Flexible and general synthesis of functionalized phosphoisoprenoids for the study of prenylation in vivo and in vitro

Das, Debapratim, Tnimov, Zakir, Nguyen, Uyen T. T., Thimmaiah, Govindaraju, Lo, Harriet, Abankwa, Daniel, Wu, Yaowen, Goody, Roger S., Waldmann, Herbert and Alexandrov, Kirill (2012) Flexible and general synthesis of functionalized phosphoisoprenoids for the study of prenylation in vivo and in vitro. ChemBioChem, 13 5: 674-683. doi:10.1002/cbic.201100733

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Author Das, Debapratim
Tnimov, Zakir
Nguyen, Uyen T. T.
Thimmaiah, Govindaraju
Lo, Harriet
Abankwa, Daniel
Wu, Yaowen
Goody, Roger S.
Waldmann, Herbert
Alexandrov, Kirill
Title Flexible and general synthesis of functionalized phosphoisoprenoids for the study of prenylation in vivo and in vitro
Journal name ChemBioChem   Check publisher's open access policy
ISSN 1439-4227
1439-7633
Publication date 2012-03
Sub-type Article (original research)
DOI 10.1002/cbic.201100733
Volume 13
Issue 5
Start page 674
End page 683
Total pages 10
Place of publication Weinheim, Germany
Publisher Wiley
Collection year 2013
Language eng
Abstract Protein modification with isoprenoid lipids affects hundreds of signaling proteins in eukaryotic cells. Modification of isoprenoids with reporter groups is the main approach for the creation of probes for the analysis of protein prenylation in vitro and in vivo. Here, we describe a new strategy for the synthesis of functionalized phosphoisoprenoids that uses an aminederivatized isoprenoid scaffold as a starting point for the synthesis of functionalized phosphoisoprenoid libraries. This overcomes a long-standing problem in the field, where multistep synthesis had to be carried out for each individual isoprenoid analogue. The described approach enabled us to synthesize a range of new compounds, including two novel fluorescent isoprenoids that previously could not be generated by conventional means. The fluorescent probes that were developed using the described approach possess significant spectroscopic advantages to all previously generated fluorescent isoprenoid analogue. Using these analogues for flow cytometry and cell imaging, we analyzed the uptake of isoprenoids by mammalian cells and zebrafish embryos. Furthermore, we demonstrate that derivatization of the scaffold can be coupled in a one-pot reaction to enzymatic incorporation of the resulting isoprenoid group into proteins. This enables rapid evaluation of functional groups for compatibility with individual prenyltransferases and identification of the prenyltransferase specific substrates.
Keyword Amine-functionalized isoprenoids
Fluorescence
Protein modifications
Protein prenylation
Protein tagging
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
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