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Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N ‐Acetyltransferase NAT2
Author(s) -
Conway Louis P.,
Rendo Veronica,
Correia Mário S. P.,
Bergdahl Ingvar A.,
Sjöblom Tobias,
Globisch Daniel
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202005915
Subject(s) - acetylation , acetyltransferases , acetyltransferase , arylamine n acetyltransferase , spermidine , chemistry , biochemistry , regioselectivity , endogeny , xenobiotic , enzyme , chemotype , gene , chromatography , catalysis , essential oil
N ‐Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamine N ‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamine N ‐acetyltransferase NAT2 also acetylates aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed increased intracellular concentrations of mono‐ and diacetylated spermidine in human cell lines expressing the rapid compared to the slow acetylator NAT2 phenotype. The regioselective N 8 ‐acetylation of monoacetylated spermidine by NAT2 answers the long‐standing question of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine‐containing drugs by NAT2, which may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2, and we suggest that this enzyme should be considered for re‐classification.