A ribose-functionalized NAD+ with versatile activity for ADP-ribosylation
Elisa N Stephens1, Xiao-Nan Zhang1, Albert T Lam1
1Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA. yongz@usc.edu.
Chemical Communications (Cambridge, England)
|November 3, 2023
Summary
Researchers developed a novel ribose-functionalized NAD+ analog that acts as a substrate for poly-ADP-ribose polymerases. This new molecule aids in identifying ADP-ribosylated proteins and developing advanced ADP-ribosylation research probes.
Area of Science:
- Biochemistry
- Molecular Biology
- Chemical Biology
Background:
- Poly-ADP-ribosylation (PARylation) is a crucial post-translational modification regulating various cellular processes.
- Existing tools for studying PARylation have limitations in substrate versatility and detection.
- Understanding NAD+ metabolism and its derivatives is key to deciphering cellular signaling.
Purpose of the Study:
- To synthesize and characterize a novel ribose-functionalized NAD+ analog.
- To evaluate its utility as a general substrate for poly-ADP-ribose polymerases (PARPs).
- To demonstrate its application in identifying mono- and poly-ADP-ribosylated proteins and developing new research probes.
Main Methods:
- Chemical synthesis of the NAD+ analog featuring an adenosyl 4'-azido group.
- Enzymatic assays using various ADP-ribosyltransferases.
- Affinity purification and mass spectrometry to identify modified proteins.
- Development of detection methods for ADP-ribosylated species.
Main Results:
- The synthesized NAD+ analog functions as a general substrate for multiple PARPs.
- Derived mono- and poly-ADP-ribosylated proteins are recognized by specific ADP-ribosylation readers.
- This represents the first ribose-functionalized NAD+ with broad activity across different ADP-ribosyltransferases.
Conclusions:
- The novel NAD+ analog is a versatile tool for studying ADP-ribosylation.
- It facilitates the identification of ADP-ribosylated proteins and their interacting partners.
- This molecule offers new avenues for developing chemical probes to investigate ADP-ribosylation pathways.
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