A ribose-functionalized NAD+ with unexpected high activity and selectivity for protein poly-ADP-ribosylation

Xiao-Nan Zhang, Qinqin Cheng, Jingwen Chen, Albert T. Lam, Yanran Lu, Zhefu Dai, Hua Pei, Nikolai M. Evdokimov, Stan G. Louie and Yong Zhang ()
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Xiao-Nan Zhang: University of Southern California
Qinqin Cheng: University of Southern California
Jingwen Chen: University of Southern California
Albert T. Lam: University of Southern California
Yanran Lu: University of Southern California
Zhefu Dai: University of Southern California
Hua Pei: University of Southern California
Nikolai M. Evdokimov: University of California
Stan G. Louie: University of Southern California
Yong Zhang: University of Southern California

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Nicotinamide adenine dinucleotide (NAD+)-dependent ADP-ribosylation plays important roles in physiology and pathophysiology. It has been challenging to study this key type of enzymatic post-translational modification in particular for protein poly-ADP-ribosylation (PARylation). Here we explore chemical and chemoenzymatic synthesis of NAD+ analogues with ribose functionalized by terminal alkyne and azido groups. Our results demonstrate that azido substitution at 3′-OH of nicotinamide riboside enables enzymatic synthesis of an NAD+ analogue with high efficiency and yields. Notably, the generated 3′-azido NAD+ exhibits unexpected high activity and specificity for protein PARylation catalyzed by human poly-ADP-ribose polymerase 1 (PARP1) and PARP2. And its derived poly-ADP-ribose polymers show increased resistance to human poly(ADP-ribose) glycohydrolase-mediated degradation. These unique properties lead to enhanced labeling of protein PARylation by 3′-azido NAD+ in the cellular contexts and facilitate direct visualization and labeling of mitochondrial protein PARylation. The 3′-azido NAD+ provides an important tool for studying cellular PARylation.

Date: 2019
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DOI: 10.1038/s41467-019-12215-4

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