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Biology LibreTexts

Protease Activation

Protease are potentially dangerous if their activity is not regulated.; A common method to avoid unwanted protease activity is to activate the enzyme from an inactive precursor called a zymogen.;; The precursor is often called; proenyzme.; Limited but regulated proteolysis of the proenzyme by either a different protease or by autoproteolysis leads to activation of the proteolytic activity of the zymogen.; One important example is activation of procaspases to active caspases, which are calcium activated cysteine proteases; that are homodimers.; Activation of caspases initiates programmed cell death.; Cancer cells which are immortal have found ways to inhibit procaspase activation.; Hence a possible cancer therapy could involve drug-induced activation of procaspases.; Wolan et used; high-thoroughput screening to identify compounds that promote the activation of procaspase-3 at physiological conditions and concentrations. A dozen compounds were found to promote such activity, and their ability to activate other similar enzymes in the procaspase family were explored.; Active caspases appear to be in equilibrium between an active state and an inactive one more similar to the inactive zymogen.; Small drug that bind preferentially to the active state would shift the equilibrium from the inactive state to the active state.; Likewise it might bind to the inactive zymogen and promote an "active" conformation of the zymogen leading to the actual activation of the zymogene by autoproteolysis.; Wolan et al discovered that procaspase was able to undergo a conformational change with the addition of a specific small molecule activator (referred to as 1541) which made the “on (active)” conformation more likely, and therefore encouraged self-activation.