Regular Article
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

https://doi.org/10.1006/bbrc.2002.6414Get rights and content

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 (Arg64→Gln) on NAT2 activity.

References (29)

  • N. Matas et al.

    Mapping AAC1, AAC2 and AACP, the genes for arylamine N-acetyltransferases, carcinogen metabolising enzymes on human chromosome 8p22, a region frequently deleted in tumours

    Cytogenet. Cell Genet.

    (1997)
  • D.W. Hein et al.

    Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms

    Cancer Epidemiol. Biomarkers Prev.

    (2000)
  • E. Sim et al.

    An update on genetic, structural and functional studies of arylamine N-acetyltransferases in eucaryotes and procaryotes [in process citation]

    Hum. Mol. Genet.

    (2000)
  • D.W. Hein et al.

    Update on consensus arylamine N-acetyltransferase gene nomenclature [letter]

    Pharmacogenetics

    (2000)
  • Cited by (49)

    • Review of NEDDylation inhibition activity detection methods

      2021, Bioorganic and Medicinal Chemistry
      Citation Excerpt :

      The idea of molecular docking can be traced back to Fisher’s “lock and key” model in the 19th century.75 With the development of receptor theory, the understanding of the interaction between two molecules changed from the rigid model of spatial matching to the flexible model of spatial interaction and energy matching.76 In the process of computer simulation of drug design, molecular docking has gradually developed into an important method for compound screen.77

    • The role of lysine<sup>100</sup> in the binding of acetylcoenzyme A to human arylamine N-acetyltransferase 1: Implications for other acetyltransferases

      2015, Biochemical Pharmacology
      Citation Excerpt :

      They are distinguished by the presence of a conserved catalytic triad that prefers aromatic amine and hydrazine substrates [2]. In humans, there are 2 NATs (NAT1 and NAT2) and their crystal structure and catalytic function have been described in detail [3–6]. Both NAT1 and NAT2 are genetically polymorphic, which impacts on the pharmacology of many therapeutic agents that are metabolized by these enzymes [7].

    • Methods for Predicting Human Drug Metabolism

      2007, Advances in Clinical Chemistry
    View all citing articles on Scopus

    Abbreviations used: Ac-CoA, acetyl-CoA; NAT, arylamine N-acetyltransferase; rmsd, root mean square deviation.

    1

    To whom correspondence and reprint requests should be addressed at CNRS UMR 7000, Faculté de Médecine Pitié-Salpêtrière, 105 Bd de l'Hôpital, 75013 Paris, France. Fax: (33 1) 53 60 08 02. E-mail: [email protected].

    View full text