1. Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N ‐Acetyltransferase NAT2
- Author
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Mário S. P. Correia, Louis P. Conway, Daniel Globisch, Ingvar A. Bergdahl, Tobias Sjöblom, and Veronica Rendo
- Subjects
Genotype ,Medicinska och farmaceutiska grundvetenskaper ,Arylamine N-Acetyltransferase ,polyamines ,Endogeny ,010402 general chemistry ,01 natural sciences ,Chemical synthesis ,Mass Spectrometry ,Catalysis ,chemistry.chemical_compound ,Cell Line, Tumor ,Humans ,Amines ,mass spectrometry ,chemistry.chemical_classification ,Arylamine N-acetyltransferase ,010405 organic chemistry ,Communication ,Biochemistry and Molecular Biology ,Acetylation ,Basic Medicine ,General Medicine ,General Chemistry ,metabolomics ,Communications ,drug metabolism ,Enzymes ,0104 chemical sciences ,Spermidine ,Kinetics ,Enzyme ,chemistry ,Biochemistry ,N-acetyltransferases ,Xenobiotic ,Biokemi och molekylärbiologi ,Intracellular ,Chromatography, Liquid - Abstract
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., Same NAT2, new substr8: NAT2 has been classified as an arylamine N‐acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Through a combination of metabolomics, chemical synthesis, and mass spectrometry it is demonstrated that unknown endogenous, aliphatic metabolites, and aliphatic amine‐containing commonly used drugs also act as substrates for NAT2.
- Published
- 2020