Novel Reagents for Selective Palmitoylation
ᵻ
Salmon ,
Olivia E.
Yu Zhao, Qing Lu and Ming Xian*
Department of Chemistry, Washington State University, Pullman, WA, 99164
Introduction
Research Design
Screening acylating reagents
Palmitoylation, or S-acylation, is the attachment of long-chain fatty
acids to cysteine molecules by means of a thioester bond.1,2 S-acylation
is a reversible process used for a number of protein interactions, such
as, membrane association, protein trafficking and facilitating enzyme
activity. The reverse of this process, deacylation, is a mechanism which
can be used for the regulation of protein activity.3 Other than the
necessary cysteine residues, it is still unclear in what sequence
palmitoylation occurs.4
Because proteins commonly contain other potential palmitoylation
sites, like hydroxyl and amino groups, producing specific S-acylated
compounds in high yields is challenging3. Our group recently
discovered that N-(acylthio)benzamides could selectively acylate thiol
groups, while not reacting with –NH2 or –OH groups. Therefore, it is
expected that these compounds are effective S-acylating reagents,
which can be used to explore protein palmitoylation.
Synthesis of S-acylating reagents
General synthesis of N-(acylthio)benzamide derivatives
*Determined by 1H NMR. Other byproduct obtained was CysS-S(CO)R1 in ratio of 3:1.
Previous Work5
Screening electronic effects
*Determined by 1H NMR. Other byproduct obtained was CysS-S(CO)R1 in ratio of 3:1.
*Percentages represent yields after four steps.
Future Work
Our Goal
Selective S-acylation
Acknowledgements
Many thanks to the NSF REU Grant (#0851502) for the funding of this work.
References
1.
2.
3.
4.
5.
Drisdel, R.C. et al. Methods. 2006, 40:127-134.
Smotrys, J. & Linder, M. Annu. Rev. Biochem. 2004, 559-587.
Leung Wai Sang, S. & Silvius, J.R. J. Peptide Res. 2005, 66:169-180.
Magee, T. & Seabra, M. Current Opinion in Cell Biology. 2005, 17:190-196.
Zhao, Y., Wang H., Xian, M. J. Am. Chem. Soc. 2011, 133:15-17
Further study must be completed to find an N-(acylthio)benzamide
derivative that produces the acylated product in a higher yield, as all the
derivatives tested produced similar results.
Future research will continue with the preparation of N(acylthio)benzamide derivatives, as well as the testing and optimization
of their reactions with cysteine derivatives and other nucleophilic
proteins.
To complete the analysis of modification of the amide activation site, an
N-(acylthio)benzamide derivative with an electron-donating group
should be tested.
 Further research can be done through modification of the R3
regioselective induction site as well.