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Article: Structural studies of intermediates along the cyclization pathway of aplysia ADP-ribosyl cyclase
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TitleStructural studies of intermediates along the cyclization pathway of aplysia ADP-ribosyl cyclase
 
AuthorsKotaka, M1
Graeff, R1
Chen, Z2
Zhang, LH2
Lee, HC1
Hao, Q1
 
Keywordscalcium signaling
cyclic ADP-ribose
NAD + cyclization
reaction mechanism
secondary messenger
 
Issue Date2012
 
PublisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
 
CitationJournal Of Molecular Biology, 2012, v. 415 n. 3, p. 514-526 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.jmb.2011.11.022
 
AbstractCyclic ADP-ribose (cADPR) is a calcium messenger that can mobilize intracellular Ca 2+ stores and activate Ca 2+ influx to regulate a wide range of physiological processes. Aplysia cyclase is the first member of the ADP-ribosyl cyclases identified to catalyze the cyclization of NAD + into cADPR. The catalysis involves a two-step reaction, the elimination of the nicotinamide ring and the cyclization of the intermediate resulting in the covalent attachment of the purine ring to the terminal ribose. Aplysia cyclase exhibits a high degree of leniency towards the purine base of its substrate, and the cyclization reaction takes place at either the N1- or the N7-position of the purine ring. To decipher the mechanism of cyclization in Aplysia cyclase, we used a crystallization setup with multiple Aplysia cyclase molecules present in the asymmetric unit. With the use of natural substrates and analogs, not only were we able to capture multiple snapshots during enzyme catalysis resulting in either N1 or N7 linkage of the purine ring to the terminal ribose, we were also able to observe, for the first time, the cyclized products of both N1 and N7 cyclization bound in the active site of Aplysia cyclase. © 2011 Elsevier Ltd. All rights reserved.
 
ISSN0022-2836
2012 Impact Factor: 3.905
2012 SCImago Journal Rankings: 2.509
 
DOIhttp://dx.doi.org/10.1016/j.jmb.2011.11.022
 
ISI Accession Number IDWOS:000300028700006
Funding AgencyGrant Number
Research Grant Council of Hong KongHKU 765909M
HKU 769107M
N_HKU 722/08
National Science Foundation of China
Funding Information:

This work is supported by grants HKU 765909M, HKU 769107M, and N_HKU 722/08 from the Research Grant Council of Hong Kong and the National Science Foundation of China (Q.H., H.C.L., and L.H.Z.). The crystallographic data were collected at the Shanghai Synchrotron Radiation Facility, China, and the National Synchrotron Radiation Research Center, Taiwan, China.

 
ReferencesReferences in Scopus
 
GrantsChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
A new method for macromolecular structure determination: envelope-based phasing
A calcium-signaling pathway mediated by cyclic ADP-ribose and NAADP
 
DC FieldValue
dc.contributor.authorKotaka, M
 
dc.contributor.authorGraeff, R
 
dc.contributor.authorChen, Z
 
dc.contributor.authorZhang, LH
 
dc.contributor.authorLee, HC
 
dc.contributor.authorHao, Q
 
dc.date.accessioned2012-02-28T01:55:54Z
 
dc.date.available2012-02-28T01:55:54Z
 
dc.date.issued2012
 
dc.description.abstractCyclic ADP-ribose (cADPR) is a calcium messenger that can mobilize intracellular Ca 2+ stores and activate Ca 2+ influx to regulate a wide range of physiological processes. Aplysia cyclase is the first member of the ADP-ribosyl cyclases identified to catalyze the cyclization of NAD + into cADPR. The catalysis involves a two-step reaction, the elimination of the nicotinamide ring and the cyclization of the intermediate resulting in the covalent attachment of the purine ring to the terminal ribose. Aplysia cyclase exhibits a high degree of leniency towards the purine base of its substrate, and the cyclization reaction takes place at either the N1- or the N7-position of the purine ring. To decipher the mechanism of cyclization in Aplysia cyclase, we used a crystallization setup with multiple Aplysia cyclase molecules present in the asymmetric unit. With the use of natural substrates and analogs, not only were we able to capture multiple snapshots during enzyme catalysis resulting in either N1 or N7 linkage of the purine ring to the terminal ribose, we were also able to observe, for the first time, the cyclized products of both N1 and N7 cyclization bound in the active site of Aplysia cyclase. © 2011 Elsevier Ltd. All rights reserved.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of Molecular Biology, 2012, v. 415 n. 3, p. 514-526 [How to Cite?]
DOI: http://dx.doi.org/10.1016/j.jmb.2011.11.022
 
dc.identifier.citeulike10050315
 
dc.identifier.doihttp://dx.doi.org/10.1016/j.jmb.2011.11.022
 
dc.identifier.epage526
 
dc.identifier.hkuros198785
 
dc.identifier.isiWOS:000300028700006
Funding AgencyGrant Number
Research Grant Council of Hong KongHKU 765909M
HKU 769107M
N_HKU 722/08
National Science Foundation of China
Funding Information:

This work is supported by grants HKU 765909M, HKU 769107M, and N_HKU 722/08 from the Research Grant Council of Hong Kong and the National Science Foundation of China (Q.H., H.C.L., and L.H.Z.). The crystallographic data were collected at the Shanghai Synchrotron Radiation Facility, China, and the National Synchrotron Radiation Research Center, Taiwan, China.

 
dc.identifier.issn0022-2836
2012 Impact Factor: 3.905
2012 SCImago Journal Rankings: 2.509
 
dc.identifier.issue3
 
dc.identifier.pmid22138343
 
dc.identifier.scopuseid_2-s2.0-84855828493
 
dc.identifier.spage514
 
dc.identifier.urihttp://hdl.handle.net/10722/145586
 
dc.identifier.volume415
 
dc.languageeng
 
dc.publisherAcademic Press. The Journal's web site is located at http://www.elsevier.com/locate/jmb
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of Molecular Biology
 
dc.relation.projectChemical synthesis and biological characterizations of antagonists of a novel calcium signaling enzyme - CD38
 
dc.relation.projectA new method for macromolecular structure determination: envelope-based phasing
 
dc.relation.projectA calcium-signaling pathway mediated by cyclic ADP-ribose and NAADP
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshADP-ribosyl Cyclase - chemistry - metabolism
 
dc.subject.meshAdenosine Diphosphate Ribose - metabolism
 
dc.subject.meshAplysia - enzymology
 
dc.subject.meshCatalytic Domain
 
dc.subject.meshCrystallography, X-Ray
 
dc.subjectcalcium signaling
 
dc.subjectcyclic ADP-ribose
 
dc.subjectNAD + cyclization
 
dc.subjectreaction mechanism
 
dc.subjectsecondary messenger
 
dc.titleStructural studies of intermediates along the cyclization pathway of aplysia ADP-ribosyl cyclase
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong Li Ka Shing Faculty of Medicine
  2. Peking University