NMR-based Model Reveals the Structural Determinants of Mammalian Arylamine N-Acetyltransferase Substrate Specificity

Naixia Zhang, Li Liu, Fen Liu, Carston R. Wagner, Patrick E. Hanna, Kylie J. Walters

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)188-200
Number of pages13
JournalJournal of Molecular Biology
Volume363
Issue number1
DOIs
StatePublished - Oct 13 2006

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Arylamine N-Acetyltransferase
Acetyltransferases
Structural Models
Substrate Specificity
2-toluidine
Acetylation
Carcinogens
4-Aminobenzoic Acid
Sunscreening Agents
Catalysis
Urinary Bladder Neoplasms
Smoke
Tobacco
Magnetic Resonance Spectroscopy
Enzymes

Keywords

  • NMR
  • arylamine N-acetyltransferase
  • arylamine carcinogens
  • structural determinants
  • substrate specificity

Cite this

NMR-based Model Reveals the Structural Determinants of Mammalian Arylamine N-Acetyltransferase Substrate Specificity. / Zhang, Naixia; Liu, Li; Liu, Fen; Wagner, Carston R.; Hanna, Patrick E.; Walters, Kylie J.

In: Journal of Molecular Biology, Vol. 363, No. 1, 13.10.2006, p. 188-200.

Research output: Contribution to journalArticle

Zhang, Naixia ; Liu, Li ; Liu, Fen ; Wagner, Carston R. ; Hanna, Patrick E. ; Walters, Kylie J. / NMR-based Model Reveals the Structural Determinants of Mammalian Arylamine N-Acetyltransferase Substrate Specificity. In: Journal of Molecular Biology. 2006 ; Vol. 363, No. 1. pp. 188-200.
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