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Article: Catalysis-based inhibitors of the calcium signaling function of CD38

TitleCatalysis-based inhibitors of the calcium signaling function of CD38
Authors
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
Citation
Biochemistry, 2012, v. 51 n. 1, p. 555-564 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/145587
ISSN
2014 Impact Factor: 3.015
2014 SCImago Journal Rankings: 1.657
ISI Accession Number ID
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).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorKwong, AKYen_HK
dc.contributor.authorChen, Zen_HK
dc.contributor.authorZhang, Hen_HK
dc.contributor.authorLeung, FPen_HK
dc.contributor.authorLam, CMCen_HK
dc.contributor.authorTing, KYen_HK
dc.contributor.authorZhang, Len_HK
dc.contributor.authorHao, Qen_HK
dc.contributor.authorZhang, LHen_HK
dc.contributor.authorLee, HCen_HK
dc.date.accessioned2012-02-28T01:55:55Z-
dc.date.available2012-02-28T01:55:55Z-
dc.date.issued2012en_HK
dc.identifier.citationBiochemistry, 2012, v. 51 n. 1, p. 555-564en_HK
dc.identifier.issn0006-2960en_HK
dc.identifier.urihttp://hdl.handle.net/10722/145587-
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.en_HK
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_HK
dc.relation.ispartofBiochemistryen_HK
dc.subjectCalcium signaling-
dc.subjectCatalytic residue-
dc.subjectCyclic ADP-ribose (cADPR)-
dc.subjectCyclization reactions-
dc.subjectHuman HL-60 cell-
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.titleCatalysis-based inhibitors of the calcium signaling function of CD38en_HK
dc.typeArticleen_HK
dc.identifier.emailKwong, AKY: kkyanna@hku.hken_HK
dc.identifier.emailZhang, H: hzhang20@hku.hken_HK
dc.identifier.emailLam, CMC: lammo@hkucc.hku.hk-
dc.identifier.emailTing, KY: ding0514@hku.hk-
dc.identifier.emailHao, Q: qhao@hku.hk-
dc.identifier.emailZhang, LH: zdszlh@bjmu.edu.cn-
dc.identifier.emailLee, HC: leehc@hku.hk-
dc.identifier.authorityZhang, H=rp00306en_HK
dc.identifier.authorityHao, Q=rp01332en_HK
dc.identifier.authorityLee, HC=rp00545-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/bi201509fen_HK
dc.identifier.pmid22142305-
dc.identifier.scopuseid_2-s2.0-84863081072en_HK
dc.identifier.hkuros198792en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84863081072&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume51en_HK
dc.identifier.issue1en_HK
dc.identifier.spage555en_HK
dc.identifier.epage564en_HK
dc.identifier.eissn1520-4995-
dc.identifier.isiWOS:000298907400057-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38-
dc.identifier.scopusauthoridLee, HC=26642959100en_HK
dc.identifier.scopusauthoridZhang, LH=10340097000en_HK
dc.identifier.scopusauthoridHao, Q=7102508868en_HK
dc.identifier.scopusauthoridZhang, L=8833065300en_HK
dc.identifier.scopusauthoridTing, KY=55267998200en_HK
dc.identifier.scopusauthoridLam, CMC=26026006700en_HK
dc.identifier.scopusauthoridLeung, FP=8615375300en_HK
dc.identifier.scopusauthoridZhang, HM=37035621300en_HK
dc.identifier.scopusauthoridChen, Z=37033573500en_HK
dc.identifier.scopusauthoridKwong, AKY=54932929500en_HK

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