N-acetyltransferase

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Arylamine N-acetyltransferase 2
Human NAT2.jpg
A 3d cartoon depiction of human N-acetyltransferase 2
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EC no. 2.3.1.5
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N-acetyltransferase (NAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines, arylhydroxylamines and arylhydrazines. [1] [2] [3] They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. N-acetyltransferases are cytosolic enzymes found in the liver and many tissues of most mammalian species, except the dog and fox, which cannot acetylate xenobiotics. [4]

Contents

Acetyl groups are important in the conjugation of metabolites from the liver, to allow excretion of the byproducts (phase II metabolism). This is especially important in the metabolism and excretion of drug products (drug metabolism).

Enzyme Mechanism

NAT enzymes are differentiated by the presence of a conserved catalytic triad that favors aromatic amine and hydrazine substrates. [5] [6] NATs catalyze the acetylation of small molecules through a double displacement reaction called the ping pong bi bi reaction. [5] The mechanism consists of two sequential reactions. [5] In reaction one acetyl-CoA initially binds to the enzyme and acetylates Cys68. [5] In reaction two, after acetyl-CoA is released, the acetyl acceptor interacts with the acetylated enzyme to form product. [5] This second reaction is independent of the acetyl donor since it leaves the enzyme before the acetyl acceptor binds. [5] However, like with many ping pong bi bi reactions, its possible there is competition between the acetyl donor and acetyl acceptor for the unacetylated enzyme. [5] This leads to substrate-dependent inhibition at high concentrations. [5]

Depiction of the N-acetyltransfersase enzyme mechanism. Mechanism of N-acetyltransferase.png
Depiction of the N-acetyltransfersase enzyme mechanism.

Enzyme Structure

3D depiction of NAT2 active site and catalytic triad. NAT catalytic triad.png
3D depiction of NAT2 active site and catalytic triad.

The two NAT enzymes in humans are NAT1 and NAT2. [4] Mice and rats express three enzymes, NAT1, NAT2, and NAT3. [4] NAT1 and NAT2 have been found to be closely related in species examined thus far, since the two enzymes share 75-95% of their amino acid sequence. [9] [10] Both also have an active site cysteine residue (Cys68) in the N-terminal region. [9] [10] Further, all functional NAT enzymes contain a triad of catalytically essential residues made up of this cysteine, histidine, and asparagine. [7] It has been hypothesized that the catalytic effects of the breast cancer drug Cisplatin are related to Cys68. [11] The inactivation of NAT1 by Cisplatin is caused by an irreversible formation of a Cisplatin adduct with the active-site cysteine residue. [11] The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. [12]

NAT1 and NAT2 have different but overlapping substrate specificities. [4] Human NAT1 preferentially acetylates 4-aminobenzoic acid (PABA), 4 amino salicylic acid, sulfamethoxazole, and sulfanilamide. [4] Human NAT2 preferentially acetylates isoniazid (treatment for tuberculosis), hydralazine, procainamide, dapsone, aminoglutethimide, and sulfamethazine. [4]

Biological Significance

NAT2 is involved in the metabolism of xenobiotics, which can lead to both the inactivation of drugs and formation of toxic metabolites that can be carcinogenic. [13] The biotransformation of xenobiotics may occur in three phases. [13] In phase I, reactive and polar groups are introduced into the substrates. In phase II, conjugation of xenobiotics with charged species occurs, and in phase III additional modifications are made, with efflux mechanisms leading to excretion by transporters. [13] A genome-wide association study (GWAS) identified human NAT2 as the top signal for insulin resistance, a key marker of diabetes and a major cardiovascular risk factor [13] and has been shown to be associated with whole-body insulin resistance in NAT1 knockout mice. [14] NAT1 is thought to have an endogenous role, likely linked to fundamental cellular metabolism. [13] This may be related to why NAT1 is more widely distributed among tissues than NAT2. [13]

