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Acetylation (or in
Acetylation refers to the process of introducing an acetyl group (resulting in an
Acetylation of proteins
Introduction
Acetylation is an important modification of proteins in
N-terminal Acetylation, an Important Example of Co-translational Acetylation on Proteins
General Introduction of N-terminal Acetylation
N-terminal acetylation is one of the most common co-translational covalent modifications of proteins in
N-terminal Acetylation is catalyzed by a set of enzyme complexes, the N-terminal acetyltransferases (NATs). NATs transfer an acetyl group from
N-terminal Acetyltransferases
In total, there are six different NATs have been reported in humans, they are NatA, NatB, NatC, NatD, NatE and NatF. Each of these different enzyme complexes is specific for different amino acids or amino acid sequences which is show in the following table.
Table 1. The Composition and Substrate specificity of NATs
NAT | Subunits | Substrates |
---|---|---|
NatA | Naa10p (Ard1p) Naa5p (Nat1p) | N-termini
|
NatB | Naa20p (Nat3p) Naa25p (Mdm20p) | N-termini
|
NatC | Naa30p (Mak3p) Naa35p (Mak10p) Naa40p (Nat5p) | N-termini
|
NatD | Naa40p (Nat4p) | N-termini
|
NatE | Naa50p (Nat5p) | N-termini
|
NatF | Naa60p | N-termini
|
NatA
NatA is composed of two subunits, the catalytic
NatA acetylates
Several different interaction partners are involved in the N-terminal acetylation by NatA. Huntingtin interacting protein K (HYPK) interacts with hNatA on ribosome to affect the N-terminal acetylation of a subset of NatA substrates. Subunits hNaa10p and hNaa15p will increase the tendency for aggregation of Huntingtin if HYPK is depleted. Hypoxia-inducible factor (HIF)-1αhas also been found to interact with hNaa10p to inhibit hNaa10p-mediated activation of β-catenin transcriptional activity.[11]
NatB
NatB complexes are composed with the catalytic subunit Naa20p and the auxiliary subunit Naa25p, which are both found in yeast and humans. In yeast, all the NatB subunits are ribosome-associated; but in humans, NatB subunits are both found to be ribosome-associated and non-ribosomal form. NatB acetylates the N-terminal methionine of substrates starting with Met-Glu-, Met-Asp-, Met-Asn- or Met-Gln- N termini.
NatC
NatC complex consists of one catalytic subunit Naa30p and two auxiliary subunits Naa35p and Naa38p. All three subunits are found on the ribosome in yeast, but they are also found in non-ribosomal NAT forms like Nat2. NatC complex acetylates the N-terminal methionine of substrates Met-Leu-, Met-Ile-, Met-Trp- or Met-Phe N-termini.
NatD
NatD is only composed with the catalytic unit Naa40p and Naa40p and it is conceptually different form the other NATs. At first, only two substrates, H2A and H4 have been identified in yeast and humans. Secondly, the substrate specificity of Naa40p lies within the first 30-50 residues which are quite larger than the substrate specificity of other NATs. The acetylation of
NatE
NatE complex consists with subunit Naa50p and two NatA subunits, Naa10p and Naa15p. The N terminus of Naa50p substrates is different from those acetylated by the NatA activity of Naa10p.[14]
NatF
NatF is a newly identified NAT in 2011, which is composed with Naa60p enzyme. Till now, NatF is only found in higher eukaryotes, but not in lower eukaryotes. Compared to yeast, NatF contributes to the higher abundance of N-terminal acetylation in humans. NatF complex acetylates the N-terminal methionine of substrates Met-Lys-, Met-Leu-, Met-Ile-, Met-Trp- and Met-Phe N termini which are partly overlapping with NatC and NatE.[15]
Function of N-terminal Acetylation
N-terminal acetylation affects protein stability
N-terminal acetylation of proteins can affect protein stability but the results and mechanism is not very clear till now.
