Acetyl Co-A synthetase
Encyclopedia
Acetyl—CoA synthetase or Acetate—CoA ligase is an enzyme
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.
and coenzyme A
(CoA). The complete reaction with all the substrates and products included is:
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. 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-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. 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.
The ACS1 form of acetyl-CoA synthetase is encoded by the gene facA, which is activated by acetate and deactivated by glucose.
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. 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.
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.
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.
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.
properly, which inevitably results in transcriptional errors.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
involved in metabolism of carbon sugars. It is in the ligase
Ligase
In biochemistry, ligase is an enzyme that can catalyse the joining of two large molecules by forming a new chemical bond, usually with accompanying hydrolysis of a small chemical group dependent to one of the larger molecules...
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 acetateAcetate
An acetate is a derivative of acetic acid. This term includes salts and esters, as well as the anion found in solution. Most of the approximately 5 billion kilograms of acetic acid produced annually in industry are used in the production of acetates, which usually take the form of polymers. In...
and coenzyme A
Coenzyme A
Coenzyme A is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All sequenced genomes encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it as a substrate...
(CoA). The complete reaction with all the substrates and products included is:
- ATPAdenosine triphosphateAdenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
+ Acetate + CoA <=> AMPAdenosine monophosphateAdenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
+ PyrophosphatePyrophosphateIn chemistry, the anion, the salts, and the esters of pyrophosphoric acid are called pyrophosphates. Any salt or ester containing two phosphate groups is called a diphosphate. As a food additive, diphosphates are known as E450.- Chemistry :...
+ Acetyl-CoAAcetyl-CoAAcetyl coenzyme A or acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main function is to convey the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production. In chemical structure, acetyl-CoA is the thioester...
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
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
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-CoA synthetase takes place in two steps. First, AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
must be bound by the enzyme to cause a conformational change in the active site
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
, which allows the reaction to take place. The active site is referred to as the A-cluster. A crucial lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
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.
The ACS1 form of acetyl-CoA 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 lysineLysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
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
SIRT3
NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein...
. This action increases activity of this enzyme. 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.
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.
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
Fatty acid synthesis
Fatty acid synthesis is the creation of fatty acids from acetyl-CoA and malonyl-CoA precursors through action of enzymes called fatty acid synthases...
, but, under normal conditions, the gene is inactive and has certain transcriptional factors that activate transcription when necessary.
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.
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 chromatinChromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
properly, which inevitably results in transcriptional errors.