August 2011

Recent developments in the generation and application of lipid probes

Another type of study that has been facilitated by bioorthogonal chemistry is that of activity-based protein profiling, which employs small molecule probes for the collective characterization of proteins based on function (9). These probes generally bear a latent handle that can be derivatized after protein labeling, often through click chemistry, to selectively characterize only those proteins that interact with the probe (1i). Such studies recently have been advanced using phospholipid analogs to identify and characterize lipid-modifying enzymes (10) and protein-lipid binding interactions (11).

References

1. Smith, M. D., Gong, D., Sudhahar, C. G., Reno, J. C., Stahelin, R. V., and Best, M. D. (2008) Synthesis and convenient functionalization of azide-labeled diacylglycerol analogues for modular access to biologically active lipid probes. Bioconjugate Chem. 19, 1855 – 1863.
2. Smith, M. D., Sudhahar, C. G., Gong, D., Stahelin, R. V., and Best, M. D. (2009) Modular synthesis of biologically active phosphatidic acid probes using click chemistry. Mol. Biosyst. 5, 962 – 972.
3. Best, M. D., Zhang, H. L., and Prestwich, G. D. (2010) Inositol polyphosphates, diphosphoinositol polyphosphates and phosphatidylinositol polyphosphate lipids: Structure, synthesis, and development of probes for studying biological activity. Nat. Prod. Rep. 27, 1403 – 1430.
4. Best, M. D. (2009) Click chemistry and bioorthogonal reactions: unprecedented selectivity in the labeling of biological molecules. Biochemistry 48, 6571 – 6584.
5. Sletten, E. M., and Bertozzi, C. R. (2009) Bioorthogonal chemistry: Fishing for selectivity in a sea of functionality. Angew. Chem., Int. Edit. 48, 6974 – 6998.
6. Charron, G., Wilson, J., and Hang, H. C. (2009) Chemical tools for understanding protein lipidation in eukaryotes. Curr. Opin. Chem. Biol. 13, 382 – 391.
7. Neef, A. B., and Schultz, C. (2009) Selective fluorescence labeling of lipids in living cells. Angew. Chem., Int. Ed. 48, 1498 – 1500.
8. Jao, C. Y., Roth, M., Welti, R., and Salic, A. (2009) Metabolic labeling and direct imaging of choline phospholipids in vivo. Proc. Natl. Acad. Sci. U.S.A. 106, 15332 – 15337.
9. Cravatt, B. F., Wright, A. T., and Kozarich, J. W. (2008)Activity-based protein profiling: From enzyme chemistry. Annu. Rev. Biochem. 77, 383 – 414.
10. Tully, S. E., and Cravatt, B. F. (2010) Activity-based probes that target functional subclasses of phospholipases in proteomes. J. Am. Chem. Soc. 132, 3264 – 3265.
11. Gubbens, J., and de Kroon, A. (2010) Proteome-wide detection of phospholipid-protein interactions in mitochondria by photocrosslinking and click chemistry. Mol. Biosyst. 6, 1751 – 1759.

Michael D. Best (mdbest@utk.edu) is an assistant professor of bioorganic chemistry at the University of Tennessee-Knoxville. 

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