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New chemical tools for profiling protein lipidation in cancer

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Protein modifications in cancer

The developed world needs, and is searching, for more effective medications to fight cancer. An in-depth investigation of protein modifications has the potential to advance novel approaches in drug discovery.

Health

The formation of lipidated proteins is controlled by enzymes, protein-lipid transferases, and the abnormal activity of these enzymes in cancer cells has been previously reported. Novel medications that inhibit activities of these enzymes might down-regulate the cancer-promoting transformations in the cells. The EU-funded Marie Curie 'New chemical tools for profiling protein lipidation in cancer' (LIPOPROT) project aimed to develop new methods to study the levels of protein lipidation in cancer. The main objectives were to synthesise probes for protein lipidation and validate them for high-throughput profiling for comparative analysis in representative cancer cells. Researchers successfully optimised synthesis of chemical probes to be cost- and time-efficient. Next, they characterised in-depth physicochemical properties of all novel compounds. The scientists applied novel lipid probes to model cervical cancer cells in culture. This led to the discovery of both the identity of lipidated proteins and their exact location as well as the nature of chemical bonding that links the fats and proteins. Relative protein lipidation efficiencies and global enzymatic activities of lipid transferases were also studied in other cell models including breast cancer and colon cancer cell lines. Researchers further utilised these models to examine the incorporation of myristic acid for protein modification in cancer, catalysed by the enzyme N-myristoyl transferase. The experiments included phenotypic and molecular analysis of the effects of N-myristoyl transferase inhibition in cancer cells. Metabolic activity measurements and quantitative proteomic analyses provided preliminary support for the hypothesis that N-myristoyl transferase is a valid drug target in cancer. Importantly, the technologies developed by LIPOPROT are universal, and might be applied to the protein lipidation analysis in other human and animal diseases.

Keywords

Protein modification, lipidation, lipidation analysis, N-myristoil transferase

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