Acetyl Co-A synthetase

Protbox
Name=Acetyl Co-A Synthetase
Photo=
Caption=The 1.75 A Crystal Structure of Acetyl-CoA Synthetase Bound to Adenosine-5'-propylphosphate and Coenzyme A
Gene_type=protein coding
Molecular_weight=
Structure=
Type=Enzyme: Ligase
Functions=converts ATP + Acetate + Coenzyme A to AMP + Pyrophosphate + Acetyl-CoA
Domains=
Motifs=
Alternative_products=
Catalytic_activity=
Cofactors=
Enzyme_regulation=
Diseases=
Pharmaceuticals=
Taxa=
Cells=
Location=mitochondrial matrix
Names=
Pathways=Pyruvate metabolism, Glycolysis, Gluconeogenesis
Interactions=
Pages=
Review=
ECnumber=6.2.1.1
Names=acetate-CoA ligase, acetic thiokinase, acetyl CoA synthase, acetyl activating enzyme, ACS

Acetyl Co-A synthetase is an enzyme (EC number|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 specifically by acetyl Co-A 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 [ [http://www.genome.ad.jp/dbget-bin/www_bget?enzyme+6.2.1.1 KEGG] ]

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. [Citation
last = Schwer
first = B
last2 = Bunkenborg
first2 = J
last3 = Verdin
first3 = R
last4 = Andersen
first4 = J
last5 = Verdin
first5 = E
title = Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2
journal = Proc Natl Acad Sci
volume = 103
issue = 27
pages = 10224-10229
date = July 5
year = 2006
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16788062] 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. [Citation
last = Ikeda
first = Yukio
last2 = Yamamoto
first2 = J
last3 = Okamura
first3 = M
last4 = Fujino
first4 = T
last5 = Takahashi
first5 = S
last6 = Takeuchi
first6 = K
last7 = Osborne
first7 = T
last8 = Yamamoto
first8 = T
last9 = Ito
first9 = S
last10 = Sakai
first10 = J
title = Transcriptional regulation of the murine acetyl CoA synthetase 1 gene through multiple clustered binding sites for SREBPs and a single neighboring site for Sp1
journal = J. Biol. Chem
volume = 276
issue = 36
pages = 34259-69
date = Sep 7
year = 2001
url = http://www.jbc.org/cgi/content/abstract/M103848200v1 ]

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. [Citation
last = Bramlett
first = M
last2 = Tan
first2 = X
last3 = Lindahl
first3 = P
title = Inactivation of Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase by Copper
journal = J. Am. Chem. Soc.
volume = 125
issue = 31
pages = 9316-9317
date = July 11
year = 2003
url = http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2003/125/i31/abs/ja0352855.html] 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. [Citation
last = Jogl
first = G
last2 = Tong
first2 = L
title = Crystal structure of yeast acetyl-coenzyme A synthetase in complex with AMP.
journal = Biochemistry
volume = 43
issue =
pages = 1425-31
date =
year = 2004
url = http://www.rcsb.org/pdb/explore/pubmed.do?structureId=1RY2]

The ACS1 form of acetyl Co-A synthetase is encoded by the gene facA which is activated by acetate and deactivated by glucose. [Citation
last = De Cima
first = S
last2 = Rua
first2 = J
last3 = Perdiguero
first3 = E
last4 = del Valle
first4 = P
last5 = Busto
first5 = F
last6 = Baroja-Mazo
first6 = A
first7 = de Arriaga
last7 = D
title = An acetyl-CoA synthetase not encoded by the facA gene is expressed under carbon starvation in Phycomyces blakesleeanus.
journal = Red Microbiol.
volume = 156
issue = 5-6
pages = 663-9
date = Apr 7
year = 2005
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15921892&query_hl=4&itool=pubmed_DocSum]

