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Effects of modification of the active site tyrosine of human DNA topoisomerase I

机译：人DNA拓扑异构酶活性位点酪氨酸的改性效果

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摘要

The human topoisomerase I-mediated DNA relaxation reaction was studied following modification of the enzyme at the active site tyrosine (position 723). A series of unnatural tyrosine analogues was incorporated into the active site of human topoisomerase I by utilizing misacylated suppressor tRNAs in an in vitro protein synthesizing system. The relaxation activities of the modified human topoisomerase I analogues having varied steric, electronic, and stereochemical features were all greatly diminished relative to that of the wild type. It was found that modifications involving replacement of the nucleophilic tyrosine OH group with NH2, SH, or I groups eliminated DNA relaxation activity, as did changing the orientation of the nucleophilic tyrosine OH group. Only tyrosine analogues having the phenolic OH group in the normal position with respect to the protein backbone were active; the relative activities could be rationalized in chemical terms on the basis of the H-bonding and the electronic effects of the substituents attached to the meta position of the aromatic ring. In addition, the poisoning of one of the modified human topoisomerase I analogues, as part of covalent binary complexes with DNA, by CPT and 20-thio CPT was evaluated.
机译：在活性位点酪氨酸（位置723）的酶改性后，研究了人拓扑异构酶I介导的DNA弛豫反应。通过利用在体外蛋白质合成系统中使用错位的抑制器TNA，将一系列非天然酪氨酸类似物掺入人拓扑异构酶I的活性位点。具有不同空间，电子和立体化学特征的改性人拓扑酶I类似物的弛豫活性在野生型中大大减少。发现涉及用NH 2，SH或I组替代亲核酪氨酸OH基团的修饰消除了DNA松弛活性，改变了亲核酪氨酸OH基团的取向。只有在正常位置相对于蛋白质骨架处具有酚OH基团的酪氨酸类似物是活性的;相对活动可以基于H键合的化学术语和附着于芳香环的元位置的取代基的电子效果来合理化。此外，评价了一种改性人拓扑异构酶I类似物的中毒作为通过CPT和20-THIO CPT的与DNA的共价二元络合物的一部分。

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