Unexpected Acetylation of Endogenous Aliphatic Amines by ArylamineN-Acetyltransferase NAT2
Unexpected Acetylation of Endogenous Aliphatic Amines by ArylamineN-Acetyltransferase NAT2
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DOI：
10.1002/anie.202005915
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发表时间：
2020-07-08
影响因子：
16.6
通讯作者：
Globisch, Daniel
中科院分区：
文献类型：
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作者：
Conway, Louis P.;Rendo, Veronica;Globisch, Daniel
N-乙酰转移酶在异生物质（包括临床药物）的失活和清除中发挥着关键作用。 NAT2被归类为芳胺N-乙酰转移酶，主要转化芳香胺、羟胺和肼。在此，我们证明人芳胺 N-乙酰转移酶 NAT2 也乙酰化脂肪族内源胺。代谢组学分析和化学合成表明，与慢速乙酰化剂 NAT2 表型相比，表达快速乙酰化剂 NAT2 表型的人类细胞系中单乙酰化亚精胺和二乙酰化亚精胺的细胞内浓度增加。 NAT2 对单乙酰化亚精胺进行区域选择性 N(8)-乙酰化，回答了长期存在的二乙酰亚精胺来源问题。我们还发现了 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变化。结果证明了 NAT2 以前未知的功能和潜在的调节作用，我们建议应考虑对该酶进行重新分类。
N-Acetyltransferases play critical roles in the deactivation and clearance of xenobiotics, including clinical drugs. NAT2 has been classified as an arylamineN-acetyltransferase that mainly converts aromatic amines, hydroxylamines, and hydrazines. Herein, we demonstrate that the human arylamineN-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 regioselectiveN(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.