Universität zu Köln

Kuhlmann, Nora, Chollet, Constance, Baldus, Linda, Neundorf, Ines ORCID: 0000-0001-6450-3991 and Lammers, Michael ORCID: 0000-0003-4168-4640 (2017). Development of Substrate-Derived Sirtuin Inhibitors with Potential Anticancer Activity. ChemMedChem, 12 (20). S. 1703 - 1715. WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1860-7187

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Abstract

RhoGDI is a key regulator of Rho proteins, coordinating their GTP/GDP and membrane/cytosol cycle. Recently, it was demonstrated by quantitative mass spectrometry that RhoGDI is heavily targeted by post-translational lysine acetylation. For one site in its N-terminal domain, namely K52, we reported earlier that acetylation completely switches off RhoGDI function. Herein we show that K52-acetylated RhoGDI is specifically deacetylated by the sirtuin deacetylase Sirt2. We show that acetylation at K52 decelerates cervical cancer cell proliferation, suggesting RhoGDI acetylation to be a promising therapeutic target. We demonstrate that treatment of cervical cancer cells with a RhoGDI-derived K52-trifluoroacetylated, substrate-derived peptidic sirtuin inhibitor severely impairs cell proliferation. Finally, we conclude that the potency of substrate-derived sirtuin inhibitors depends on structural features, the substrate-derived amino acid sequence as a determinant for selectivity, as well as the presence of an acetyl-lysine analogue to increase its potency. These data reveal a prospective therapeutic potential for novel substrate-derived sirtuin inhibitors.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuhlmann, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Chollet, Constance UNSPECIFIED UNSPECIFIED UNSPECIFIED Baldus, Linda UNSPECIFIED UNSPECIFIED UNSPECIFIED Neundorf, Ines UNSPECIFIED orcid.org/0000-0001-6450-3991 UNSPECIFIED Lammers, Michael UNSPECIFIED orcid.org/0000-0003-4168-4640 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-214070
DOI:	10.1002/cmdc.201700414
Journal or Publication Title:	ChemMedChem
Volume:	12
Number:	20
Page Range:	S. 1703 - 1715
Date:	2017
Publisher:	WILEY-V C H VERLAG GMBH
Place of Publication:	WEINHEIM
ISSN:	1860-7187
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RHO-GTPASES; LYSINE ACETYLATION; CANCER-CELLS; FARNESYLTRANSFERASE INHIBITORS; HISTONE DEACETYLASES; REGULATOR RHOGDI; PROTEINS; RAS; PEPTIDE; COMPLEX Multiple languages Chemistry, Medicinal; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21407