Acetylation
Encyclopedia
Acetylation describes a reaction that introduces an acetyl
functional group
into a chemical compound. (Deacetylation is the removal of the acetyl group.)
Specifically, acetylation refers to that process of introducing an acetyl group (resulting in an acetoxy group
) into a compound, to be specific, the substitution of an acetyl group for an active hydrogen
atom. A reaction involving the replacement of the hydrogen atom of a hydroxyl
group with an acetyl group (CH3
CO) yields a specific ester
, the acetate
. Acetic anhydride
is commonly used as an acetylating agent reacting with free hydroxyl groups. For example, it is used in the synthesis of aspirin
and heroin.
s, acetylation occurs as a co-translational and post-translational modification of protein
s, for example, histone
s, p53
, and tubulin
s.
s (NATs), a sub-family of the GNAT superfamily of acetyltransferase
s, which also include histone acetyl transferase
s. The GNATs transfer the acetylgroup from acetyl-coenzyme A to the amine group.
The NATs have been most extensively studied in yeast. Here, three NAT complexes, NatA/B/C, have been found to perform most N-alpha-terminal acetylations. They have sequence specificity for their substrates, and it is believed that they are associated with the ribosome, where they acetylate the nascent polypeptide chain.
In humans, the human NatA and NatB complexes have been identified and characterized. Subunits of the human NatA complex have been coupled to cancer-related processes such as hypoxia-response and the beta-catenin pathway
. It has been found to be over-expressed in papillary thyroid carcinoma and neuroblastoma
. The human NatB complex have been coupled to cell cycle. The hNat3 subunit of the hNatB complex has been found overexpressed in some forms of cancer.
Despite being a conserved and widespread modification, little is known about the biological role of N-alpha-terminal acetylation. Proteins such as actin and tropomyosin have been found to be dependent of NatB acetylation to form proper actin filaments. Yet this is only one example pointing to the potential importance of this modification.
For unknown reasons 20% of Asians have an isozyme that results in slower N-acetylation of drugs, while 50% of Whites and African-Americans do.
, the histones are acetylated and deacetylated on lysine
residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzyme
s with "histone acetyltransferase
" (HAT) or "histone deacetylase
" (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.
The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation/deacetylation is emerging as a significant post-translational regulatory mechanism analogous to phosphorylation by the action of kinases
or dephosphorylated by the action of phosphatases. Not only can the acetylation state of a protein modify its activity, there has been recent suggestion that this post-translational modification might crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling.
The tubulin
acetylation and deacetylation system is well worked out in Chlamydomonas
. A tubulin acetyltransferase located in the axoneme
acetylates a specific lysine residue in the α-tubulin subunit in assembled microtubule. Once disassembled, this acetylation can be removed by another specific deacetylase that is cytosolic. Thus the axonemal microtubules (long half-life) carry this signature acetylation absent from cytosolic microtubules (short half-life).
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
functional group
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
into a chemical compound. (Deacetylation is the removal of the acetyl group.)
Specifically, acetylation refers to that process of introducing an acetyl group (resulting in an acetoxy group
Acetoxy group
Acetoxy group, abbreviated AcO or OAc, is a chemical functional group of the structure CH3-C-O-. It differs from the acetyl group CH3-C- by the presence of one additional oxygen atom...
) into a compound, to be specific, the substitution of an acetyl group for an active hydrogen
Hydrogen
Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...
atom. A reaction involving the replacement of the hydrogen atom of a hydroxyl
Hydroxyl
A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...
group with an acetyl group (CH3
CO) yields a specific ester
Ester
Esters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
, the acetate
Acetate
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...
. Acetic anhydride
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
is commonly used as an acetylating agent reacting with free hydroxyl groups. For example, it is used in the synthesis of aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
and heroin.
Acetylation of proteins
In biology, i.e., in living cellCell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
s, acetylation occurs as a co-translational and post-translational modification of protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, for example, histone
Histone
In biology, histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. They are the chief protein components of chromatin, acting as spools around which DNA winds, and play a role in gene regulation...
s, p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, and tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
s.
N-alpha-terminal Acetylation
Acetylation of the N-terminal alpha-amine of proteins is a widespread modification in eukaryotes. Forty to fifty percent of yeast proteins, and 80-90% of human proteins are modified in this manner, and the pattern of modification is found to be conserved throughout evolution. The modification is performed by N-alpha-acetyltransferaseNatA Acetyltransferase
NatA Acetyltransferase, is an enzyme that serves to catalyze the addition of acetyl groups to various proteins emerging from the ribosome. Upon translation, the NatA binds to the ribosome and then "stretches" to the front end of the forming, or nascent, polypeptide, where it adds this acetyl group...
s (NATs), a sub-family of the GNAT superfamily of acetyltransferase
Acetyltransferase
Acetyltransferase is a type of transferase enzyme that transfers an acetyl group.Examples include:* Histone acetyltransferases including CBP histone acetyltransferase* Choline acetyltransferase* Chloramphenicol acetyltransferase...
s, which also include histone acetyl transferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
s. The GNATs transfer the acetylgroup from acetyl-coenzyme A to the amine group.
