Facile chemoenzymatic synthesis of a novel stable mimic of NAD+
Facile chemoenzymatic synthesis of a novel stable mimic of NAD+
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DOI：
10.1039/c8sc03899f
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发表时间：
2018-11-28
期刊：
影响因子：
8.4
通讯作者：
Zhang, Yong
中科院分区：
文献类型：
--
作者：
Dai, Zhefu;Zhang, Xiao-Nan;Zhang, Yong
烟酰胺腺嘌呤二核苷酸（NAD（+））是一种重要的辅因子，参与多种重要的酶催化的生理和病理生理过程。NAD（+）类似物为研究NAD（+）依赖性酶提供了关键和有价值的试剂。在这项研究中，我们报告了一种新的稳定的NAD（+）模拟物，4 0 -硫代核糖NAD（+）（S-NAD（+））的制备，使用一种简单而有效的化学酶的方法。底物活性测定表明，所得S-NAD（+）对人CD 38和沉默调节蛋白2酶是化学惰性的，但能够以与NAD（+）类似的方式参与氧化还原反应。X射线晶体学分析显示S-NAD（+）与人CD 38的活性位点和参与离去基团活化和催化的关键残基结合。通过在几何和静电学上更接近地模拟NAD（+），所产生的S-NAD（+）提供了一种独特而重要的工具，可以扩展到研究利用NAD（+）的酶。
Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor participating in a variety of important enzyme-catalyzed physiological and pathophysiological processes. Analogues of NAD(+) provide key and valuable agents for investigating NAD(+)-dependent enzymes. In this study, we report the preparation of a novel stable NAD(+) mimic, 4 0 -thioribose NAD(+) (S-NAD(+)), using a facile and efficient chemoenzymatic approach. Substrate activity assays indicated the resulting S-NAD(+) is chemically inert to human CD38 and sirtuin 2 enzymes, but capable of participating in redox reactions in a manner similar to NAD(+). X-ray crystallographic analysis revealed binding of S-NAD(+) to the active site of human CD38 and critical residues involved in leaving group activation and catalysis. By more closely mimicking NAD(+) in geometry and electrostatics, the generated S-NAD(+) offers a unique and important tool that can be extended to study enzymes utilizing NAD(+).