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
2011 Impact Factor: 3.422
2011 SCImago Journal Rankings: 0.498
DOIhttp://dx.doi.org/10.1021/bi201509f
ReferencesReferences in Scopus
GrantsChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
DC Field
Value
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.grantChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
dc.description.grantcode99408
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.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
2011 Impact Factor: 3.422
2011 SCImago Journal Rankings: 0.498
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.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
Author Affiliations
  1. The University of Hong Kong
  2. Peking University