The NATs have been most extensively studied in yeast. Here, three NAT complexes, NatA/B/C, have been found to perform most N-alpha-terminal acetylations. They have sequence specificity for their substrates, and it is believed that they are associated with the ribosome, where they acetylate the nascent polypeptide chain.
In humans, the human NatA and NatB complexes have been identified and characterized. Subunits of the human NatA complex have been coupled to cancer-related processes such as hypoxia-response and the beta-catenin pathway
Wnt signaling pathway
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
. It has been found to be over-expressed in papillary thyroid carcinoma and neuroblastoma
Neuroblastoma
Neuroblastoma is the most common extracranial solid cancer in childhood and the most common cancer in infancy, with an annual incidence of about 650 cases per year in the US , and 100 cases per year in the UK . Close to 50 percent of neuroblastoma cases occur in children younger than two years old...
. The human NatB complex have been coupled to cell cycle. The hNat3 subunit of the hNatB complex has been found overexpressed in some forms of cancer.
Despite being a conserved and widespread modification, little is known about the biological role of N-alpha-terminal acetylation. Proteins such as actin and tropomyosin have been found to be dependent of NatB acetylation to form proper actin filaments. Yet this is only one example pointing to the potential importance of this modification.
For unknown reasons 20% of Asians have an isozyme that results in slower N-acetylation of drugs, while 50% of Whites and African-Americans do.
Lysine Acetylation and Deacetylation
In histone acetylation and deacetylationHistone acetylation and deacetylation
In histone acetylation and deacetylation, the histones are acetylated and deacetylated on lysine residues in the N-terminal tail and on the surface of the nucleosome core as part of gene regulation. These reactions are typically catalyzed by enzymes with "histone acetyltransferase" or "histone...
, the histones are acetylated and deacetylated on 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....
residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzyme
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...
s with "histone acetyltransferase
Histone acetyltransferase
Histone acetyltransferases are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl CoA to form ε-N-acetyl lysine....
" (HAT) or "histone deacetylase
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
" (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.
The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation/deacetylation is emerging as a significant post-translational regulatory mechanism analogous to phosphorylation by the action of kinases
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
or dephosphorylated by the action of phosphatases. Not only can the acetylation state of a protein modify its activity, there has been recent suggestion that this post-translational modification might crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling.
The tubulin
Tubulin
Tubulin is one of several members of a small family of globular proteins. The most common members of the tubulin family are α-tubulin and β-tubulin, the proteins that make up microtubules. Each has a molecular weight of approximately 55 kiloDaltons. Microtubules are assembled from dimers of α- and...
acetylation and deacetylation system is well worked out in Chlamydomonas
Chlamydomonas
Chlamydomonas is a genus of green algae. They are unicellular flagellates. Chlamydomonas is used as a model organism for molecular biology, especially studies of flagellar motility and chloroplast dynamics, biogenesis, and genetics...
. A tubulin acetyltransferase located in the axoneme
Axoneme
Numerous eukaryotic cells carry whip-like appendages whose inner core consists of a cytoskeletal structure called the axoneme....
acetylates a specific lysine residue in the α-tubulin subunit in assembled microtubule. Once disassembled, this acetylation can be removed by another specific deacetylase that is cytosolic. Thus the axonemal microtubules (long half-life) carry this signature acetylation absent from cytosolic microtubules (short half-life).
See also
- Acetoxy groupAcetoxy groupAcetoxy group, abbreviated AcO or OAc, is a chemical functional group of the structure CH3-C-O-. It differs from the acetyl group CH3-C- by the presence of one additional oxygen atom...
- AcylationAcylationIn chemistry, acylation is the process of adding an acyl group to a compound. The compound providing the acyl group is called the acylating agent....
- AmideAmideIn chemistry, an amide is an organic compound that contains the functional group consisting of a carbonyl group linked to a nitrogen atom . The term refers both to a class of compounds and a functional group within those compounds. The term amide also refers to deprotonated form of ammonia or an...
- Compendium of protein lysine acetylationCompendium of protein lysine acetylationThe compendium of protein lysine acetylation database contains the sites of experimentally identified lysine acetylation sites....
- EsterEsterEsters are chemical compounds derived by reacting an oxoacid with a hydroxyl compound such as an alcohol or phenol. Esters are usually derived from an inorganic acid or organic acid in which at least one -OH group is replaced by an -O-alkyl group, and most commonly from carboxylic acids and...
- Organic synthesisOrganic synthesisOrganic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...