An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes.
Arylamine N:-acetyltransferase (NAT) was first identified as the inactivator of the anti-tubercular drug isoniazid. The enzyme was shown to catalyse the transfer of an acetyl group from acetyl-CoA to the terminal nitrogen of the hydrazine drug. The rate of inactivation of isoniazid was polymorphically distributed in the population and was one of the first examples of pharmacogenetic variation. NAT was identified recently in Mycobacterium tuberculosis and is a candidate for modulating the response to isoniazid. Genome sequences have revealed many homologous members of this unique family of enzymes. The first three-dimensional structure of a member of the NAT family identifies a catalytic triad consisting of aspartate, histidine and cysteine proposed to form the activation mechanism. So far, all procaryotic NATs resemble the human enzyme which acetylates isoniazid (NAT2). Human NAT2 is characteristic of drug-metabolizing enzymes: it is found in liver and intestine. In humans and other mammals, there are up to three different isoenzymes. If only one isoenzyme is present, it is like human NAT1. Human NAT1 and its murine equivalent specifically acetylate the folate catabolite p-aminobenzoylglutamate. NAT1 and its murine homologue each have a ubiquitous tissue distribution and are expressed early in development at the blastocyst stage. During murine embryonic development, NAT is expressed in the developing neural tube. The proposed endogenous role of NAT in folate metabolism, and its multi-allelic nature, indicate that its role in development should be assessed further.
Sim
E
E
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK. esim@molbiol.ox.ac.uk
Payton
M
M
Noble
M
M
Minchin
R
R
D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D005057:Eukaryotic Cells; D006801:Humans; D011387:Prokaryotic Cells; D011487:Protein Conformation
D001191:Arylamine N-Acetyltransferase