ASSIGNMENT 1

How Acetyltransferase play a role in drug development?

Name: Phm Tng Vi ID: BTIU09327

Acetyltransferase (or transacetylase) transfers an acetyl group.

is

type

of transferase enzyme that

CH3-C-CoAS + R-NH2 -> CH3-CO-NHR

The enzymes contain an aromatic amine or a hydrazinemoiety (eg, isoniazid) are substrates of cytosolic N -acetyltransferases [NATs ], encoded by NAT1 and NAT2 genes. In result, drugs are formed in acetylation which are less polar than the parent drug and still have pharmaceutical. Some examples of Acetyltransferase are: N-acetyltransferase (Serotonin N-acetyl transferase, HGSNAT, ARD1A) Histone acetyltransferase (P300/CBP, NAT2) Choline acetyltransferase Acetyl-Coenzyme A acetyltransferase Acetyl-CoA C-acyltransferase Chloramphenicol acetyltransferase

palmitoyltransferases: Carnitine O-palmitoyltransferase (CPT1, CPT2)

Serine C-palmitoyltransferase (SPTLC1, SPTLC2)

N-acetyltransferase
N-acetyltransferase is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines.[1] They have wide specificity for aromatic amines, particularly serotonin, and can also catalyze acetyl transfer between arylamines without CoA. EC 2.3.1.5. Investigations have indicated the existence of more than one N-acetyltransferase (EC 2.3.1.5). At least two enzymes, possibly isoenzymes, were partially characterized. The enzymes differed in their tissue distribution, substrate specificity, stability and pH characteristics. Scientists have developed drugs Based on characteristics of N-acetyltransferase:

Role of N-acetyltransferase polymorphisms in

Persistent infection with hepatitis B virus (HBV) causes chronic phasic necroinflammation and regenerative proliferation in the liver. The sustained hepatocellular proliferation may render chronic HBV carriers more susceptible to the effects of environmental carcinogens. Aromatic amines are potential hepatocarcinogens in humans.N-acetyltransferase (NAT) is involved in the metabolic activation and detoxification of these compounds.

hepatitis B related hepatocellular carcinoma: impact of smoking on risk Dr M-W Yu, Graduate Institute of Epidemiology, College of Public Health

Characterization of N-acetyltransferase 1 and 2

polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma BMC Medical Genetics 2007

N-acetyltransferase 1 (NAT1) and 2 (NAT2) are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD) consist of Crohn's disease (CD) and ulcerative colitis (UC), both are associated with increased colorectal cancer (CRC) risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD.

 Arylamine N-acetyltransferase and drug response

Peter Meisel

Arylamine N-acetyltransferase (NATs) play an important role in the

interaction of competing metabolic pathways determining the fate of and response to xenobiotics as therapeutic drugs, occupational chemicals and carcinogenic substances. Individual susceptibility for drug response and possible adverse drug reactions are modulated by the genetic predisposition (manifested for example, by polymorphisms) and the phenotype of these enzymes. For all drugs metabolized by NATs, the impact of different in vivo enzyme activities is reviewed with regard to therapeutic use, prevention of side effects and possible indications for risk assessment by phenotyping and/or genotyping. As genes of NATs are susceptibility genes for multifactorial adverse effects and xenobiotic-related diseases, risk prediction can only be made possible by taking the complexity of events into consideration.

Using N-acetyltransferase type 2 genotyping to personalize isoniazid doses by Martina Kinzig-Schippers Metabolism by N-Acetyltransferase 1 In Vitro and in Healthy Volunteers: A Prototype for Targeted Inhibition

Jerry M. Collins, PhD Metabolic drug-drug interaction studies in vitro successfully predicted inhibition of acetylation via N-acetyltransferase 1 in vivo. Although no specific toxic species was investigated in this work, the potential was demonstrated for improving the therapeutic index of drugs that have toxic metabolites.

Cigarette smoking, N-acetyltransferase genes and

the risk of advanced colorectal adenoma. Division of

Cancer Epidemiology and Genetics, National Cancer Institute

Cigarette use is associated with greater risk for colorectal adenoma, a colorectal cancer precursor. N-acetyltransferases, NAT1 and NAT2, are important enzymes involved in the metabolism of aromatic amine carcinogens present in cigarette smoke. the polymorphisms within the NAT1 and NAT2 genes that influence the tobacco-colorectal tumor relationship by impacting on the metabolic activation and detoxification of tobacco smoke-derived carcinogens. The study indicated that NAT2 gene variants associated with a slow acetylator phenotype were more susceptible to the effects of tobacco

smoking with respect to adenoma risk, providing leads for disease prevention.

N-Acetyltransferase-related drug intolerance Dipl.

Biol. Birgit Busse

Several active ingredients belonging to different categories of substances are metabolised by polymorphs and therefore by enzymes which vary in their effectiveness. During the phase II reaction of drug metabolism, substances which were modified in phase I are conjugated with the bodys own molecules. These reactions involve several specific transferases, with Nacetyltransferases (NAT) playing a particularly significant role. Variations in the rate at which the anti-tuberculosis drug, isoniazid, is metabolised were described more than 40 years ago, when variants in the NAT2 gene were identified as the cause. The slow acetylator (SA) phenotype is determined by homozygous or combined heterozygous variants in the encoded region of the NAT2 gene, with 4 allele variants (NAT2*5a/b, *6a, *7a/b, *14a) being particularly prevalent. The frequency of the NAT2-allele variant varies greatly according to the different ethnic groups: 40-70% of Europeans, 90% of North Africans, and just 10% of oriental populations are slow acetylators. Clinically relevant undesirable effects include peripheral neuropathy in slow acetylators receiving isoniazid therapy, hypersensitivity to sulfonamides and leucopoenia in fast acetylators on amonafid, a prodrug used in chemotherapy.

References

The Journal of Clinical Pharmacology http://jcp.sagepub.com/

Drug-drug interactions in pharmaceutical development
BioInfoBank Library http://lib.bioinfo.pl/
A. P. Li

http://en.wikipedia.org/wiki/Acetyltransferase