Importance in Humans

Each individual metabolizes xenobiotics at different rates, resulting from polymorphisms of the xenobiotic metabolism genes. [13] Both NAT1 and NAT2 are encoded by two highly polymorphic genes located on chromosome 8. [4] NAT2 polymorphisms were one of the first variations to explain this inter-individual variability for drug metabolism. [15] These polymorphisms modify the stability and/ or catalytic activity of enzymes that alter acetylation rates for drugs and xenobiotics, a trait called acetylator phenotype. [16] For NAT2, the acetylator phenotype is described as either slow, intermediate, or rapid. [17] Beyond modifying enzymatic activity, epidemiological studies have found an association of NAT2 polymorphisms with various cancers, likely from varying environmental carcinogens. [13]

Indeed, NAT2 is highly polymorphic in several human populations. [18] Polymorphisms of NAT2 include the single amino acid substitutions R64Q, I114T, D122N, L137F, Q145P, R197Q, and G286E. [18] These are classified as slow acetylators, while the wild-type NAT2 is classified as a fast acetylator. [18] Slow acetylators tend to be associated with drug toxicity and cancer susceptibility. [18] For instance, the NAT2 slow acetylator genotype is associated with an increased risk of bladder cancer, especially among cigarette smokers. [19] Single nucleotide polymorphisms (SNPs) of NAT1 include R64W, V149I, R187Q, M205V, S214A, D251V, E26K, and I263V, and are related to genetic predisposition to cancer, birth defects, and other diseases. [20] The effect of the slow acetylator SNPs in the coding region predominantly act through creating an unstable protein that aggregates intracellularly prior to ubiquitination and degradation. [3]

50% of the British population are deficient in hepatic N-acetyltransferase. This is known as a negative acetylator status. Drugs affected by this are:

Adverse events from this deficiency include peripheral neuropathy and hepatoxicity. [21] The slowest acetylator haplotype, NAT2*5B (strongest association with bladder cancer), seems to have been selected for in the last 6,500 years in western and central Eurasian people, suggesting slow acetylation gave an evolutionary advantage to this population, despite the recent unfavorable epidemiological health outcomes data. [22]

Examples

The following is a list of human genes that encode N-acetyltransferase enzymes:

SymbolName
AANAT aralkylamine N-acetyltransferase
ARD1A ARD1 homolog A, N-acetyltransferase (S. cerevisiae)
GNPNAT1 glucosamine-phosphate N-acetyltransferase 1
HGSNAT heparan-alpha-glucosaminide N-acetyltransferase
MAK10 MAK10 homolog, amino-acid N-acetyltransferase subunit (S. cerevisiae)
NAT1 N-acetyltransferase 1 (arylamine N-acetyltransferase)
NAT2 N-acetyltransferase 2 (arylamine N-acetyltransferase)
NAT5 N-acetyltransferase 5 (GCN5-related, putative)
NAT6 N-acetyltransferase 6 (GCN5-related)
NAT8 N-acetyltransferase 8 (GCN5-related, putative)
NAT8L N-acetyltransferase 8-like (GCN5-related, putative)
NAT9 N-acetyltransferase 9 (GCN5-related, putative)
NAT10 N-acetyltransferase 10 (GCN5-related)
NAT11 N-acetyltransferase 11 (GCN5-related, putative)
NAT12 N-acetyltransferase 12 (GCN5-related, putative)
NAT13 N-acetyltransferase 13 (GCN5-related)
NAT14 N-acetyltransferase 14 (GCN5-related, putative)
NAT15 N-acetyltransferase 15 (GCN5-related, putative)

Related Research Articles

<span class="mw-page-title-main">Histone acetyltransferase</span> Enzymes that catalyze acyl group transfer from acetyl-CoA to histones

Histone acetyltransferases (HATs) are enzymes that acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine. DNA is wrapped around histones, and, by transferring an acetyl group to the histones, genes can be turned on and off. In general, histone acetylation increases gene expression.

Drug metabolism is the metabolic breakdown of drugs by living organisms, usually through specialized enzymatic systems. More generally, xenobiotic metabolism is the set of metabolic pathways that modify the chemical structure of xenobiotics, which are compounds foreign to an organism's normal biochemistry, such as any drug or poison. These pathways are a form of biotransformation present in all major groups of organisms and are considered to be of ancient origin. These reactions often act to detoxify poisonous compounds. The study of drug metabolism is called pharmacokinetics.

