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

  • Author(s): Zhang, Xiao-Nan
  • Cheng, Qinqin
  • Chen, Jingwen
  • Lam, Albert T
  • Lu, Yanran
  • Dai, Zhefu
  • Pei, Hua
  • Evdokimov, Nikolai M
  • Louie, Stan G
  • Zhang, Yong
  • et al.
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.

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