Discovery of an NAD+ analogue with enhanced specificity for PARP1. Issue 7 (27th January 2022)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Chemical science. Volume 13:Issue 7(2022)
• Page Start: 1982
• Page End: 1991
• Publication Date: 2022-01-27
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/d1sc06256e
• Languages: English
• ISSNs: 2041-6520

Abstract

Abstract : An analogue of nicotinamide adenine dinucleotide (NAD + ) featuring an azido group at 3′-OH of adenosine moiety is found to possess high specificity for human PARP1-catalyzed protein poly-ADP-ribosylation. Abstract : 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.