Psoromic acid is a selective and covalent rab-prenylation inhibitor targeting autoinhibited RabGGTase

Deraeve, Celine, Guo, Zhong, Bon, Robin S., Blankenfeldt, Wulf, DiLucrezia, Raffaella, Wolf, Alexander, Menninger, Sascha, Stigter, E. Anouk, Wetzel, Stefan, Choidas, Axel, Alexandrov, Kirill, Waldmann, Herbert, Goody, Roger S. and Wu, Yao-Wen (2012) Psoromic acid is a selective and covalent rab-prenylation inhibitor targeting autoinhibited RabGGTase. Journal of the American Chemical Society, 134 17: 7384-7391. doi:10.1021/ja211305j

Author Deraeve, Celine
Guo, Zhong
Bon, Robin S.
Blankenfeldt, Wulf
DiLucrezia, Raffaella
Wolf, Alexander
Menninger, Sascha
Stigter, E. Anouk
Wetzel, Stefan
Choidas, Axel
Alexandrov, Kirill
Waldmann, Herbert
Goody, Roger S.
Wu, Yao-Wen
Title Psoromic acid is a selective and covalent rab-prenylation inhibitor targeting autoinhibited RabGGTase
Journal name Journal of the American Chemical Society   Check publisher's open access policy
ISSN 0002-7863
Publication date 2012-05-01
Year available 2012
Sub-type Article (original research)
DOI 10.1021/ja211305j
Open Access Status Not Open Access
Volume 134
Issue 17
Start page 7384
End page 7391
Total pages 8
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Formatted abstract
Post-translational attachment of geranylgeranyl isoprenoids to Rab GTPases, the key organizers of intracellular vesicular transport, is essential for their function. Rab geranylgeranyl transferase (RabGGTase) is responsible for prenylation of Rab proteins. Recently, RabGGTase inhibitors have been proposed to be potential therapeutics for treatment of cancer and osteoporosis. However, the development of RabGGTase selective inhibitors is complicated by its structural and functional similarity to other protein prenyltransferases. Herein we report identification of the natural product psoromic acid (PA) that potently and selectively inhibits RabGGTase with an IC 50 of 1.3 μM. Structure-activity relationship analysis suggested a minimal structure involving the depsidone core with a 3-hydroxyl and 4-aldehyde motif for binding to RabGGTase. Analysis of the crystal structure of the RabGGTase:PA complex revealed that PA forms largely hydrophobic interactions with the isoprenoid binding site of RabGGTase and that it attaches covalently to the N-terminus of the α subunit. We found that in contrast to other protein prenyltransferases, RabGGTase is autoinhibited through N-terminal αHis2 coordination with the catalytic zinc ion. Mutation of αHis dramatically enhances the reaction rate, indicating that the activity of RabGGTase is likely regulated in vivo. The covalent binding of PA to the N-terminus of the RabGGTase α subunit seems to potentiate its interaction with the active site and explains the selectivity of PA for RabGGTase. Therefore, psoromic acid provides a new starting point for the development of selective RabGGTase inhibitors.
Keyword Geranylgeranyl transferase
Fluorometric assay
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

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Created: Tue, 14 Aug 2012, 22:51:12 EST by Susan Allen on behalf of Institute for Molecular Bioscience