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Article: Catalysis-based inhibitors of the calcium signaling function of CD38
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TitleCatalysis-based inhibitors of the calcium signaling function of CD38
 
AuthorsKwong, AKY1
Chen, Z2
Zhang, H1
Leung, FP1
Lam, CMC1
Ting, KY1
Zhang, L2
Hao, Q1
Zhang, LH2
Lee, HC1
 
KeywordsCalcium signaling
Catalytic residue
Cyclic ADP-ribose (cADPR)
Cyclization reactions
Human HL-60 cell
 
Issue Date2012
 
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
 
CitationBiochemistry, 2012, v. 51 n. 1, p. 555-564 [How to Cite?]
DOI: http://dx.doi.org/10.1021/bi201509f
 
AbstractCD38 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 alpha-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. © 2011 American Chemical Society.
 
Descriptioneid_2-s2.0-84863081072
 
ISSN0006-2960
2013 Impact Factor: 3.194
 
DOIhttp://dx.doi.org/10.1021/bi201509f
 
ISI Accession Number IDWOS:000298907400057
Funding AgencyGrant Number
RGC769107
768408
769309
770610
765909
766510
National Natural Sciences Foundation of China/RGCN_HKU 722/08
NSFCNSFC-RGC 20831160506
NSFC 81172917
Funding Information:

This work was supported by grants from the Hong Kong General Research Fund (RGC) (769107, 768408, 769309, and 770610 to H.C.L. and 765909 and 766510 to Q.H.), the National Natural Sciences Foundation of China/RGC Joint Research Scheme (NSFC/RGC Grant N_HKU 722/08 to H.C.L.), and a NSFC grant to L.-H.Z. (NSFC-RGC 20831160506 and NSFC 81172917).

 
ReferencesReferences in Scopus
 
GrantsChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
 
DC FieldValue
dc.contributor.authorKwong, AKY
 
dc.contributor.authorChen, Z
 
dc.contributor.authorZhang, H
 
dc.contributor.authorLeung, FP
 
dc.contributor.authorLam, CMC
 
dc.contributor.authorTing, KY
 
dc.contributor.authorZhang, L
 
dc.contributor.authorHao, Q
 
dc.contributor.authorZhang, LH
 
dc.contributor.authorLee, HC
 
dc.date.accessioned2012-02-28T01:55:55Z
 
dc.date.available2012-02-28T01:55:55Z
 
dc.date.issued2012
 
dc.description.abstractCD38 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 alpha-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. © 2011 American Chemical Society.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.descriptioneid_2-s2.0-84863081072
 
dc.identifier.citationBiochemistry, 2012, v. 51 n. 1, p. 555-564 [How to Cite?]
DOI: http://dx.doi.org/10.1021/bi201509f
 
dc.identifier.doihttp://dx.doi.org/10.1021/bi201509f
 
dc.identifier.eissn1520-4995
 
dc.identifier.epage564
 
dc.identifier.hkuros198792
 
dc.identifier.isiWOS:000298907400057
Funding AgencyGrant Number
RGC769107
768408
769309
770610
765909
766510
National Natural Sciences Foundation of China/RGCN_HKU 722/08
NSFCNSFC-RGC 20831160506
NSFC 81172917
Funding Information:

This work was supported by grants from the Hong Kong General Research Fund (RGC) (769107, 768408, 769309, and 770610 to H.C.L. and 765909 and 766510 to Q.H.), the National Natural Sciences Foundation of China/RGC Joint Research Scheme (NSFC/RGC Grant N_HKU 722/08 to H.C.L.), and a NSFC grant to L.-H.Z. (NSFC-RGC 20831160506 and NSFC 81172917).

 
dc.identifier.issn0006-2960
2013 Impact Factor: 3.194
 
dc.identifier.issue1
 
dc.identifier.pmid22142305
 
dc.identifier.scopuseid_2-s2.0-84863081072
 
dc.identifier.spage555
 
dc.identifier.urihttp://hdl.handle.net/10722/145587
 
dc.identifier.volume51
 
dc.languageeng
 
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
 
dc.publisher.placeUnited States
 
dc.relation.ispartofBiochemistry
 
dc.relation.projectChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAntigens, CD38 - antagonists and inhibitors - deficiency - physiology
 
dc.subject.meshArabinose - analogs and derivatives - pharmacology
 
dc.subject.meshCalcium signaling - drug effects - genetics
 
dc.subject.meshEnzyme inhibitors - chemical synthesis - metabolism - pharmacology
 
dc.subject.meshNicotinamide mononucleotide - analogs and derivatives - pharmacology
 
dc.subjectCalcium signaling
 
dc.subjectCatalytic residue
 
dc.subjectCyclic ADP-ribose (cADPR)
 
dc.subjectCyclization reactions
 
dc.subjectHuman HL-60 cell
 
dc.titleCatalysis-based inhibitors of the calcium signaling function of CD38
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Peking University