The Importance Of Acetylation
Acetylation is a phase Two detoxification process that processes drugs, caffeine and other potentially toxic items. People who have poor ability to acetylate have been shown to be more likely to have certain types of cancers. In humans, acetylation is a major route of biotransformation for many arylamine and hydrazine drugs, as well as for a number of known carcinogens present in the diet, cigarette smoke, and car exhaust fumes. Although acetylation is not one of the more common xenobiotic (foreign chemical compound)-conjugation pathways, for some agents it is the major or only reaction utilized for their metabolism. Most detoxification reactions have back-up plans. When a detox reaction is the only one available, and it is not working well, that is a serious situation.
The Acetylation Conjugation Process
Acetylation is a phase II liver detoxification pathway that usually uses the molecule called acetyl co-A to attach it to toxins to make those toxins less harmful, and easier to excrete. This is a common metabolic reaction that occurs with amino, hydroxyl, or sulfhydryl groups.
In the acetylation reaction an acetyl group (CH3C=O) is added to another compound. The acetyl group can be viewed here: https://study.com/academy/lesson/what-is-acetylation-mechanism-definition.html
In our bodies, there is both acetylation that is enzyme dependent and enzyme independent taking place. When enzyme dependent, the enzymes used for this reaction are N-acetyltransferases. The acetyl group is transferred to the toxin from the substance called Acetyl-coenzyme A.
Acetylation of proteins may affect how they act in the body. Most of the proteins in the human body undergo acetylation. The process of acetylation is important for many vital chemical reactions in the body. This includes:
- Protein formation
- Regulation of deoxyribonucleic acid (DNA) and other genetic elements using histone acetylation.
- Cell cycle progression
- DNA replication
- Chromatin assembly
- Regulation of gene expression
- Drug biotransformation
- Acetylation of some nuclear hormone receptors
- Plays a role in folate metabolism through the acetylation of the folate metabolite p–aminobenzoylglutamate
Acetylation of proteins, generally on lysine residues, via an acetyl-coenzyme A donor, can have functional consequences, as in proteins contained within chromatin and the metabolic enzymes.
N-alpha-acetyltransferases are enzymes that help in mediating acetylation reactions. There are two common varieties of these enzymes found in humans. They are NAT1 and NAT2. NAT1 is present in most cells, while NAT2 is present predominantly in the intestine and liver .
Polymorphisms (different forms, variances) can result in slower than normal, or faster than normal ability to add an acetyl group to toxins. Slow acetylators have a build up of toxins in the system and rapid acetylators add acetyl groups so rapidly that they make mistakes in the process. It appears that both slow, and rapid acetylators may be at increased risk if they are exposed to environmental toxins. If the toxin exposure is reduced, the risk is reduced.
The Importance Of Understanding Acetylation
Many drugs are transformed by acetylation prior to excretion. Many adverse drug and chemical reactions have been associated with aetylator status. Therefore it can be helpful to know the acetylator phenotype of individuals before being given a drug that undergoes acetylation.
N-acetyltransferase-2 (NAT2) is an enzyme that catalyzes the acetylation of aromatic and heterocyclic amine carcinogens. Because of its involvement in the detoxification of carcinogens, mutations within NAT2 that affect the enzymatic acetylator activity may also modify risk of cancer development.
The rate of acetylation is genetically determined. People are distinguished by their genetic variants as either slow, average, or fast acetylators. The fast acetylator is considered to be the most common type in Asian and African populations. Caucasian people are more commonly average acetylators or slow acetylators.
A number of single nucleotide polymorphisms (SNPs) within the NAT2 gene have been found to affect the NAT2 acetylator phenotype.
Regulation of Deoxyribonucleic Acid (DNA) And Other Genetic Elements Using Histone Acetylation
Proteins that replicate DNA, and repair damaged genetic material are created directly by acetylation. Acetylation also helps in DNA transcription. Acetylation determines the energy that proteins use during duplication and this determines the accuracy of copying the genes. Acetylation is triggered by cellular proteins. When the reaction begins, chemicals are added to the DNA-controlling proteins.
