ICE processing and kinetic mechanism

Interleukin-1 beta converting enzyme (ICE) has been the focus of major scientific efforts to discover pharmaceutically effective inhibitors. Little is known about the rates of the individual steps in catalysis. We report here that the rates of the two individual chemical steps in catalysis (acylation and deacylation) are each partially rate-limiting. This keeps the overall rate of the reaction less than 3% of the rate of the reaction for papain with its optimized substrate. Eight human ICE-like proteases have been published to date. They have levels of sequence identity that range from around 30% to greater than 50% throughout the full lengths of the proteins. This degree of relatedness increases when only the active domains are compared. This indicates that the greatest variability between family members occurs in their N-terminal prodomains. We propose several possibilities for the role for these prodomains in the regulation of enzyme processing.