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首页> 外文期刊>Biochemistry >Isotope effects reveal that para-substituted benzylamines are poor reactivity probes of the quinoprotein mechanism for aromatic amine dehydrogenase
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Isotope effects reveal that para-substituted benzylamines are poor reactivity probes of the quinoprotein mechanism for aromatic amine dehydrogenase

机译：同位素效应表明对位取代的苄胺是芳香胺脱氢酶喹蛋白机制反应性差的探针

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摘要

Structure-activity correlations have been employed previously in the mechanistic interpretation of TTQ-dependent amine dehydrogenases using a series of para-substituted benzylamines. However, by combining the use of kinetic isotope effects (KIEs) and crystallographic analysis, in conjunction with structure-reactivity correlation studies, we show that para-substituted benzylamines are poor reactivity probes for TTQ-dependent aromatic amine dehydrogenase (AADH). Stopped-flow kinetic studies of the reductive half-reaction, with para-substituted benzylamines and their dideuterated counterparts, demonstrate that C-H or C-D bond breakage is not fully rate limiting (KIEs similar to unity). Contrary to previous reports, Hammett plots exhibit a poor correlation of structure-reactivity data with electronic substituent effects for para-substituted benzylamines and phenylethylamines. Crystallographic studies of enzyme-substrate complexes reveal that the observed structure-reactivity correlations are not attributed to distinct binding modes for para-substituted benzylamines in the active site, although two binding sites for p-nitrobenzylamine are identified. We identify structural rearrangements, prior to the H-transfer step, which are likely to limit the rate of TTQ reduction by benzylamines. This work emphasizes (i) the need for caution when applying structure-activity correlations to enzyme-catalyzed reactions and (ii) the added benefit of using both isotope effects and structural analysis, in conjunction with structure-reactivity relationships, to study chemical steps in enzyme reaction cycles.
机译：先前已使用一系列对位取代的苄胺在TTQ依赖的胺脱氢酶的机械解释中采用了结构活性相关性。但是，通过结合使用动力学同位素效应（KIEs）和晶体学分析以及结构反应性相关研究，我们表明对位取代的苄胺对于TTQ依赖性芳香胺脱氢酶（AADH）的反应性较差。用对位取代的苄胺及其双氘代对应物进行的还原半反应的停止流动力学研究表明，C-H或C-D键断裂不是完全限速的（KIE与单位相似）。与以前的报告相反，哈米特图显示了结构反应性数据与对位取代的苄胺和苯乙胺的电子取代基效应之间的不良关联。酶-底物复合物的晶体学研究表明，尽管确定了对硝基苄胺的两个结合位点，但观察到的结构-反应性相关性并不归因于活性位点中对位取代的苄胺的独特结合模式。我们在H转移步骤之前确定了结构重排，这很可能会限制苄胺对TTQ的还原速率。这项工作强调（i）在将结构活性相关性应用于酶催化反应时需要谨慎，以及（ii）同时使用同位素效应和结构分析以及结构反应性关系来研究化学反应中的额外益处。酶反应周期。

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