The erroneous zones while copying the DNA are removed by proteins, and the segments are later attached. Less faulty pieces may be allowed to remain while the more flawed ones are removed. Reactions triggered by acetyltransferases can lead to cancer and other diseases.
Some drugs are processed in the body through the acetylation reaction, either by biotransformation into an effective compound and used, or to be metabolized into substances that the body can excrete in a more simpler manner. Common genetic variations in acetylation can result in striking differences in the half-life and plasma concentrations of drugs metabolized by N-acetyltransferase. People who have deficient acetylation capacity (slow acetylators) may have prolonged, or toxic responses to normal doses of certain drugs because of decreased rates of metabolism
Drugs That Undergo Acetylation
- isoniazid (an anti–tuberculotic drug)
- hydralazine and endralazine (anti–hypertensive drugs)
- sulphonamides (anti–bacterial drugs)
- clonazepam, nitrazepam (benzodiazepines)
- procainamide (anti–arrhythmic drug)
- aminoglutethimide (an inhibitor of adrenocortical steroid synthesis)
- nitrazepam (a benzodiazepine)
- dapsone, an anti–inflammatory drug
Conjugation of toxins with acetyl-CoA is the primary method by which the body eliminates sulfa drugs. This system appears to be especially sensitive to genetic variation, with those having a poor acetylation system being far more susceptible to sulfa drugs and other antibiotics.
Salicylic Acid To Aspirin
When salicylic acid is acetylated it becomes aspirin.
Acetylation And Glutathione
I use an acetylated form of glutathione as it has better absorption when acetylated. By acetylating it, the glutathione is not oxidized and broken down into it's componant amino acids as other gluathiones usually are.
Acetylation And Sleep
We know that melatonin is necessary for good sleep and acetylation is necessary to make melatonin from serotonin. Serotonin is converted to melatonin by three steps involving a series of enzymes that add an acetyl, methyl and finally a hydroxyl group to the indole ring.
Acetylator Status And Testing
The rate of acetylation is genetically determined. People are distinguished by their genetics as either slow, average, or fast acetylators.
A person's acetylation ability can be measured by a simple test using caffeine ingestion. The individual ingests 300 mg of caffeine, and the urine is collected for 24 hours thereafter.
Acetylator status can also be tested through genetic testing at Genova or or other similar labs. 23 and me will have most of these available in their results also. I have included a decoder for the 23 and Me testing below so you can use it in a free software program to determine if you are a slow, average or fast acetylator. You will find it below.
Slow Metabolizer Single Nucleotide Polymorphisms Tested
NAT1 R64W - in all cells
NAT1 R187Q - Liver and intestines
NAT2 I114T - SNP T341C* - Liver and intestines
NAT2 R197Q - SNP G590A* - Liver and intestines
NAT2 G286E - SNP G857A* - Liver and intestines
NAT2 R64Q - Liver and intestines
Fast Metabolizer Polymorphism
NAT2 K268R - SNP A803G*- Liver and intestines
The test will show either --,-+, or ++ for the various possible polymorphisms. Here is how to interpret this.
If the person has is negative (--) for both chromosomes, then neither carries the genetic variation.
If the person has one negative (-+) and one positive result, then one chromosome carries the genetic variation.
If the person have two (++) positive results, then both chromosomes carry the genetic variation.
What It Means To Be A Slow Or Fast Acetylator
N-acetyltransferase 1 has been found in most body tissues, while NAT2 is found predominantly in the liver and the gut. Both are used in the Phase II acetylation of numerous environmental toxins, including heterocyclic aromatic amines. We know that slow acetylators do not clear toxins well. Many studies suggested a relationship between acetylation phenotypes (in particular, arising from NAT2 genotypes) and the risk of various cancer including colorectal, liver, breast, prostate, head and neck (Agúndez, 2008) and other disease conditions such as birth defects (Lammer et al., 2004) or neurodegenerative and autoimmune diseases (Ladero, 2008).