<span class="mw-page-title-main">Chloramphenicol acetyltransferase</span> Class of enzymes

Chloramphenicol acetyltransferase is a bacterial enzyme that detoxifies the antibiotic chloramphenicol and is responsible for chloramphenicol resistance in bacteria. This enzyme covalently attaches an acetyl group from acetyl-CoA to chloramphenicol, which prevents chloramphenicol from binding to ribosomes. A histidine residue, located in the C-terminal section of the enzyme, plays a central role in its catalytic mechanism.

<span class="mw-page-title-main">Iproniazid</span> Antidepressant

Iproniazid is a non-selective, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine class. It is a xenobiotic that was originally designed to treat tuberculosis, but was later most prominently used as an antidepressant drug. However, it was withdrawn from the market because of its hepatotoxicity. The medical use of iproniazid was discontinued in most of the world in the 1960s, but remained in use in France until its discontinuation in 2015.

<span class="mw-page-title-main">Thiopurine methyltransferase</span>

Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) is an enzyme that in humans is encoded by the TPMT gene. A pseudogene for this locus is located on chromosome 18q.

<span class="mw-page-title-main">Coactivator (genetics)</span> Class of proteins involved in regulation of transcription

A coactivator is a type of transcriptional coregulator that binds to an activator to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA promoter site or a specific DNA regulatory sequence called an enhancer. Binding of the activator-coactivator complex increases the speed of transcription by recruiting general transcription machinery to the promoter, therefore increasing gene expression. The use of activators and coactivators allows for highly specific expression of certain genes depending on cell type and developmental stage.

<span class="mw-page-title-main">Acecainide</span> Antiarrythmic drug

Acecainide is an antiarrhythmic drug. Chemically, it is the N-acetylated metabolite of procainamide. It is a Class III antiarrhythmic agent, whereas procainamide is a Class Ia antiarrhythmic drug. It is only partially as active as procainamide; when checking levels, both must be included in the final calculation.

<span class="mw-page-title-main">UGT2B7</span> Protein-coding gene in the species Homo sapiens

UGT2B7 (UDP-Glucuronosyltransferase-2B7) is a phase II metabolism isoenzyme found to be active in the liver, kidneys, epithelial cells of the lower gastrointestinal tract and also has been reported in the brain. In humans, UDP-Glucuronosyltransferase-2B7 is encoded by the UGT2B7 gene.

Aralkylamine <i>N</i>-acetyltransferase Class of enzymes

Aralkylamine N-acetyltransferase (AANAT), also known as arylalkylamine N-acetyltransferase or serotonin N-acetyltransferase (SNAT), is an enzyme that is involved in the day/night rhythmic production of melatonin, by modification of serotonin. It is in humans encoded by the ~2.5 kb AANAT gene containing four exons, located on chromosome 17q25. The gene is translated into a 23 kDa large enzyme. It is well conserved through evolution and the human form of the protein is 80 percent identical to sheep and rat AANAT. It is an acetyl-CoA-dependent enzyme of the GCN5-related family of N-acetyltransferases (GNATs). It may contribute to multifactorial genetic diseases such as altered behavior in sleep/wake cycle and research is on-going with the aim of developing drugs that regulate AANAT function.

<span class="mw-page-title-main">Histone acetylation and deacetylation</span>

Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.

<span class="mw-page-title-main">N-acetyltransferase 2</span> Protein-coding gene in the species Homo sapiens

N-acetyltransferase 2 , also known as NAT2, is an enzyme which in humans is encoded by the NAT2 gene.

In enzymology, an alpha-tubulin N-acetyltransferase is an enzyme which is encoded by the ATAT1 gene.

In enzymology, an arylamine N-acetyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Glucosamine-phosphate N-acetyltransferase</span>

In enzymology, glucosamine-phosphate N-acetyltransferase (GNA) is an enzyme that catalyzes the transfer of an acetyl group from acetyl-CoA to the primary amine in glucosamide-6-phosphate, generating a free CoA and N-acetyl-D-glucosamine-6-phosphate.

In enzymology, a peptide alpha-N-acetyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">KAT5</span> Protein-coding gene in the species Homo sapiens

Histone acetyltransferase KAT5 is an enzyme that in humans is encoded by the KAT5 gene. It is also commonly identified as TIP60.

