title: NMR-based model reveals the structural determinants of mammalian arylamine N-acetyltransferase substrate specificity.
abstract: Arylamine N-acetyltransferases (NATs) catalyze the acetylation of arylamines, a key step in the detoxification of many carcinogens. The determinants of NAT substrate specificity are not known, yet this knowledge is required to understand why NAT enzymes acetylate some arylamines, but not others. Here, we use NMR spectroscopy and homology modeling to reveal the structural determinants of arylamine acetylation by NATs. In particular, by using chemical shift perturbation analysis, we have identified residues that play a critical role in substrate binding and catalysis. This study reveals why human NAT1 acetylates the sunscreen additive p-aminobenzoic acid and tobacco smoke carcinogen 4-aminobiphenyl, but not o-toluidine and other arylamines linked to bladder cancer. Our results represent an important step toward predicting whether arylamines present in new products can be detoxified by mammalian NATs.
authors.affiliation: Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Naixia
authors.initials: N
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.forename: Fen
authors.initials: F
authors.lastname: Liu
authors.forename: Carston R
authors.initials: CR
authors.lastname: Wagner
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Hanna
authors.forename: Kylie J
authors.initials: KJ
authors.lastname: Walters
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001191:Arylamine N-Acetyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity / Q000235:genetics
chemical_list: D007527:Isoenzymes; D001191:Arylamine N-Acetyltransferase; C089384:N-acetyltransferase 1