Andorfer Mary C, Grob Jonathan E, Hajdin Christine E, Chael Julia R, Siuti Piro, Lilly Jeremiah, Tan Kian L, Lewis Jared C
Department of Chemistry, University of Chicago, Chicago, IL 60637.
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 250 Massachusetts Ave, Cambridge, MA 02139.
ACS Catal. 2017 Mar 3;7(3):1897-1904. doi: 10.1021/acscatal.6b02707. Epub 2017 Jan 31.
The activity of four native FDHs and four engineered FDH variants on 93 low molecular weight arenes was used to generate FDH substrate activity profiles. These profiles provided insights into how substrate class, functional group substitution, electronic activation, and binding impact FDH activity and selectivity. The enzymes studied could halogenate a far greater range of substrates than previously recognized, but significant differences in their substrate specificity and selectivity were observed. Trends between the electronic activation of each site on a substrate and halogenation conversion at that site were established, and these data, combined with docking simulations, suggest that substrate binding can override electronic activation even on compounds differing appreciably from native substrates. These findings provide a useful framework for understanding and exploiting FDH reactivity for organic synthesis.
利用四种天然甲醛脱氢酶（FDHs）和四种工程改造的FDH变体对93种低分子量芳烃的活性来生成FDH底物活性谱。这些谱图为底物类别、官能团取代、电子活化和结合如何影响FDH活性和选择性提供了见解。所研究的酶能够卤化的底物范围比以前认识到的要广泛得多，但观察到它们在底物特异性和选择性上存在显著差异。确定了底物上每个位点的电子活化与该位点卤化转化率之间的趋势，并且这些数据与对接模拟相结合表明，即使对于与天然底物有明显差异的化合物，底物结合也可以超越电子活化。这些发现为理解和利用FDH在有机合成中的反应性提供了一个有用的框架。
