Deubiquitylating enzymes (DUBs) remove ubiquitin (Ub) from its cellular targets and confer functionally critical dynamism to Ub-mediated signaling in eukaryotes. The misregulation of protein ubiquitylation in humans is associated with cancer as well as neurodegenerative, inflammatory and muscle-wasting diseases. Hence there is an urgent need to identify specific DUBs associated with therapeutically relevant targets of Ub. The development of two facile selenocysteine-based strategies to generate the DUB probe Ub-dehydroalanine (Dha) will be described. The high utility of alkylative elimination, which is compatible with multiple thiols in Ub targets, and its application toward profiling DUB activity will be demonstrated. Finally, a hybrid chemical biological strategy to incorporate DUB probes in full-length proteins, which greatly expands the scope of DUB profiling, will be described.

Selenocysteine as a latent bioorthogonal probe for deubiquitylating enzymes

255th National Meeting (2018)

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