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Article: Flourescent analogs of cyclic ADP-ribose: Synthesis, spectral characterization, and use

TitleFlourescent analogs of cyclic ADP-ribose: Synthesis, spectral characterization, and use
Authors
KeywordsChemicals And Cas Registry Numbers
Issue Date1996
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 1996, v. 35 n. 2, p. 379-386 How to Cite?
AbstractCyclic ADP-ribose (cADPR) is a Ca2+-mobilizing cyclic nucleotide derived from NAD+. Accumulating evidence indicates that it is an endogenous modulator of the Ca2+-induced Ca2+ release mechanism in cells. In this study, we show that ADP-ribosyl cyclase catalyzes the cyclization of not only NAD+ but also several of its analogs with various purine bases (guanine, hypoxanthine, or xanthine) substituting for adenine. Unlike cADPR, the resulting cyclic products are fluorescent. Comparisons with various model compounds indicate that only 7-methyl substituted purine nucleosides and nucleotides are fluorescent, and the pH-dependence of their UV spectra is most similar to that of the fluorescent cADPR analogs, indicating that the site of cyclization of these analogs is at the NT-position of the purine ring. This finding is novel since the site of cyclization is at the N1-position for cADPR as determined by X-ray crystallography. That a single enzyme can cyclize a variety of substrates at two different sites has important implications mechanistically, and a model is proposed to account for these novel catalytic properties. Among the analogs synthesized, cyclic GDP-ribose is highly resistant to hydrolysis, while cyclic IDP-ribose can be readily hydrolyzed by CD38, a bifunctional enzyme involved in the metabolism of cADPR. These unique properties of the analogs can be used to develop fluorimetric assays for monitoring separately the cyclization and hydrolytic reactions catalyzed by the metabolic enzymes of cADPR. The convenience of the method in measuring kinetic parameters, pH-dependence, and modulator activity of the metabolic enzymes of cADPR is illustrated.
Persistent Identifierhttp://hdl.handle.net/10722/132578
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGraeff, RMen_HK
dc.contributor.authorWalseth, TFen_HK
dc.contributor.authorHill, HKen_HK
dc.contributor.authorLee, HCen_HK
dc.date.accessioned2011-03-28T09:26:29Z-
dc.date.available2011-03-28T09:26:29Z-
dc.date.issued1996en_HK
dc.identifier.citationBiochemistry, 1996, v. 35 n. 2, p. 379-386en_HK
dc.identifier.issn0006-2960en_HK
dc.identifier.urihttp://hdl.handle.net/10722/132578-
dc.description.abstractCyclic ADP-ribose (cADPR) is a Ca2+-mobilizing cyclic nucleotide derived from NAD+. Accumulating evidence indicates that it is an endogenous modulator of the Ca2+-induced Ca2+ release mechanism in cells. In this study, we show that ADP-ribosyl cyclase catalyzes the cyclization of not only NAD+ but also several of its analogs with various purine bases (guanine, hypoxanthine, or xanthine) substituting for adenine. Unlike cADPR, the resulting cyclic products are fluorescent. Comparisons with various model compounds indicate that only 7-methyl substituted purine nucleosides and nucleotides are fluorescent, and the pH-dependence of their UV spectra is most similar to that of the fluorescent cADPR analogs, indicating that the site of cyclization of these analogs is at the NT-position of the purine ring. This finding is novel since the site of cyclization is at the N1-position for cADPR as determined by X-ray crystallography. That a single enzyme can cyclize a variety of substrates at two different sites has important implications mechanistically, and a model is proposed to account for these novel catalytic properties. Among the analogs synthesized, cyclic GDP-ribose is highly resistant to hydrolysis, while cyclic IDP-ribose can be readily hydrolyzed by CD38, a bifunctional enzyme involved in the metabolism of cADPR. These unique properties of the analogs can be used to develop fluorimetric assays for monitoring separately the cyclization and hydrolytic reactions catalyzed by the metabolic enzymes of cADPR. The convenience of the method in measuring kinetic parameters, pH-dependence, and modulator activity of the metabolic enzymes of cADPR is illustrated.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.subjectChemicals And Cas Registry Numbersen_US
dc.titleFlourescent analogs of cyclic ADP-ribose: Synthesis, spectral characterization, and useen_HK
dc.typeArticleen_HK
dc.identifier.emailGraeff, RM: graeffr@hku.hken_HK
dc.identifier.emailLee, HC: leehc@hku.hken_HK
dc.identifier.authorityGraeff, RM=rp01464en_HK
dc.identifier.authorityLee, HC=rp00545en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid8555207-
dc.identifier.scopuseid_2-s2.0-0030024344en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030024344&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume35en_HK
dc.identifier.issue2en_HK
dc.identifier.spage379en_HK
dc.identifier.epage386en_HK
dc.identifier.isiWOS:A1996TQ22500003-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridGraeff, RM=7003614053en_HK
dc.identifier.scopusauthoridWalseth, TF=7005424273en_HK
dc.identifier.scopusauthoridHill, HK=7402256500en_HK
dc.identifier.scopusauthoridLee, HC=26642959100en_HK

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