage at residue Asn547 of acetoacetyl-CoA synthetase by legumain, a lysosomal asparaginyl endopeptidase. The cleaved form of AACS (1-547) loses the ability to convert acetoacetate to acetoacetyl-CoA
additional information
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site-specific cleavage at residue Asn547 of acetoacetyl-CoA synthetase by legumain, a lysosomal asparaginyl endopeptidase. The cleaved form of AACS (1-547) loses the ability to convert acetoacetate to acetoacetyl-CoA
additional information
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transcription mechanism of AACS, expression of AACS is regulated by cholesterol depletion, overview
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). AACS_MOUSE
672
0
75200
Swiss-Prot
other Location (Reliability: 1)
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
proteolytic modification
proteolytic modification
enzyme AACS is posttranslationally regulated, being cleaved at a specific site in the kidney. In vivo cleavage of enzyme AACS by legumain in HEK 293 cells generates the 55 kDa product from AACS. Incubation of recombinant AACS with recombinant legumain results in the degradation of AACS, optimally at pH 4.5. Knockdown of legumain with short-hairpin RNA against legumain using the hydrodynamics method leads to a decrease in the 55 kDa band of AACS in mouse kidney. Legumain is involved in the processing of AACS through the lysosomal degradation pathway in the kidney. Suppression of legumain results in a decrease in the cleaved form of AACS protein, and an increase in the full-length form of AACS protein. Legumain is involved in the cleavage of AACS in the kidney, suggesting that AACS is degraded by the lysosomal pathway
proteolytic modification
site-specific cleavage at residue AACS Asn503 and Asn547 of acetoacetyl-CoA synthetase by recombinant autoactivated legumain, a lysosomal asparaginyl endopeptidase, at pH 5.0 and 30°C. The cleaved form of AACS (1-547) loses the ability to convert acetoacetate to acetoacetyl-CoA. AACS is cleaved by legumain in the liver and the kidney to give two primary bands of approximately 56 kDa and 48 kDa, AACS (1-547) and AACS (1-503) are approximately 56 kDa and 55 kDa, respectively. The cleavage site for the formation of the 56-kDa product is located in the C-terminal side region from amino acid 487, whereas that of the 48-kDa product is located in the N-terminal side region from amino acid 468
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
N503Q
site-directed mutagenesis, the mutant iscleaved by legumain, but the mutation abolishes the formation of the 56-kDa band through cleavage by legumain
N545Q
site-directed mutagenesis, catalytically inactive mutant, that is cleaved by legumain
N547Q
site-directed mutagenesis, the mutant iscleaved by legumain, but the mutation abolishes the formation of the 56-kDa band through cleavage by legumain
additional information
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enzyme downregulation by shAACS targeted lentivirus expression in 3T3-L1 cells
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
acetoacetyl-CoA synthetase (AACS) is cleaved by legumain, a lysosomal asparaginyl endopeptidase. Asn547 is the specific cleavage site of AACS in mouse livers. The cleaved form of AACS (1-547) loses the ability to convert acetoacetate to acetoacetyl-CoA
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant FLAG-tagged enzyme from Lenti-X-293T cells by affinity chromatography and ultrafiltration
recombinant FLAG-tagged enzyme from Lenti-X-293T cells by affinity chromatography and ultrafiltration
recombinant FLAG-tagged enzyme from Lenti-X-293T cells by affinity chromatography and ultrafiltration
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Aacs, cloning and recombinant expression of FLAG-tagged enzyme in Lenti-X-293T cells. AACS and legumain are transiently expressed in HEK-293 cells
gene Aacs, recombinant expression of FLAG-tagged enzyme in Lenti-X-293T cells, overexpression of wild-type and mutant enzymes in HEK-293 cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
treatment of hepatocytes with U18666A results in the upregulation of AACS gene expression
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hasegawa, S.; Yamasaki, M.; Inage, T.; Takahashi, N.; Fukui, T.
Transcriptional regulation of ketone body-utilizing enzyme, acetoacetyl-CoA synthetase, by C/EBPalpha during adipocyte differentiation
Biochim. Biophys. Acta
1779
414-419
2008
Mus musculus
Hasegawa, S.; Noda, K.; Maeda, A.; Matsuoka, M.; Yamasaki, M.; Fukui, T.
Acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, is controlled by SREBP-2 and affects serum cholesterol levels
Mol. Genet. Metab.
107
553-560
2012
Mus musculus, Mus musculus ddY
Hasegawa, S.; Ikeda, Y.; Yamasaki, M.; Fukui, T.
The role of acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, in 3T3-L1 adipocyte differentiation
Biol. Pharm. Bull.
35
1980-1985
2012
Mus musculus
Hasegawa, S.; Yamasaki, M.; Fukui, T.
Degradation of acetoacetyl-CoA synthetase, a ketone body-utilizing enzyme, by legumain in the mouse kidney
Biochem. Biophys. Res. Commun.
453
631-635
2014
Mus musculus (Q9D2R0), Mus musculus, Mus musculus ddY (Q9D2R0)
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