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. [Citation
last = Schwer
first = B
last2 = Bunkenborg
first2 = J
last3 = Verdin
first3 = R
last4 = Andersen
first4 = J
last5 = Verdin
first5 = E
title = Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2
journal = Proc Natl Acad Sci
volume = 103
issue = 27
pages = 10224-10229
date = July 5
year = 2006
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16788062] 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. [Citation
last = Hallows
first = William C.
last2 = Lee
first2 = Susan
last3 = Denu
first3 = John M.
title = Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases
journal = Proc Natl Acad Sci
volume = 103
issue = 27
pages = 10230-10235
date = July 5
year = 2006
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16790548] 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. [Citation
last = Bramlett
first = M
last2 = Tan
first2 = X
last3 = Lindahl
first3 = P
title = Inactivation of Acetyl-CoA Synthase/Carbon Monoxide Dehydrogenase by Copper
journal = J. Am. Chem. Soc.
volume = 125
issue = 31
pages = 9316-9317
date = July 11
year = 2003
url = http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/2003/125/i31/abs/ja0352855.html] 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. [Citation
last = Ikeda
first = Yukio
last2 = Yamamoto
first2 = J
last3 = Okamura
first3 = M
last4 = Fujino
first4 = T
last5 = Takahashi
first5 = S
last6 = Takeuchi
first6 = K
last7 = Osborne
first7 = T
last8 = Yamamoto
first8 = T
last9 = Ito
first9 = S
last10 = Sakai
first10 = J
title = Transcriptional regulation of the murine acetyl CoA synthetase 1 gene through multiple clustered binding sites for SREBPs and a single neighboring site for Sp1
journal = J. Biol. Chem
volume = 276
issue = 36
pages = 34259-69
date = Sep 7
year = 2001
url = http://www.jbc.org/cgi/content/abstract/M103848200v1 ] 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. [Citation
last = Gardner
first = Jeffrey G.
last2 = Grundy
first2 = Frank J.
last3 = Henkin
first3 = Tina M.
last4 = Escalante-Semerena
first4 = Jorge C.
title = Control of Acetyl-Coenzyme A Synthetase (AcsA) Activity by Acetylation/Deacetylation without NAD+ Involvement in Bacillus subtilis
journal = J Bacteriol
volume = 188
issue = 15
pages = 5460-5468
date = August
year = 2006
url = http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=16855235]

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. [Citation
last = Takahashi
first = H
last2 = McCaffery
first2 = JM
last3 = Irizarry
first3 = RA
last4 = Boeke
first4 = JD
title = Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription.
journal = Mol Cell
volume = 23
issue = 2
pages = 207-217
date = Jul 21
year = 2006
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16857587&query_hl=3&itool=pubmed_docsum]

Participation in Wood-Ljungdahl Pathway

Acetyl-CoA synthetase also participates in the Wood-Ljungdahl Pathway which fixes anaerobic CO₂. [Citation
last = Seravalli
first = Javier
last2 = Kumar
first2 = Manoj
last3 = Ragsdale
first3 = Stephen
title = Rapid Kinetic Studies of Acetyl-CoA Synthesis: Evidence Supporting the Catalytic Intermediacy of a Paramagnetic NiFeC Species in the Autotrophic Wood-Ljungdahl Pathway
journal = Biochemistry
volume = 41
issue = 6
pages = 1807-1819
date = January 16
year = 2002
url = http://pubs.acs.org/cgi-bin/abstract.cgi/bichaw/2002/41/i06/abs/bi011687i.html] 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. [Citation
last = Ragsdale
first = SW
title = The eastern and western branches of the Wood/Ljungdahl pathway: how the east and west were won.
journal = Biofactors
volume = 6
issue = 1
pages = 3-11
date =
year = 1997
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9233535&dopt=Abstract] Specifically, ACS combines carbon monoxide and a methyl group to produce acetyl-CoA at a nickel containing active site. [Citation
last = Hegg
first = EL
author-link = EL Hegg
title = Unraveling the structure and mechanism of acetyl-coenzyme A synthase.
journal = Acc Chem Res.
volume = 37
issue = 10
pages = 775-83
date = Oct
year = 2004
url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15491124&query_hl=4&itool=pubmed_DocSum]

References