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Article: The bicyclic intermediate structure provides insights into the desuccinylation mechanism of human sirtuin 5 (SIRT5)

TitleThe bicyclic intermediate structure provides insights into the desuccinylation mechanism of human sirtuin 5 (SIRT5)
Authors
Issue Date2012
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, 2012, v. 287 n. 34, p. 28307-28314 How to Cite?
AbstractSirtuins are pivotal regulators in various cellular processes, including transcription, DNA repair, genome stability, and energy metabolism. Their functions have been generally attributed to NAD-dependent deacetylase activity. However, human SIRT5 (sirtuin 5), which has been reported to exhibit little deacetylase activity, was recently identified as an NAD-dependent demalonylase and desuccinylase. Biochemical studies suggested that the mechanism of SIRT5-catalyzed demalonylation and desuccinylation is similar to that of deacetylation catalyzed by other sirtuins. Previously, we solved the crystal structure of a SIRT5-succinyl-lysine peptide-NAD complex. Here, we present two more structures: a binary complex of SIRT5 with an H3K9 succinyl peptide and a binary complex of SIRT5 with a bicyclic intermediate obtained by incubating SIRT5-H3K9 thiosuccinyl peptide co-crystals with NAD. To our knowledge, this represents the first bicyclic intermediate for a sirtuin-catalyzed deacylation reaction that has been captured in a crystal structure, thus providing unique insights into the reaction mechanism. The structural information should benefit the design of specific inhibitors for SIRT5 and help in exploring the therapeutic potential of targeting sirtuins for treating human diseases.
Persistent Identifierhttp://hdl.handle.net/10722/171798
ISSN
2015 Impact Factor: 4.258
2015 SCImago Journal Rankings: 3.151
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorZhou, Yen_US
dc.contributor.authorZhang, Hen_US
dc.contributor.authorHe, Ben_US
dc.contributor.authorDu, Jen_US
dc.contributor.authorLin, Hen_US
dc.contributor.authorCerione, RAen_US
dc.contributor.authorHao, Qen_US
dc.date.accessioned2012-10-30T06:17:12Z-
dc.date.available2012-10-30T06:17:12Z-
dc.date.issued2012en_US
dc.identifier.citationJournal of Biological Chemistry, 2012, v. 287 n. 34, p. 28307-28314en_US
dc.identifier.issn0021-9258en_US
dc.identifier.urihttp://hdl.handle.net/10722/171798-
dc.description.abstractSirtuins are pivotal regulators in various cellular processes, including transcription, DNA repair, genome stability, and energy metabolism. Their functions have been generally attributed to NAD-dependent deacetylase activity. However, human SIRT5 (sirtuin 5), which has been reported to exhibit little deacetylase activity, was recently identified as an NAD-dependent demalonylase and desuccinylase. Biochemical studies suggested that the mechanism of SIRT5-catalyzed demalonylation and desuccinylation is similar to that of deacetylation catalyzed by other sirtuins. Previously, we solved the crystal structure of a SIRT5-succinyl-lysine peptide-NAD complex. Here, we present two more structures: a binary complex of SIRT5 with an H3K9 succinyl peptide and a binary complex of SIRT5 with a bicyclic intermediate obtained by incubating SIRT5-H3K9 thiosuccinyl peptide co-crystals with NAD. To our knowledge, this represents the first bicyclic intermediate for a sirtuin-catalyzed deacylation reaction that has been captured in a crystal structure, thus providing unique insights into the reaction mechanism. The structural information should benefit the design of specific inhibitors for SIRT5 and help in exploring the therapeutic potential of targeting sirtuins for treating human diseases.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.rightsJournal of Biological Chemistry. Copyright © American Society for Biochemistry and Molecular Biology, Inc.-
dc.rightsThis research was originally published in [Journal of Biological Chemistry]. Y Zhou, H Zhang, B He, J Du, H Lin, RA Cerione and Q Hao. The bicyclic intermediate structure provides insights into the desuccinylation mechanism of human sirtuin 5 (SIRT5). Journal of Biological Chemistry, 2012, v. 287 n. 34, p. 28307-28314. © the American Society for Biochemistry and Molecular Biology-
dc.subject.meshHistone Deacetylases - chemistry - metabolism-
dc.subject.meshHistones - chemistry - metabolism-
dc.subject.meshNAD - chemistry - metabolism-
dc.subject.meshPeptides - chemistry - metabolism-
dc.subject.meshSirtuins - chemistry - metabolism-
dc.titleThe bicyclic intermediate structure provides insights into the desuccinylation mechanism of human sirtuin 5 (SIRT5)en_US
dc.typeArticleen_US
dc.identifier.emailZhang, H: hzhang20@hku.hken_US
dc.identifier.emailHao, Q: qhao@hku.hk-
dc.identifier.authorityHao, Q=rp01332en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1074/jbc.M112.384511en_US
dc.identifier.pmid22767592-
dc.identifier.pmcidPMC3436533-
dc.identifier.scopuseid_2-s2.0-84865225339en_US
dc.identifier.hkuros209309-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84865225339&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume287en_US
dc.identifier.issue34en_US
dc.identifier.spage28307en_US
dc.identifier.epage28314en_US
dc.identifier.isiWOS:000308074600008-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridHao, Q=7102508868en_US
dc.identifier.scopusauthoridCerione, RA=7102225792en_US
dc.identifier.scopusauthoridLin, H=55341137900en_US
dc.identifier.scopusauthoridDu, J=55267872200en_US
dc.identifier.scopusauthoridHe, B=55256307100en_US
dc.identifier.scopusauthoridZhang, H=37035621300en_US
dc.identifier.scopusauthoridZhou, Y=49562143100en_US

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