Acetyl Co-A synthetase

Acetyl Co-A synthetase is an enzyme involved metabolism in of carbon sugars. It is in the ligase class of enzymes, meaning that it catalyzes the formation of a new chemical bond between two large molecules.

Reaction
The two molecules joined specifically by acetyl Co-A synthetase are acetate and coenzyme A. The complete reaction with all the substrates and products included is:

ATP + Acetate + CoA <=> AMP + Pyrophosphate + Acetyl-CoA

Once acetyl Co-A is formed it can be used in the TCA cycle in aerobic respiration to produce energy and electron carriers. This is an alternate method to starting the cycle as the more common way is producing acetyl Co-A from pyruvate through the pyruvate dehydrogenase complex. The enzyme’s activity takes place in the mitochondrial matrix so that the products are in the proper place to be used in the following metabolic steps. Acetyl Co-A can also be used in fatty acid synthesis and a common function of the synthetase is to produce acetyl Co-A for this purpose.

The reaction catalyzed by acetyl Co-A synthetase takes place in two steps. First AMP must be bound by the enzyme to cause a conformational change in the active site which allows the reaction to take place. The active site is referred to as the A-cluster. A crucial lysine residue must be present in the active site to catalyze the first reaction where Co-A is bound. Co-A then rotates in the active site into the position where acetate can covalently bind to acetate. The covalent bond is formed between the sulfur atom in Co-A and the central carbon atom of acetate.

The ACS1 form of acetyl Co-A synthetase is encoded by the gene facA which is activated by acetate and deactivated by glucose.

Regulation
The activity of the enzyme is controlled in several ways. The essential lysine residue in the active site plays an important role in regulation of activity. The lysine molecule can be deacetylated by another class of enzyme called sirtuins. This action activates the enzymatic function of acetyl Co-A synthetase and the reverse action by the sirtuin will deactivate the enzyme. The exact location of the lysine residue varies between species with it occurring at Lys-642 in humans, but is always present in the active site of the enzyme. Since there is an essential allosteric change that occurs with the binding of an AMP molecule, the presence of AMP can contribute to regulation of the enzyme. Concentration of AMP must be high enough so that it can bind in the allosteric binding site and allow the other substrates to enter the active site. Also, copper ions deactivates acetyl Co-A synthetase by occupying the proximal site of the A-cluster active site which prevents the enzyme from accepting a methyl group to participate in the Wood-Ljungdahl Pathway. The presence of all the reactants in the proper concentration is also needed for proper functioning as in all enzymes. Acetyl Co-A synthetase is also regulated transcriptionally. The enzyme is produced when it is needed for fatty acid synthesis, but normally the gene is inactive and has certain transcriptional factors that activate transcription when necessary. In addition to sirtuins, protein deacetylase (AcuC) also modify acetyl Co-A at a lysine residue. However, unlike sirtuins, acetyl Co-A does not require NAD+ as a cosubstrate.

Role in gene expression
While acetyl-CoA synthetase’s activity is usually associated with metabolic pathways, the enzyme also participates in gene expression. In yeast, acetyl-CoA synthetase delivers acetyl-CoA to histone acetyltransferases for histone acetylation. Without correct acetylation, DNA cannot condense into chromatin properly which inevitably results in transcriptional errors.

Participation in Wood-Ljungdahl Pathway
Acetyl-CoA synthetase also participates in the Wood-Ljungdahl Pathway which fixes anaerobic CO2. The Wood-Ljungdahl Pathway consists of an eastern branch which all organisms use in one-carbon metabolism and a western branch which only anaerobes use for fixing carbon dioxide and carbon monoxide. Specifically, ACS combines carbon monoxide and a methyl group to produce acetyl-CoA at a nickel containing active site.