TY - JOUR
T1 - NMR-based Model Reveals the Structural Determinants of Mammalian Arylamine N-Acetyltransferase Substrate Specificity
AU - Zhang, Naixia
AU - Liu, Li
AU - Liu, Fen
AU - Wagner, Carston R.
AU - Hanna, Patrick E.
AU - Walters, Kylie J.
PY - 2006/10/13
Y1 - 2006/10/13
N2 - 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.
AB - 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.
KW - NMR
KW - arylamine N-acetyltransferase
KW - arylamine carcinogens
KW - structural determinants
KW - substrate specificity
UR - http://www.scopus.com/inward/record.url?scp=33748764946&partnerID=8YFLogxK
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U2 - 10.1016/j.jmb.2006.08.026
DO - 10.1016/j.jmb.2006.08.026
M3 - Article
C2 - 16959263
AN - SCOPUS:33748764946
SN - 0022-2836
VL - 363
SP - 188
EP - 200
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
IS - 1
ER -
