UniProt functional annotation for O00763



	UniProt functional annotation for O00763

UniProt code: O00763.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism (PubMed:16854592, PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:19900410, PubMed:26976583). Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:26976583). Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation (By similarity). Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage (By similarity). {ECO:0000250|UniProtKB:E9Q4Z2, ECO:0000269|PubMed:16854592, ECO:0000269|PubMed:19236960, ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:20457939, ECO:0000269|PubMed:20952656, ECO:0000269|PubMed:26976583}.

Catalytic activity: Reaction=acetyl-CoA + ATP + hydrogencarbonate = ADP + H(+) + malonyl- CoA + phosphate; Xref=Rhea:RHEA:11308, ChEBI:CHEBI:15378, ChEBI:CHEBI:17544, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:456216; EC=6.4.1.2; Evidence={ECO:0000269|PubMed:16854592, ECO:0000269|PubMed:19236960, ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:20457939, ECO:0000269|PubMed:20952656, ECO:0000269|PubMed:26976583}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11309; Evidence={ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:26976583};

Cofactor: Name=biotin; Xref=ChEBI:CHEBI:57586; Evidence={ECO:0000269|PubMed:16854592, ECO:0000269|PubMed:18247344};

Cofactor: Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000255|PROSITE-ProRule:PRU00409, ECO:0000255|PROSITE-ProRule:PRU00969}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000255|PROSITE-ProRule:PRU00409, ECO:0000255|PROSITE-ProRule:PRU00969}; Note=Binds 2 magnesium or manganese ions per subunit. {ECO:0000255|PROSITE-ProRule:PRU00409, ECO:0000255|PROSITE- ProRule:PRU00969};

Activity regulation: Activity is increased by oligomerization of the protein into filaments (PubMed:19900410). The oligomerization and the activity of the enzyme are inhibited by phosphorylation at Ser-222 (PubMed:12488245). Inhibited by its product, malonyl-CoA (PubMed:16854592). Activated by citrate (PubMed:16854592). Activation by MID1IP1 is citrate-dependent (PubMed:20457939). Soraphen A, inhibits the enzyme by preventing the formation of active filamentous oligomers (Probable). {ECO:0000269|PubMed:12488245, ECO:0000269|PubMed:16854592, ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:20457939, ECO:0000305|PubMed:19236960}.

Biophysicochemical properties: Kinetic parameters: KM=120 uM for ATP {ECO:0000269|PubMed:16854592}; KM=110 uM for ATP (isoform 2) {ECO:0000269|PubMed:19190759}; KM=58 uM for acetyl-CoA {ECO:0000269|PubMed:16854592}; KM=94 uM for acetyl-CoA (isoform 3) {ECO:0000269|PubMed:19190759}; KM=6.5 mM for NaHCO3 (isoform 3) {ECO:0000269|PubMed:19190759}; KM=3.0 mM for NaHCO(3) {ECO:0000269|PubMed:16854592}; pH dependence: Optimum pH is 7.5. {ECO:0000305|PubMed:19236960};

Pathway: Lipid metabolism; malonyl-CoA biosynthesis; malonyl-CoA from acetyl-CoA: step 1/1. {ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:26976583}.

Subunit: Monomer, homodimer, and homotetramer (PubMed:20952656, PubMed:18772397). Forms filamentous polymers (PubMed:20457939, PubMed:20952656, PubMed:19900410). Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity in a citrate-dependent manner (PubMed:20952656, PubMed:20457939). {ECO:0000269|PubMed:18772397, ECO:0000269|PubMed:19900410, ECO:0000269|PubMed:20457939, ECO:0000269|PubMed:20952656}.

Subcellular location: Mitochondrion {ECO:0000269|PubMed:10677481}.

Tissue specificity: Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759). {ECO:0000269|PubMed:19190759, ECO:0000269|PubMed:9099716}.

Domain: Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the ATP-dependent transient carboxylation of the biotin covalently attached to the central biotinyl-binding/biotin carboxyl carrier (BCC) domain (Probable). The C-terminal carboxyl transferase (CT) domain catalyzes the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA to produce malonyl-CoA (Probable). {ECO:0000305|PubMed:18247344, ECO:0000305|PubMed:19390150}.

Ptm: The biotin cofactor is covalently attached to the central biotinyl-binding domain and is required for the catalytic activity. {ECO:0000305|PubMed:18247344}.

Ptm: Phosphorylation at Ser-222 by AMPK inactivates the enzyme (PubMed:12488245). Required for the maintenance of skeletal muscle lipid and glucose homeostasis (By similarity). {ECO:0000250|UniProtKB:E9Q4Z2, ECO:0000269|PubMed:12488245}.

Biotechnology: Inhibition of ACACB may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme a potential pharmaceutical target for treatment of obesity and type 2 diabetes. {ECO:0000305}.

Sequence caution: Sequence=AAB58382.1; Type=Miscellaneous discrepancy; Note=Many Frameshifts and conflicts.; Evidence={ECO:0000305}; Sequence=CAE01470.2; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism (PubMed:16854592, PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:19900410, PubMed:26976583). Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:26976583). Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation (By similarity). Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage (By similarity). {ECO:0000250\|UniProtKB:E9Q4Z2, ECO:0000269\|PubMed:16854592, ECO:0000269\|PubMed:19236960, ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:20457939, ECO:0000269\|PubMed:20952656, ECO:0000269\|PubMed:26976583}.


