Zhang Xiao-Nan, Lam Albert T, Cheng Qinqin, Courouble Valentine V, Strutzenberg Timothy S, Li Jiawei, Wang Yiling, Pei Hua, Stiles Bangyan L, Louie Stan G, Griffin Patrick R, Zhang Yong
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California Los Angeles CA 90089 USA
Department of Molecular Medicine, The Scripps Research Institute Jupiter FL 33458 USA.
Chem Sci. 2022 Jan 27;13(7):1982-1991. doi: 10.1039/d1sc06256e. eCollection 2022 Feb 16.
Among various protein posttranslational modifiers, poly-ADP-ribose polymerase 1 (PARP1) is a key player for regulating numerous cellular processes and events through enzymatic attachments of target proteins with ADP-ribose units donated by nicotinamide adenine dinucleotide (NAD). Human PARP1 is involved in the pathogenesis and progression of many diseases. PARP1 inhibitors have received approvals for cancer treatment. Despite these successes, our understanding about PARP1 remains limited, partially due to the presence of various ADP-ribosylation reactions catalyzed by other PARPs and their overlapped cellular functions. Here we report a synthetic NAD featuring an adenosyl 3'-azido substitution. Acting as an ADP-ribose donor with high activity and specificity for human PARP1, this compound enables labelling and profiling of possible protein substrates of endogenous PARP1. It provides a unique and valuable tool for studying PARP1 in biology and pathology and may shed light on the development of PARP isoform-specific modulators.
在各种蛋白质翻译后修饰因子中，聚ADP - 核糖聚合酶1（PARP1）是通过将靶蛋白与烟酰胺腺嘌呤二核苷酸（NAD）提供的ADP - 核糖单元进行酶促连接来调节众多细胞过程和事件的关键因子。人PARP1参与多种疾病的发病机制和进展。PARP1抑制剂已获批用于癌症治疗。尽管取得了这些成功，但我们对PARP1的了解仍然有限，部分原因是存在由其他PARP催化的各种ADP - 核糖基化反应及其重叠的细胞功能。在此，我们报道了一种具有腺苷3'-叠氮取代的合成NAD。该化合物作为对人PARP1具有高活性和特异性的ADP - 核糖供体，能够对内源性PARP1的可能蛋白质底物进行标记和分析。它为在生物学和病理学中研究PARP1提供了一种独特且有价值的工具，并可能为PARP异构体特异性调节剂的开发提供线索。
