Acetyl-CoA carboxylase
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Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme that catalyses the irreversible carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). In muscle cells, this inhibits beta-oxidation. ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of ACC can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. Human genome contains the genes for two different ACCs - ACACA and ACACB.
[edit] StructureACACA (2346 aa) and ACACB (2483 aa) have four functional regions each, starting from NH2- to COOH-terminal: biotin carboxylating (BC), biotin binding (BB), carboxyltransferase (CT), and ATP-binding (AB). AT lies within BC. Biotin is covalently attached through an amide bond to the long side chain of a lysine reside in BB. As BB is between BC and CT regions, biotin can be easily delivered to their active sites. [edit] MechanismThe overall reaction of ACAC(A,B) proceeds by a two-step mechanism. The first half-reaction is carried out by BC and involves the ATP-dependent carboxylation of biotin with bicarbonate serving as the source of CO2. The carboxyl group is transferred from biotin to acetyl CoA to form malonyl CoA in the second half-reaction, which is catalyzed by CT. | |||||||||||||||||||||||||||||||||||||||||||||||||||
 The reaction mechanism of ACAC(A,B). The color scheme is as follows: enzyme, coenzymes, substrate names, metal ions, phosphate, and carbonate | |||||||||||||||||||||||||||||||||||||||||||||||||||
[edit] Function
In muscle cells, the function of ACAC is to regulate the fatty mechanism. When the enzyme is active, the product, malonyl-CoA is produced and inhibit the transfer of the fatty acyl group from acyl CoA to carnitine with carnitine acyltransferase, which inhibits the beta-oxidation of the fatty acid in mitochondria.
[edit] Regulation
The inactive dimer form of this enzyme is induced to polymerize by citrate, resulting in the active polymer form.
The activity of the enzyme is controlled by the reversible phosphorylation. The activities of the enzyme is inhibited if phosphorylated; the phosphorylation takes place when the hormones, glucagon or epinephrine bind to the receptors or the energy status of the cell is low, leading to the activation of the AMP-activated protein kinase.
The presence of fatty acid inhibits the activities of the enzyme.
When insulin binds to its receptors of the cell, it activates a phosphatase to dephosphorylate the enzyme; the activities of the acetyl-CoA carboxylase is thus enhanced.
[edit] Clinical implications
Bacterial Acetyl-CoA carboxylase has recently become a target in the design of new anti-obesity and antibiotic drugs.
[edit] See also
[edit] References
- Levert K, Waldrop G, Stephens J (2002). "A biotin analog inhibits acetyl-CoA carboxylase activity and adipogenesis". J. Biol. Chem. 277 (19): 16347–50. doi:. PMID 11907024.
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