Hollis T, Lau A, Ellenberger T
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Prog Nucleic Acid Res Mol Biol. 2001;68:305-14. doi: 10.1016/s0079-6603(01)68109-1.
Chemically damaged bases are removed from DNA by glycosylases that locate the damage and cleave the bond between the modified base and the deoxyribose sugar of the DNA backbone. The detection of damaged bases in DNA poses two problems: (1) The aberrant bases are mostly buried within the double helix, and (2) a wide variety of chemically different modifications must be efficiently recognized and removed. The human alkyladenine glycosylase (AAG) and Escherichia coli Alka DNA glycosylases excise many different types of alkylated bases from DNA. Crystal structures of these enzymes show how substrate bases are exposed to the enzyme active site and they suggest mechanisms of catalytic specificity. Both enzymes bend DNA and flip substrate bases out of the double helix and into the enzyme active site for cleavage. Although AAG and AlkA have very different overall folds, some common features of their substrate-binding sites suggest related strategies for the selective recognition of a chemically diverse group of alkylated substrates.
糖基化酶可将化学损伤的碱基从DNA中去除，这些酶能够定位损伤部位，并切断修饰碱基与DNA主链脱氧核糖之间的化学键。检测DNA中的损伤碱基存在两个问题：（1）异常碱基大多埋藏在双螺旋内部；（2）必须有效识别并去除多种化学性质不同的修饰。人类烷基腺嘌呤糖基化酶（AAG）和大肠杆菌Alka DNA糖基化酶可从DNA中切除许多不同类型的烷基化碱基。这些酶的晶体结构展示了底物碱基如何暴露于酶的活性位点，并提示了催化特异性的机制。两种酶都会使DNA弯曲，将底物碱基从双螺旋中翻转出来并进入酶的活性位点进行切割。尽管AAG和AlkA的整体折叠结构非常不同，但它们底物结合位点的一些共同特征表明，对于选择性识别化学性质多样的烷基化底物，存在相关策略。