<span class="mw-page-title-main">N-alpha-acetyltransferase 10</span> Protein-coding gene in the species Homo sapiens

N-alpha-acetyltransferase 10 (NAA10) also known as NatA catalytic subunit Naa10 and arrest-defective protein 1 homolog A (ARD1A) is an enzyme subunit that in humans is encoded NAA10 gene. Together with its auxiliary subunit Naa15, Naa10 constitutes the NatA complex that specifically catalyzes the transfer of an acetyl group from acetyl-CoA to the N-terminal primary amino group of certain proteins. In higher eukaryotes, 5 other N-acetyltransferase (NAT) complexes, NatB-NatF, have been described that differ both in substrate specificity and subunit composition.

<span class="mw-page-title-main">N-acetyltransferase 1</span> Protein-coding gene in the species Homo sapiens

N-acetyltransferase 1 is a protein that in humans is encoded by the NAT1 gene.

Protein acetylation are acetylation reactions that occur within living cells as drug metabolism, by enzymes in the liver and other organs. Pharmaceuticals frequently employ acetylation to enable such esters to cross the blood–brain barrier, 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. Conversely, drugs such as isoniazid are acetylated within the liver during drug metabolism. A drug that depends on such metabolic transformations in order to act is termed a prodrug.

<span class="mw-page-title-main">Nourseothricin</span> Chemical compound

Nourseothricin (NTC) is a member of the streptothricin-class of aminoglycoside antibiotics produced by Streptomyces species. Chemically, NTC is a mixture of the related compounds streptothricin C, D, E, and F. NTC inhibits protein synthesis by inducing miscoding. It is used as a selection marker for a wide range of organisms including bacteria, yeast, filamentous fungi, and plant cells. It is not known to have adverse side-effects on positively selected cells, a property cardinal to a selection drug.

