Facile chemoenzymatic synthesis of a novel stable mimic of NAD.
Chemical science
confidence
Key findings
Synthesis of stable NAD+ mimic S-NAD+; chemically inert to CD38 and sirtuin 2 but participates in redox reactions like NAD+; X-ray crystallography of binding.
View source on PubMed (PMID 30568770) ↗
- Sample size
- Not reported
- Population
- In vitro (human CD38 and sirtuin 2 enzymes)
- Dosing
- Not reported
- Duration
- Not reported
- Route
- Not reported
- Blinding
- not_reported
- Controls
- none
- Drug class
- coenzyme
Full abstract
Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor participating in a variety of important enzyme-catalyzed physiological and pathophysiological processes. Analogues of NAD+ provide key and valuable agents for investigating NAD+-dependent enzymes. In this study, we report the preparation of a novel stable NAD+ mimic, 4'-thioribose NAD+ (S-NAD+), using a facile and efficient chemoenzymatic approach. Substrate activity assays indicated the resulting S-NAD+ is chemically inert to human CD38 and sirtuin 2 enzymes, but capable of participating in redox reactions in a manner similar to NAD+. X-ray crystallographic analysis revealed binding of S-NAD+ to the active site of human CD38 and critical residues involved in leaving group activation and catalysis. By more closely mimicking NAD+ in geometry and electrostatics, the generated S-NAD+ offers a unique and important tool that can be extended to study enzymes utilizing NAD+.