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Article: Structural determinants of nicotinic acid adenine dinucleotide phosphate important for its calcium-mobilizing activity

TitleStructural determinants of nicotinic acid adenine dinucleotide phosphate important for its calcium-mobilizing activity
Authors
Issue Date1997
PublisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/
Citation
Journal Of Biological Chemistry, 1997, v. 272 n. 33, p. 20378-20383 How to Cite?
AbstractNicotinic acid adenine dinucleotide phosphate (NAADP) mobilizes Ca2+ through a mechanism totally independent of cyclic ADP-ribose or inositol trisphosphate. The structural determinants important for its Ca2+ release activity were investigated using a series of analogs. It is shown that changing the 3-carboxyl group of the nicotinic acid (NA) moiety in NAADP to either an uncharged carbinol or from the 3-position to the 4-position of the pyridine ring totally eliminates the Ca2+ release activity. Conversion of the 3-carboxyl to other negatively charged groups, either 3-sulfonate, 3- acetate, or 3-quinoline carboxylate, retains the Ca2+ release activity, although their half-maximal effective concentrations (EC50) are 100-200- fold higher. Changing the 6-amino group of the adenine to a hydroxyl group results in more than a 1000-fold decrease in the Ca2+ release activity. Conversion of the 2'-phosphate to 2',3'-cyclic phosphate or 3'-phosphate likewise increases the EC50 by about 5- and 20-fold, respectively. Similar to NAADP, all of the active analogs can also desensitize the Ca2+ release mechanism at subthreshold concentrations, suggesting that this novel property is intrinsic to the release mechanism. The series of analogs used was produced by using ADP-ribosyl cyclase to catalyze the exchange of the nicotinamide group of various analogs of NADP with various analogs of NA. An important determinant in NA that is crucial to the base exchange reaction was shown to be the 2-position of the pyridine ring. Neither pyridine-2- carboxylate nor 2-methyl-NA support the exchange reaction. The negative charge and the position of the 3-carboxyl group are nonessential since both pyridine-3-carbinol and pyridine-4-carboxylate support the base exchange reaction. In addition to the information on the structure-activity relationships of NAADP and NA, this study also demonstrates the utility of the base exchange reaction as a general approach for synthesizing NAADP analogs.
Persistent Identifierhttp://hdl.handle.net/10722/171636
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLee, HCen_US
dc.contributor.authorAarhus, Ren_US
dc.date.accessioned2012-10-30T06:16:05Z-
dc.date.available2012-10-30T06:16:05Z-
dc.date.issued1997en_US
dc.identifier.citationJournal Of Biological Chemistry, 1997, v. 272 n. 33, p. 20378-20383en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/171636-
dc.description.abstractNicotinic acid adenine dinucleotide phosphate (NAADP) mobilizes Ca2+ through a mechanism totally independent of cyclic ADP-ribose or inositol trisphosphate. The structural determinants important for its Ca2+ release activity were investigated using a series of analogs. It is shown that changing the 3-carboxyl group of the nicotinic acid (NA) moiety in NAADP to either an uncharged carbinol or from the 3-position to the 4-position of the pyridine ring totally eliminates the Ca2+ release activity. Conversion of the 3-carboxyl to other negatively charged groups, either 3-sulfonate, 3- acetate, or 3-quinoline carboxylate, retains the Ca2+ release activity, although their half-maximal effective concentrations (EC50) are 100-200- fold higher. Changing the 6-amino group of the adenine to a hydroxyl group results in more than a 1000-fold decrease in the Ca2+ release activity. Conversion of the 2'-phosphate to 2',3'-cyclic phosphate or 3'-phosphate likewise increases the EC50 by about 5- and 20-fold, respectively. Similar to NAADP, all of the active analogs can also desensitize the Ca2+ release mechanism at subthreshold concentrations, suggesting that this novel property is intrinsic to the release mechanism. The series of analogs used was produced by using ADP-ribosyl cyclase to catalyze the exchange of the nicotinamide group of various analogs of NADP with various analogs of NA. An important determinant in NA that is crucial to the base exchange reaction was shown to be the 2-position of the pyridine ring. Neither pyridine-2- carboxylate nor 2-methyl-NA support the exchange reaction. The negative charge and the position of the 3-carboxyl group are nonessential since both pyridine-3-carbinol and pyridine-4-carboxylate support the base exchange reaction. In addition to the information on the structure-activity relationships of NAADP and NA, this study also demonstrates the utility of the base exchange reaction as a general approach for synthesizing NAADP analogs.en_US
dc.languageengen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology, Inc. The Journal's web site is located at http://www.jbc.org/en_US
dc.relation.ispartofJournal of Biological Chemistryen_US
dc.subject.meshAnimalsen_US
dc.subject.meshCalcium - Metabolismen_US
dc.subject.meshNadp - Analogs & Derivatives - Chemistry - Physiologyen_US
dc.subject.meshNiacin - Chemistryen_US
dc.subject.meshSea Urchinsen_US
dc.subject.meshStructure-Activity Relationshipen_US
dc.titleStructural determinants of nicotinic acid adenine dinucleotide phosphate important for its calcium-mobilizing activityen_US
dc.typeArticleen_US
dc.identifier.emailLee, HC:leehc@hku.hken_US
dc.identifier.authorityLee, HC=rp00545en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1074/jbc.272.33.20378en_US
dc.identifier.pmid9252343-
dc.identifier.scopuseid_2-s2.0-0030846558en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030846558&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume272en_US
dc.identifier.issue33en_US
dc.identifier.spage20378en_US
dc.identifier.epage20383en_US
dc.identifier.isiWOS:A1997XR22100013-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridLee, HC=26642959100en_US
dc.identifier.scopusauthoridAarhus, R=6701339421en_US

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