Back to Search
Start Over
Catalysis-based inhibitors of the calcium signaling function of CD38
- Source :
- Biochemistry. 51(1)
- Publication Year :
- 2011
-
Abstract
- CD38 is a signaling enzyme responsible for catalyzing the synthesis of cyclic ADP ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate; both are universal Ca(2+) messenger molecules. Ablation of the CD38 gene in mice causes multiple physiological defects, including impaired oxytocin release, that result in altered social behavior. A series of catalysis-based inhibitors of CD38 were designed and synthesized, starting with arabinosyl-2'-fluoro-2'-deoxynicotinamide mononucleotide. Structure-function relationships were analyzed to assess the structural determinants important for inhibiting the NADase activity of CD38. X-ray crystallography was used to reveal the covalent intermediates that were formed with the catalytic residue, Glu226. Metabolically stable analogues that were resistant to inactivation by phosphatase and esterase were synthesized and shown to be effective in inhibiting intracellular cADPR production in human HL-60 cells during induction of differentiation by retinoic acid. The inhibition was species-independent, and the analogues were similarly effective in blocking the cyclization reaction of CD38 in rat ventricular tissue extracts, as well as inhibiting the α-agonist-induced constriction in rat mesentery arteries. These compounds thus represent the first generally applicable and catalysis-based inhibitors of the Ca(2+) signaling function of CD38.
- Subjects :
- Male
Phosphatase
Retinoic acid
HL-60 Cells
CD38
Crystallography, X-Ray
Biochemistry
Cyclic ADP-ribose
Catalysis
Pichia
Rats, Sprague-Dawley
chemistry.chemical_compound
Inhibitory Concentration 50
Mice
NAD+ Nucleosidase
Animals
Humans
Calcium Signaling
Enzyme Inhibitors
Nicotinamide Mononucleotide
Calcium signaling
chemistry.chemical_classification
Nicotinic acid adenine dinucleotide phosphate
Chemistry
Hydrolysis
ADP-ribosyl Cyclase 1
Arabinose
Rats
Enzyme
Intracellular
Subjects
Details
- ISSN :
- 15204995
- Volume :
- 51
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Biochemistry
- Accession number :
- edsair.doi.dedup.....20c0767dbd98f95c9034bdca810a04b6