Acetyl—CoA synthetase

Acetyl—CoA synthetase or Acetate—CoA ligase is an enzyme (EC 6.2.1.1) involved in metabolism 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 by acetyl-CoA synthetase are acetate and coenzyme A (CoA). The complete reaction with all the substrates and products included is:

ATP + Acetate + CoA <=> AMP + Pyrophosphate + Acetyl-CoA ^[1]

Once acetyl-CoA 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-CoA 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.^[2] 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.^[3]

The reaction catalyzed by acetyl-CoA 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.^[4] 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 CoA. The covalent bond is formed between the sulfur atom in Co-A and the central carbon atom of acetate.^[5]

The ACS1 form of acetyl-CoA synthetase is encoded by the gene facA, which is activated by acetate and deactivated by glucose.^[6]

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, to be more specific, Sirt3. This action increases activity of this enzyme.^[7] The exact location of the lysine residue varies between species, occurring at Lys-642 in humans, but is always present in the active site of the enzyme.^[8] 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 deactivate 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.^[4] The presence of all the reactants in the proper concentration is also needed for proper functioning as in all enzymes. Acetyl—CoA synthetase is also produced when it is needed for fatty acid synthesis, but, under normal conditions, the gene is inactive and has certain transcriptional factors that activate transcription when necessary.^[3] In addition to sirtuins, protein deacetylase (AcuC), also, modify acetyl—CoA at a lysine residue. However, unlike sirtuins, acetyl-CoA does not require NAD+ as a cosubstrate.^[9]

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.^[10]

Participation in Wood-Ljungdahl Pathway

Acetyl—CoA synthetase also participates in the Wood-Ljungdahl Pathway, which fixes anaerobic CO₂.^[11] 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.^[12] To be specific, ACS combines carbon monoxide and a methyl group to produce acetyl-CoA at a nickel-containing active site.^[13]

References