Protein acetylation
Pharmaceuticals frequently employ acetylation to enable such esters to cross the blood–brain barrier (and placenta), where they are deacetylated by enzymes (carboxylesterases) in a manner similar to acetylcholine.
Examples of acetylated pharmaceuticals are diacetylmorphine (heroin), acetylsalicylic acid (aspirin), THC-O-acetate, and diacerein.
[1][2][3] Acetylation occurs as a co-translational and post-translational modification of proteins, for example, histones, p53, and tubulins.
N-terminal acetylation plays an important role in the synthesis, stability and localization of proteins.
[7] To date, seven different NATs have been found in humans - NatA, NatB, NatC, NatD, NatE, NatF and NatH.
These amino acids are more frequently expressed in the N-terminal of proteins in eukaryotes, so NatA is the major NAT corresponding to the whole number of its potential substrates.
NatB acetylates the N-terminal methionine of substrates starting with Met-Glu-, Met-Asp-, Met-Asn- or Met-Gln- N termini.
NatC complex acetylates the N-terminal methionine of substrates Met-Leu-, Met-Ile-, Met-Trp- or Met-Phe N-termini.
The acetylation of histones by NatD is partially associate with ribosomes and the amino acids substrates are the very N-terminal residues, which makes it different from lysine N-acetyltransferases (KATs).
[19] 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.
[6] NatF has been shown to have an organellar localization and acetylates cytosolic N-termini of transmembrane proteins.
[33] The regulation of transcription factors, effector proteins, molecular chaperones, and cytoskeletal proteins by acetylation and deacetylation is a significant post-translational regulatory mechanism[34] These regulatory mechanisms are analogous to phosphorylation and dephosphorylation by the action of kinases and phosphatases.
Not only can the acetylation state of a protein modify its activity but there has been recent suggestion that this post-translational modification may also crosstalk with phosphorylation, methylation, ubiquitination, sumoylation, and others for dynamic control of cellular signaling.
In the field of epigenetics, histone acetylation (and deacetylation) have been shown to be important mechanisms in the regulation of gene transcription.
The following are examples of various other proteins with roles in regulating signal transduction, whose activities are also affected by acetylation and deacetylation.
The p53 protein is a tumor suppressor that plays an important role in the signal transactions in cells, especially in maintaining the stability of the genome by preventing mutation.
Under severe DNA damage, it also initiates programmed cell death.The function of p53 is negatively regulated by oncoprotein Mdm2.
However, if multiple acetylation sites are blocked, the expression of p21 and the suppression of cell growth caused by p53 is completely lost.
[43] Since the major function of p53 is tumor suppressor, the idea that activation of p53 is an appealing strategy for cancer treatment.
[45] Reports also shown that the cancer cell under the Nutilin-3a treatment, acetylation of lys 382 was observed in the c-terminal of p53.
[53] For example, the vinca alkaloids and taxanes selectively bind and inhibit microtubules, leading to cell cycle arrest.
[54] The identification of the crystal structure of acetylation of α-tubulin acetyl-transferase (α-TAT) also sheds a light on the discovery of small molecule that could modulate the stability or de-polymerization of tubulin.
This strategy is supported by treating resveratrol, an inhibitor of acetylation of STAT3, in cancer cell line reverses aberrant CpG island methylation.
