title: 3D model of human arylamine N-acetyltransferase 2: structural basis of the slow acetylator phenotype of the R64Q variant and analysis of the active-site loop.
abstract: The human arylamine N-acetyltransferase NAT2 is responsible for the biotransformation of numerous arylamine drugs and carcinogens. A common polymorphism of the NAT2 gene has been associated with susceptibility to drug toxicity and various malignancies. In this study, we used the crystal structure of the Salmonella typhimurium NAT (StNAT) to construct a high-quality model of a catalytic N-terminal region of NAT2 (residues 34-131). We show that this region has a similar structure in StNAT and the human isoforms NAT1 and NAT2. Comparison of the structures of these three molecules suggests that NATs have an active-site loop with a conserved structure, which is involved in substrate recognition. Our model is consistent with previous experimental data and provides the first plausible structural basis of the effects of a common genetic polymorphism (Arg(64)-->Gln) on NAT2 activity.
authors.affiliation: CNRS-UMR7000, Faculté de Médecine Pitié-Salpêtrière, 105 boulevard de l'Hôpital, Paris, 75013, France.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rodrigues-Lima
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Dupret
mesh_terms: D000105:Acetyl Coenzyme A / Q000737:chemistry; D000107:Acetylation; D019943:Amino Acid Substitution; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry*; D001665:Binding Sites / Q000502:physiology; D003198:Computer Simulation; D017124:Conserved Sequence; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D008958:Models, Molecular; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012486:Salmonella typhimurium / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D000105:Acetyl Coenzyme A; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1; C478900:NAT2 protein, human