N-terminal acetylation affects protein localization
N-terminal acetylation has been shown that it can steer the localization of proteins. Arl3p contains a
N-terminal acetylation affects metabolism and apoptosis
Protein N-terminal acetylation has also been proved to relate with cell cycle regulation and apoptosis with protein knockdown experiments. Knockdown of the NatA or the NatC complex leads to the induction of
N-terminal acetylation affects protein synthesis
Ribosome proteins play an important role in the protein synthesis, which could also be N-terminal acetylated. The N-terminal acetylation of the ribosome proteins may have an effect on protein synthesis. A decrease of 27% and 23% in the protein synthesis rate was observed with NatA and NatB deletion strains. A reduction of translation fidelity was observed in the NatA deletion strain and a defect in ribosome was noticed in the NatB deletion strain.[23]
N-terminal Acetylation in Cancer
NATs have been suggested to act as both onco-proteins and tumor suppressors in human cancers, and NAT expression may be increased and decreased in cancer cells. Ectopic expression of hNaa10p increased cell proliferation and up regulation of gene involved in cell survival proliferation and metabolism. Overexpression of hNaa10p was in the urinary bladder cancer, breast cancer and cervical carcinoma.[24] But a high level expression of hNaa10p could also suppress tumor growth and a reduced level of expressed hNaa10p is associated with a poor prognosis, large tumors and more lymph node metastases.
Table 2. Overview of the expression of NatA subunits in various cancer tissues[25]
Nat subunits | Cancer tissue | Expression pattern |
---|---|---|
hNaa10p | lung cancer, breast cancer, colorectal cancer, hepatocellular carcinoma | high in tumors |
hNaa10p | lung cancer, breast cancer, pancreatic cancer, ovarian cancer | loss of heterozygosity in tumors |
hNaa10p | gastric cancer, lung cancer |
high in primary tumors, but low with lymph node metastases |
hNaa10p | Non-small cell lung cancer |
low in tumors |
hNaa15p | gastric cancer |
high in tumors |
hNaa15p | neuroblastoma | high in advanced stage tumors |
hNaa11p | hepatocellular carcinoma | loss of heterozygosity in tumors |
Lysine acetylation
Proteins are typically acetylated on lysine residues and this reaction relies on acetyl-coenzyme A as the acetyl group donor. In
The regulation of transcription factors, effector proteins,
The discovery of
Important examples of lysine acetylation in proteins
p53
Background information
Acetylation of p53
The acetylation of p53 is in dispensable for its activation. It has been reported that the acetylation level of p53 will increase significantly when cell undergo stress. There are three major acetylation site on p53: K164, K120 and C terminus.
Therapeutic implications for cancer therapy
Since the major function of
Microtubule
Background information
The structure of
Acetylation of tubulin
The acetylated residue of α-
Therapeutic implications for cancer therapy
Since the
STAT3
Background information
Signal transducer and activator of transcription 3 (
Acetylation of STAT3
The acetylation of Lys685 of
Therapeutic implications for cancer therapy
Since the acetylation of
Acetylation of wood
Since the beginning of the 20th century, acetylation of wood was researched as a method to upgrade the durability of wood in resistance against rotting processes and molds. Secondary benefits include the improvement of dimensional stability, improved surface hardness, and no decrease in mechanical properties due to the treatment. The physical properties of any material are determined by its chemical structure. Wood contains an abundance of chemical groups called “free hydroxyls”. Free hydroxyl groups adsorb and release water according to changes in the climatic conditions to which the wood is exposed. This is the main reason why wood swells and shrinks. It is also believed that the digestion of wood by enzymes initiates at the free hydroxyl sites – which is one of the principal reasons why wood is prone to decay.
Acetylation changes the free hydroxyls within the wood into acetyl groups. This is done by reacting the wood with acetic anhydride, which comes from acetic acid (known as vinegar when in its dilute form). When the free hydroxyl group is transformed to an acetyl group, the ability of the wood to absorb water is greatly reduced, rendering the wood more dimensionally stable and, because it is no longer digestible, extremely durable.
See also
References
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Category:Organic reactions Category:Proteins Category:Posttranslational modification