Covalent and noncovalent intermediates of an NAD utilizing enzyme, human CD38.
Covalent and noncovalent intermediates of an NAD utilizing enzyme, human CD38.
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DOI：
10.1016/j.chembiol.2008.08.007
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发表时间：
2008-10-20
影响因子：
--
通讯作者：
Hao Q
中科院分区：
文献类型：
--
作者：
Liu Q;Kriksunov IA;Jiang H;Graeff R;Lin H;Lee HC;Hao Q
烟酰胺腺嘌呤二核苷酸（NAD）的酶促利用在基因调控、信号转导和蛋白质修饰中具有重要作用。许多方法需要从底物上裂解烟酰胺部分并形成反应性中间体。使用X射线晶体学，我们表明，人CD 38，NAD利用酶，能够催化裂解反应，通过共价和非共价中间体，这取决于所使用的底物。共价中间体对亲核试剂的进一步攻击具有抗性，导致基于机制的酶失活。非共价中间体主要通过H-键相互作用稳定，但似乎仍具有反应性。我们的结构结果有利于建议的非共价中间体在正常的酶促利用NAD的人CD 38，并提供结构的见解设计共价和非共价抑制剂靶向NAD利用途径。
Enzymatic utilization of nicotinamide adenine dinucleotide (NAD) has increasingly been shown to have fundamental roles in gene regulation, signal transduction, and protein modification. Many of the processes require the cleavage of the nicotinamide moiety from the substrate and the formation of a reactive intermediate. Using X-ray crystallography we show that human CD38, an NAD utilizing enzyme, is capable of catalyzing the cleavage reactions through both covalent and non-covalent intermediates, depending on the substrate used. The covalent intermediate is resistant to further attack by nucleophiles, resulting in mechanism-based enzyme inactivation. The non-covalent intermediate is stabilized mainly through H-bond interactions, but appears to remain reactive. Our structural results favor the proposal of a non-covalent intermediate during normal enzymatic utilization of NAD by human CD38 and provide structural insights into the design of covalent and non-covalent inhibitors targeting NAD utilization pathways.
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