Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Box 574, 75123, Uppsala, Sweden.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75123, Uppsala, Sweden.
Angew Chem Int Ed Engl. 2020 Aug 17;59(34):14342-14346. doi: 10.1002/anie.202005915. Epub 2020 Jul 8.
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 -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.
N-乙酰基转移酶在包括临床药物在内的外源化学物质的失活和清除中起着关键作用。NAT2 被归类为芳基胺 N-乙酰基转移酶，主要将芳香胺、羟胺和肼转化。在此，我们证明人类芳基胺 N-乙酰基转移酶 NAT2 还乙酰化脂族内源性胺。代谢组学分析和化学合成揭示了在表达快速乙酰化酶 NAT2 表型的人细胞系中，单乙酰化和二乙酰化 spermidine 的细胞内浓度增加。NAT2 对单乙酰化 spermidine 的区域选择性 N-乙酰化回答了二乙酰 spermidine 来源的长期存在的问题。我们还鉴定了 NAT2 对结构多样的含烷基胺药物的选择性乙酰化，这可能导致患者反应的差异。结果表明了 NAT2 以前未知的功能和潜在的调节作用，我们建议重新分类该酶。
