ABSTRACT
Ubiquitination involves a series of complex steps: initially, an El ubiquitin-activating enzyme uses ATP to form an El-ubiquitin thiolester through the carboxyl terminal glycine of ubiquitin. The best described system is the ubiquitin-proteasome pathway which requires ATP and degrades the bulk of cellular and some membrane proteins. Based on the potential problems, it is not surprising that genetic alterations in proteolytic enzymes/cofactors or the protein substrates that render them more or less susceptible to degradation are responsible for inherited disorders. A variety of inherited diseases have been linked to dysfunctional proteolysis by the ubiquitin-proteasome system. Selectivity of the proteolytic process occurs at the level of ubiquitin activation and conjugation and possibly at other steps. Phosphorylation is a prerequisite for ubiquitin conjugation which, in turn, is necessary for c-myc degradation by the 26S proteasome. The Angelman syndrome is a rare genetic disorder that is characterized by severe mental retardation, seizures and an ataxic gait.