Catalytic activity:		Reaction=acetyl-CoA + ATP + hydrogencarbonate = ADP + H(+) + malonyl- CoA + phosphate; Xref=Rhea:RHEA:11308, ChEBI:CHEBI:15378, ChEBI:CHEBI:17544, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:456216; EC=6.4.1.2; Evidence={ECO:0000269\|PubMed:16854592, ECO:0000269\|PubMed:19236960, ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:20457939, ECO:0000269\|PubMed:20952656, ECO:0000269\|PubMed:26976583}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11309; Evidence={ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:26976583};
Cofactor:		Name=biotin; Xref=ChEBI:CHEBI:57586; Evidence={ECO:0000269\|PubMed:16854592, ECO:0000269\|PubMed:18247344};
Cofactor:		Name=Mg(2+); Xref=ChEBI:CHEBI:18420; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00409, ECO:0000255\|PROSITE-ProRule:PRU00969}; Name=Mn(2+); Xref=ChEBI:CHEBI:29035; Evidence={ECO:0000255\|PROSITE-ProRule:PRU00409, ECO:0000255\|PROSITE-ProRule:PRU00969}; Note=Binds 2 magnesium or manganese ions per subunit. {ECO:0000255\|PROSITE-ProRule:PRU00409, ECO:0000255\|PROSITE- ProRule:PRU00969};
Activity regulation:		Activity is increased by oligomerization of the protein into filaments (PubMed:19900410). The oligomerization and the activity of the enzyme are inhibited by phosphorylation at Ser-222 (PubMed:12488245). Inhibited by its product, malonyl-CoA (PubMed:16854592). Activated by citrate (PubMed:16854592). Activation by MID1IP1 is citrate-dependent (PubMed:20457939). Soraphen A, inhibits the enzyme by preventing the formation of active filamentous oligomers (Probable). {ECO:0000269\|PubMed:12488245, ECO:0000269\|PubMed:16854592, ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:20457939, ECO:0000305\|PubMed:19236960}.
Biophysicochemical properties:		Kinetic parameters: KM=120 uM for ATP {ECO:0000269\|PubMed:16854592}; KM=110 uM for ATP (isoform 2) {ECO:0000269\|PubMed:19190759}; KM=58 uM for acetyl-CoA {ECO:0000269\|PubMed:16854592}; KM=94 uM for acetyl-CoA (isoform 3) {ECO:0000269\|PubMed:19190759}; KM=6.5 mM for NaHCO3 (isoform 3) {ECO:0000269\|PubMed:19190759}; KM=3.0 mM for NaHCO(3) {ECO:0000269\|PubMed:16854592}; pH dependence: Optimum pH is 7.5. {ECO:0000305\|PubMed:19236960};
Pathway:		Lipid metabolism; malonyl-CoA biosynthesis; malonyl-CoA from acetyl-CoA: step 1/1. {ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:26976583}.
Subunit:		Monomer, homodimer, and homotetramer (PubMed:20952656, PubMed:18772397). Forms filamentous polymers (PubMed:20457939, PubMed:20952656, PubMed:19900410). Interacts with MID1IP1; interaction with MID1IP1 promotes oligomerization and increases its activity in a citrate-dependent manner (PubMed:20952656, PubMed:20457939). {ECO:0000269\|PubMed:18772397, ECO:0000269\|PubMed:19900410, ECO:0000269\|PubMed:20457939, ECO:0000269\|PubMed:20952656}.
Subcellular location:		Mitochondrion {ECO:0000269\|PubMed:10677481}.
Tissue specificity:		Widely expressed with highest levels in heart, skeletal muscle, liver, adipose tissue, mammary gland, adrenal gland and colon (PubMed:9099716). Isoform 3 is expressed in skeletal muscle, adipose tissue and liver (at protein level) (PubMed:19190759). Isoform 3 is detected at high levels in adipose tissue with lower levels in heart, liver, skeletal muscle and testis (PubMed:19190759). {ECO:0000269\|PubMed:19190759, ECO:0000269\|PubMed:9099716}.
Domain:		Consists of an N-terminal biotin carboxylation/carboxylase (BC) domain that catalyzes the ATP-dependent transient carboxylation of the biotin covalently attached to the central biotinyl-binding/biotin carboxyl carrier (BCC) domain (Probable). The C-terminal carboxyl transferase (CT) domain catalyzes the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA to produce malonyl-CoA (Probable). {ECO:0000305\|PubMed:18247344, ECO:0000305\|PubMed:19390150}.
Ptm:		The biotin cofactor is covalently attached to the central biotinyl-binding domain and is required for the catalytic activity. {ECO:0000305\|PubMed:18247344}.
Ptm:		Phosphorylation at Ser-222 by AMPK inactivates the enzyme (PubMed:12488245). Required for the maintenance of skeletal muscle lipid and glucose homeostasis (By similarity). {ECO:0000250\|UniProtKB:E9Q4Z2, ECO:0000269\|PubMed:12488245}.
Biotechnology:		Inhibition of ACACB may prevent lipid-induced insulin resistance and type 2 diabetes, making the enzyme a potential pharmaceutical target for treatment of obesity and type 2 diabetes. {ECO:0000305}.
Sequence caution:		Sequence=AAB58382.1; Type=Miscellaneous discrepancy; Note=Many Frameshifts and conflicts.; Evidence={ECO:0000305}; Sequence=CAE01470.2; Type=Erroneous translation; Note=Wrong choice of CDS.; Evidence={ECO:0000305};