Arylamine N-acetyltransferases: a pharmacogenomic approach to drug metabolism and endogenous function

Biochemical Society Transactions
E SimMartin E M Noble

Abstract

The arylamine N-acetyltransferases (NATs) are a unique family of enzymes that catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of hydrazine and arylamine drugs and carcinogens. The NATs have been shown to be important in drug detoxification and carcinogen activation, with humans possessing two isoenzymes encoded by polymorphic genes. This polymorphism has pharmacogenetic implications, leading to different rates of inactivation of drugs, including the anti-tubercular agent isoniazid and the anti-hypertensive drug hydralazine. Mice provide a good model for human NAT, allowing genetic manipulation of expression to explore possible endogenous roles of these enzymes. The first three-dimensional NAT structure was resolved for NAT from Salmonella typhimurium, and subsequently the structure of NAT from Mycobacterium smegmatis has been elucidated. These identified a 'Cys-His-Asp' catalytic triad (conserved in all NATs), which is believed to be responsible for the activation of the active site cysteine residue. As more genomic data become available, NAT homologues continue to be found in prokaryotic species, many of which are pathogenic, including Mycobacterium tuberculosis. The discovery of NAT in M. tub...Continue Reading

Citations

Jul 26, 2005·The Pharmacogenomics Journal·W CaoR P Erickson
Jun 24, 2008·Journal of Toxicology and Environmental Health. Part a·Hermann C RoemerKlaus Golka
May 12, 2011·The Journal of Antimicrobial Chemotherapy·Pedro Eduardo Almeida Almeida Da Silva, Juan Carlos Palomino
Sep 6, 2008·PloS One·Francesca LucaAndrea Novelletto
Nov 21, 2008·Pharmacogenomics·Lesley A Stanley, Edith Sim
Apr 13, 2007·Expert Opinion on Drug Metabolism & Toxicology·Edith SimElizabeth Fullam
Nov 1, 2005·Drug Metabolism Reviews·Sotiria Boukouvala, Giannoulis Fakis
Nov 26, 2009·Life Sciences·Wen CaoRobert P Erickson
Mar 30, 2007·The International Journal of Biochemistry & Cell Biology·Rodney F MinchinNeville J Butcher
May 6, 2005·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Larissa WakefieldEdith Sim
Dec 2, 2005·Journal of Pharmacokinetics and Pharmacodynamics·Peter BuchwaldNicholas Bodor
Dec 13, 2006·Journal of Bacteriology·Hirokazu SuzukiSueharu Horinouchi
Jan 15, 2004·Molecular Pharmacology·Joanna E Summerscales, P David Josephy

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