Unexpected Acetylation of Endogenous Aliphatic Amines by Arylamine N-Acetyltransferase NAT2.
2020
N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has previously been classified as an arylamine N-acetyltransferase that mainly converts aromatic amines, hydroxylamines and hydrazines. Here, we demonstrate that the human arylamine N-acetyltransferase NAT2 also acetylates a series of aliphatic endogenous amines. Metabolomic analysis and chemical synthesis revealed significantly 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 in polyamine metabolism of the source of diacetylspermidine. We also identified selective acetylation of structurally diverse alkylamine-containing commonly used drugs by NAT2. Such moieties are present in 21% of prescribed drugs in the US and acetylation by NAT2 may contribute to variations in patient responses. The results demonstrate a previously unknown functionality and potential regulatory role for NAT2 and we therefore suggest that this enzyme should be considered for re-classification.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
43
References
7
Citations
NaN
KQI