Whilst reports of non-lysine ubiquitination have been in existence for many years, it has remained unclear whether this process is intrinsic to mammals. The identification of E3 ligases (E3s) and deubiquitinating enzymes (DUBs) devoid of activity towards lysine residues would suggest this unconventional form of ubiquitination is of importance. However, the vast number and huge size of many E3 ligases has prevented comprehensive assessment of their mechanistic diversity and amino acid preference. I will discuss work we have done where we have used chemical probe technologies to identify E3s with novel and highly unusual mechanisms and non-lysine (esterification) activity. I will also present work on the identification of DUBs with non-lysine (esterase) activity. Taken together, these findings suggest that non-lysine ubiquitination is an integral part of the ubiquitin system whose cellular function is beginning to emerge.

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