Wu Hong, Dombrovsky Ludmila, Tempel Wolfram, Martin Fernando, Loppnau Peter, Goodfellow Geoffrey H, Grant Denis M, Plotnikov Alexander N
Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L5.
J Biol Chem. 2007 Oct 12;282(41):30189-97. doi: 10.1074/jbc.M704138200. Epub 2007 Jul 26.
The human arylamine N-acetyltransferases NAT1 and NAT2 play an important role in the biotransformation of a plethora of aromatic amine and hydrazine drugs. They are also able to participate in the bioactivation of several known carcinogens. Each of these enzymes is genetically variable in human populations, and polymorphisms in NAT genes have been associated with various cancers. Here we have solved the high resolution crystal structures of human NAT1 and NAT2, including NAT1 in complex with the irreversible inhibitor 2-bromoacetanilide, a NAT1 active site mutant, and NAT2 in complex with CoA, and have refined them to 1.7-, 1.8-, and 1.9-A resolution, respectively. The crystal structures reveal novel structural features unique to human NATs and provide insights into the structural basis of the substrate specificity and genetic polymorphism of these enzymes.
人类芳胺N - 乙酰基转移酶NAT1和NAT2在众多芳香胺和肼类药物的生物转化中发挥着重要作用。它们还能够参与多种已知致癌物的生物活化过程。在人类群体中，这两种酶的基因都具有多态性，NAT基因的多态性与多种癌症相关。在此，我们解析了人类NAT1和NAT2的高分辨率晶体结构，包括与不可逆抑制剂2 - 溴乙酰苯胺结合的NAT1、一个NAT1活性位点突变体以及与辅酶A结合的NAT2，并分别将它们精修至1.7埃、1.8埃和1.9埃的分辨率。晶体结构揭示了人类NATs独特的新结构特征，并为这些酶的底物特异性和基因多态性的结构基础提供了深入见解。
