Acetyl—CoA synthetase

Acetate-CoA ligase
Identifiers
EC number 6.2.1.1
CAS number 9012-31-1
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Acetyl—CoA synthetase or Acetate—CoA ligase is an enzyme (EC 6.2.1.1) involved in metabolism of acetate. 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 together that make up 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. In mammals, the cytoplasmic-nuclear synthetase (AceCS1) is activated by SIRT1 while the mitochondrial synthetase (AceCS2) is activated by 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 can modify acetyl—CoA synthetase at a lysine residue. However, unlike sirtuins, AcuC 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 CO2 under anaerobic conditions.[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

  1. ↑ KEGG
  2. ↑ Schwer, B; Bunkenborg, J; Verdin, R; Andersen, J; Verdin, E (July 5, 2006), "Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2", Proc. Natl. Acad. Sci. USA 103 (27): 10224–9, doi:10.1073/pnas.0603968103, PMC 1502439, PMID 16788062
  3. 1 2 Ikeda, Yukio; Yamamoto, J; Okamura, M; Fujino, T; Takahashi, S; Takeuchi, K; Osborne, T; Yamamoto, T; Ito, S; Sakai, J (Sep 7, 2001), "Transcriptional regulation of the murine acetyl CoA synthetase 1 gene through multiple clustered binding sites for SREBPs and a single neighboring site for Sp1", J. Biol. Chem. 276 (36): 34259–69, doi:10.1074/jbc.M103848200, PMID 11435428
  4. 1 2 Bramlett, M; Tan, X; Lindahl, P (July 11, 2003), "Inactivation of Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase by Copper", J. Am. Chem. Soc. 125 (31): 9316–7, doi:10.1021/ja0352855
  5. ↑ Jogl, G; Tong, L (2004), "Crystal structure of yeast acetyl-coenzyme A synthetase in complex with AMP.", Biochemistry 43: 1425–31, doi:10.1021/bi035911a, PMID 14769018
  6. ↑ De Cima, S; Rua, J; Perdiguero, E; del Valle, P; Busto, F; Baroja-Mazo, A; D, de Arriaga (Apr 7, 2005), "An acetyl-CoA synthetase not encoded by the facA gene is expressed under carbon starvation in Phycomyces blakesleeanus.", Red Microbiol. 156 (5-6): 663–9, doi:10.1016/j.resmic.2005.03.003, PMID 15921892
  7. ↑ Schwer, B; Bunkenborg, J; Verdin, R; Andersen, J; Verdin, E (July 5, 2006), "Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2", Proc. Natl. Acad. Sci. USA 103 (27): 10224–9, doi:10.1073/pnas.0603968103, PMC 1502439, PMID 16788062
  8. ↑ Hallows, William C.; Lee, Susan; Denu, John M. (July 5, 2006), "Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases", Proc. Natl. Acad. Sci. USA 103 (27): 10230–5, doi:10.1073/pnas.0604392103, PMC 1480596, PMID 16790548
  9. ↑ Gardner, Jeffrey G.; Grundy, Frank J.; Henkin, Tina M.; Escalante-Semerena, Jorge C. (August 2006), "Control of Acetyl-Coenzyme A Synthetase (AcsA) Activity by Acetylation/Deacetylation without NAD+ Involvement in Bacillus subtilis", J Bacteriol 188 (15): 5460–8, doi:10.1128/JB.00215-06, PMC 1540023, PMID 16855235
  10. ↑ Takahashi, H; McCaffery, JM; Irizarry, RA; Boeke, JD (Jul 21, 2006), "Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.", Mol Cell 23 (2): 207–17, doi:10.1016/j.molcel.2006.05.040, PMID 16857587
  11. ↑ Seravalli, Javier; Kumar, Manoj; Ragsdale, Stephen (January 16, 2002), "Rapid Kinetic Studies of Acetyl-CoA Synthesis: Evidence Supporting the Catalytic Intermediacy of a Paramagnetic NiFeC Species in the Autotrophic Wood-Ljungdahl Pathway", Biochemistry 41 (6): 1807–19, doi:10.1021/bi011687i, PMID 11827525
  12. ↑ Ragsdale, SW (1997), "The eastern and western branches of the Wood/Ljungdahl pathway: how the east and west were won.", BioFactors 6 (1): 3–11, doi:10.1002/biof.5520060102, PMID 9233535
  13. ↑ Hegg, EL (Oct 2004), "Unraveling the structure and mechanism of acetyl-coenzyme A synthase.", Acc Chem Res 37 (10): 775–83, doi:10.1021/ar040002e, PMID 15491124
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