Download MendeleyNicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling.
Kao, G., Zhang, X.N., Nasertorabi, F., Katz, B.B., Li, Z., Dai, Z., Zhang, Z., Zhang, L., Louie, S.G., Cherezov, V., Zhang, Y.(2024) JACS Au 4: 4345-4360
- PubMed: 39610739
- DOI: https://doi.org/10.1021/jacsau.4c00695
- Primary Citation of Related Structures:
8VAU - PubMed Abstract:
Nicotinamide adenine dinucleotide (NAD + ) is required for a myriad of metabolic, signaling, and post-translational events in cells. Its levels in tissues and organs are closely associated with health conditions. The homeostasis of NAD + is regulated by biosynthetic pathways and consuming enzymes. As a membrane-bound protein with robust NAD + hydrolase activity, cluster of differentiation 38 (CD38) is a major degrader of NAD + . Deficiency or inhibition of CD38 enhances NAD + levels in vivo, resulting in various therapeutic benefits. As a metabolic precursor of NAD + , nicotinamide mononucleotide can be rapidly hydrolyzed by CD38, whereas nicotinamide riboside (NR) lacks CD38 substrate activity. Given their structural similarities, we explored the inhibition potential of NR. To our surprise, NR exhibits marked inhibitory activity against CD38 by forming a stable ribosyl-ester bond with the glutamate residue 226 at the active site. Inspired by this discovery, we designed and synthesized a clickable NR featuring an azido substitution at the 5'-OH position. This cell-permeable NR analogue enables covalent labeling and imaging of both extracellular and intracellular CD38 in live cells. Our work discovers an unrecognized molecular function of NR and generates a covalent probe for health-related CD38. These findings offer new insights into the role of NR in modulating NAD + metabolism and CD38-mediated signaling as well as an innovative tool for in-depth studies of CD38 in physiology and pathophysiology.
Organizational Affiliation:
Department of Pharmacology and Pharmaceutical Sciences, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, California 90089, United States.