References

  1. ↑ Evans DA (1989). "N-acetyltransferase". Pharmacology & Therapeutics. 42 (2): 157–234. doi:10.1016/0163-7258(89)90036-3. PMID   2664821.
  2. ↑ Ma Y, Ghoshdastider U, Wang J, Ye W, Dötsch V, Filipek S, Bernhard F, Wang X (2012). "Cell-free expression of human glucosamine 6-phosphate N-acetyltransferase (HsGNA1) for inhibitor screening". Protein Expr. Purif. 86 (2): 120–6. doi:10.1016/j.pep.2012.09.011. PMID   23036358.
  3. 1 2 Sim, Edith; Lack, Nathan; Wang, Chan-Ju; et al. (May 2008). "Arylamine N-acetyltransferases: Structural and functional implications of polymorphisms". Toxicology. 254 (3): 170–183. doi:10.1016/j.tox.2008.08.022. PMID   18852012.
  4. 1 2 3 4 5 6 7 Klaassen, Curtis D. (2008). Casarett and Doull's Toxicology: The Basic Science of Poisons 7th Ed. McGraw-Hill. ISBN   978-0071470513.
  5. 1 2 3 4 5 6 7 8 Minchin, Rodney F.; Neville, Butcher J. (April 2015). "The role of lysine100 in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: Implications for other acetyltransferases" (PDF). Biochemical Pharmacology. 94 (3): 195–202. doi:10.1016/j.bcp.2015.01.015. PMID   25660616.
  6. ↑ Weber, W.W.; Cohen, S.N.; Steinberg, M.S. (1968). "Purification and properties of N-acetyltransferase from mammalian liver". Ann N Y Acad Sci. 151 (2): 734–741. doi:10.1111/j.1749-6632.1968.tb11934.x. PMID   4984197. S2CID   44602517.
  7. 1 2 Westwood, I.M.; Kawamura, A.; Fullam, E.; et al. (2006). "Structure and Mechanism of Arylamine N-Acetyltransferases". Current Topics in Medicinal Chemistry. 6 (15): 1641–1654. doi:10.2174/156802606778108979. PMID   16918475.
  8. ↑ Sinclair, J.C.; Sandy, J.; Delgoda, R.; Sim, E.; Noble, M.E. (2000). "Structure of arylamine N-acetyltransferase reveals a catalytic triad". Nature Structural Biology. 7 (7): 560–564. doi:10.1038/76783. PMID   10876241. S2CID   23694257.
  9. 1 2 Grant, D.M.; Blum, M.; Meyer, U.A. (1992). "Polymorphisms of N-acetyltransferase genes". Xenobiotica. 22 (9–10): 1073–1081. doi:10.3109/00498259209051861. PMID   1441598.
  10. 1 2 Vatsis, K.P.; Weber, W.W.; Bell, D.A. (1995). "Nomenclature for N-acetyltransferases". Pharmacogenetics. 5 (1): 1–17. doi:10.1097/00008571-199502000-00001. PMID   7773298.
  11. 1 2 Ragunathan, Nilusha; Dairou, Julien; Pulvinage, Benjamin; et al. (June 2008). "Identification of the Xenobiotic-Metabolizing Enzyme Arylamine N-Acetyltransferase 1 as a New Target of Cisplatin in Breast Cancer Cells: Molecular and Cellular Mechanisms of Inhibition". Molecular Pharmacology. 73 (6): 1761–1768. doi:10.1124/mol.108.045328. PMID   18310302. S2CID   9214220.
  12. ↑ Sim, E.; Abuhammad, A.; Ryan, A. (May 2014). "Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery". Br J Pharmacol. 171 (11): 2705–2725. doi:10.1111/bph.12598. PMC   4158862 . PMID   24467436.
  13. 1 2 3 4 5 6 7 8 Laureri, Nicola; Sim, Edith (2018). Arylamine N-Acetyltransferases in Health and Disease: From Pharmacogenetics to Drug Discovery and Diagnostics. World Scientific. ISBN   9789813232006.
  14. ↑ Camporez, João Paulo; Wang, Yongliang; Faarkrog, Kasper; et al. (Dec 2017). "Mechanism by which arylamine N-acetyltransferase 1 ablation causes insulin resistance in mice". PNAS. 114 (52): E11285–E11292. doi: 10.1073/pnas.1716990115 . PMC   5748223 . PMID   29237750.
  15. ↑ McDonagh, E.M.; et al. (2014). "PharmGKB summary: very important pharmacogene infor- mation for N-acetyltransferase 2". Pharmacogenet. Genomics. 24 (8): 409–425. doi:10.1097/FPC.0000000000000062. PMC   4109976 . PMID   24892773.
  16. ↑ Evans, D.A.; White, T.A. (1964). "Human acetylation polymorphism". J. Lab. Clin. Med. 63: 394–403. PMID   14164493.
  17. ↑ Hein, D.W.; Doll, M.A. (2012). "Accuracy of various human NAT2 SNP genotyping panels to infer rapid, intermediate and slow acetylator phenotypes". Pharmacogenomics. 13 (1): 31–41. doi:10.2217/pgs.11.122. PMC   3285565 . PMID   22092036.
  18. 1 2 3 4 Rajasekaran, M.; Abirami, Santhanam; Chen, Chinpan (2011). "Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation". PLOS ONE. 6 (9): e25801. Bibcode:2011PLoSO...625801R. doi: 10.1371/journal.pone.0025801 . PMC   3183086 . PMID   21980537.
  19. ↑ Hein, D.W. (2000). "Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms". Cancer Epidemiol. Biomarkers Prev. 9 (1): 29–42. PMID   10667461.
  20. ↑ Walraven, Jason M.; Trent, John O.; Hein, David W. (2008). "Structure-Function Analysis of Single Nucleotide Polymorphisms in Human N-Acetyltransferase 1". Drug Metabolism Reviews. 40 (1): 169–184. doi:10.1080/03602530701852917. PMC   2265210 . PMID   18259988 – via Informa Healthcare.
  21. ↑ Unissa, Ameeruddin Nusrath; Subbian, Selvakumar; Hanna, Luke Elizabeth; Selvakumar, Nagamiah (2016). "Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis". Infection, Genetics and Evolution. 45: 474–492. doi:10.1016/j.meegid.2016.09.004. PMID   27612406.
  22. ↑ Patin, E.; Barreiro, L.B.; Sabeti, P.C.; et al. (2006). "Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes". Am J Hum Genet. 78 (3): 423–436. doi:10.1086/500614. PMC   1380286 . PMID   16416399.
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