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dc.contributor.authorMellini Paolo
dc.contributor.author Itoh Yukihiro
dc.contributor.authorTsumoto Hiroki
dc.contributor.author Li Ying
dc.contributor.authorSuzuki Miki
dc.contributor.authorTokuda Natsuko
dc.contributor.authorKakizawa Taeko
dc.contributor.authorMiura Yuri
dc.contributor.authorTakeuchi Jun
dc.contributor.authorLahtela-Kakkonen Maija
dc.contributor.author Suzuki Takayoshi
dc.date.accessioned2018-01-08T14:05:08Z
dc.date.available2018-01-08T14:05:08Z
dc.date.issued2017
dc.identifier.urihttps://erepo.uef.fi/handle/123456789/5136
dc.description.abstractSirtuin 2 (SIRT2), a member of the NAD+-dependent histone deacetylase family, has recently received increasing attention due to its potential involvement in neurodegenerative diseases and the progression of cancer. Potent and selective SIRT2 inhibitors thus represent desirable biological probes. Based on the X-ray crystal structure of SIRT2 in complex with a previously reported weak inhibitor (6), we identified in this study the potent mechanism-based inactivator KPM-2 (36), which is selective toward SIRT2. Compound 36 engages in a nucleophilic attack toward NAD+ at the active site of SIRT2, which affords a stable 36-ADP-ribose conjugate that simultaneously occupies the substrate-binding site, the “selectivity pocket” and the NAD+-binding site. Moreover, 36 exhibits antiproliferative activity in cancer cells and remarkable neurite outgrowth activity. This strategy for the selective inhibition of SIRT2 should allow further probing of the biology of SIRT2, and promote the development of new disease treatment strategies.en
dc.language.isoENen
dc.publisherRoyal Society of Chemistry (RSC)en
dc.relation.ispartofseriesChemical scienceen
dc.relation.urihttp://dx.doi.org/10.1039/C7SC02738Aen
dc.rightsCC BY http://creativecommons.org/licenses/by/3.0/en
dc.titlePotent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, "selectivity pocket" and NAD+-binding siteen
dc.description.versionpublished versionen
dc.contributor.departmentSchool of Pharmacy, Activitiesen
uef.solecris.id49335218en
dc.type.publicationinfo:eu-repo/semantics/articleen
dc.rights.accessrights© The Royal Society of Chemistryen
dc.relation.doi10.1039/C7SC02738Aen
dc.description.reviewstatuspeerRevieweden
dc.format.pagerange6400-6408en
dc.publisher.countryBritanniaen
dc.relation.issn2041-6520en
dc.relation.issue8en
dc.rights.accesslevelopenAccessen
dc.type.okmA1en
dc.type.versioninfo:eu-repo/semantics/publishedVersionen
uef.solecris.openaccessOpen access -julkaisukanavassa ilmestynyt julkaisu


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