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Issue 9, 2017
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Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD+-binding site

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Abstract

Sirtuin 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.

Graphical abstract: Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD+-binding site

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Publication details

The article was received on 20 Jun 2017, accepted on 14 Jul 2017 and first published on 21 Jul 2017


Article type: Edge Article
DOI: 10.1039/C7SC02738A
Citation: Chem. Sci., 2017,8, 6400-6408
  • Open access: Creative Commons BY license
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    Potent mechanism-based sirtuin-2-selective inhibition by an in situ-generated occupant of the substrate-binding site, “selectivity pocket” and NAD+-binding site

    P. Mellini, Y. Itoh, H. Tsumoto, Y. Li, M. Suzuki, N. Tokuda, T. Kakizawa, Y. Miura, J. Takeuchi, M. Lahtela-Kakkonen and T. Suzuki, Chem. Sci., 2017, 8, 6400
    DOI: 10.1039/C7SC02738A

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