NAT1 and NAT2 acetylator genotypes are important modifiers of human cancer susceptibility. The studies do not all agree, but currently it appears that NAT1 genetic variants show an increased risk of bladder, colon, breast, lung, prostate and pancreatic cancers. NAT2 slow acetylator phenotype is associated with an increased risk of bladder cancer in smokers whereas the rapid acetylator phenotype is over-represented in patients with colorectal cancer (Brockmöller et al., 1996; Ilett et al., 1987). Another study has shown that carriers of the NAT2*4/*4 genotype, which results in a high acetylation capacity, are at a significantly increased risk of lung cancer (Cascorbi et al., 1996).
Smoking has increased risks for NAT1 slow acetylator variants. Both NAT1 slow and average variants have higher firsk for esophageal and lung cancer in smokers than the fast acetylators.
The slow acetylators also have more trouble detoxifying carcinogenic amines from grilled meat. Red meat in general may be related to increased esophageal cancer risk in sow and average acetylators.
Slow acetylators are more likely to be "chemical sensitive".
There are a lot of slow acetylators world-wide so the question is , what evolutionary advantage would slow acetylators have? There probably is one.
Software For Predicting Acetylation Status
If you have the genotypes for the 282,341, 481,590,803 and 857 NAT2 sequence positions you can use a free software program to calculate if you are a slow or fast acetylator at this web-server where the University of Albany implements a support vector machine (SVM) predictor of the human NAT2 acetylator phenotype that uses a combination of SNPs found in the NAT2 gene positions 282, 341, 481, 590, 803, and 857. The predictor assigns one of the three NAT2 phenotypes based on the genotypes observed for these six SNPs. http://nat2pred.rit.albany.edu/
If using your SNPs from 23 and Me, you will be confused. To relate this to 23 And Me, your NAT2 alleles are as follows:
282 = rs1041983
341 = rs1801280
481 = rs1799929
590 = rs1799930
803 = rs1208
857 = rs1799931
Simply look up the reference SNP number (rs number) on 23 and Me and use the allele such as AT, CG etc and put those allele numbers into the web-server vector machine.
Deconjugation Of Acetylation
Deconjugation is possible. The opposite chemical reaction is called deacetylation – it is the removal of the acetyl group.
While not much is known about how to directly improve the activity of this system, it is known that acetylation depends on vitamin C, thiamine (B1), pantothenic acid (B5) and Cobalamin (B12).
For Science Geeks
Histone acetylation occurs by the enzymatic addition of an acetyl group (COCH3) from acetyl coenzyme A. The process of histone acetylation is tightly involved in the regulation of many cellular processes including chromatin dynamics and transcription, gene silencing, cell cycle progression, apoptosis, differentiation, DNA replication, DNA repair, nuclear import, and neuronal repression. The modifying enzymes involved in histone acetylation are called histone acetyltransferases (HATs) and they play a critical role in controlling histone H3 and H4 acetylation. More than 20 HATs have been identified which can be classified into five families: GNAT1, MYST, TAFII250, P300/CBP, and nuclear receptor coactivators such as ACTR.1 Histone H3 acetylation may be increased by inhibition of histone deacetylases (HDACs) and decreased by HAT inhibition.
Histone deacetylaces (HDACs) catalyze the hydrolytic removal of acetyl groups from histone lysine residues. An imbalance in the equilibrium of histone acetylation has been associated with tumorigenesis and cancer progression. Detecting whether histone H3 is acetylated at its lysine residues would provide useful information for further characterization of acetylation patterns or sites, thereby leading to a better understanding of epigenetic regulation of gene activation as well as the development of HAT-targeted drugs. Similar to HATs, HDACs play a critical role in various cellular processes involving histone H3 and H4. So far, at least 4 classes of HDACs have been identified. Class I HDACs include 1, 2, 3, and 8. Class II HDACs are comprised of 4, 5, 6, 7, 9, and 10. Class III enzymes, known as sirtuins, require NAD+ cofactors and include SIRTs 1-7. The Class IV enzyme, which contains only HDAC11, has features of both Class I and II. HDAC inhibition displays significant effects.
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