The activation strategies for three classes of proteases. The peptide carbonyl group is attacked by (A) a histidine-activated cysteine in the cysteine proteases, (B) an aspartate-activated water molecule in the aspartyl proteases, and (C) a metal-activated water molecule in the metalloproteases. For the metalloproteases, the letter B represents a base (often glutamate) that helps deprotonate the metal-bound water.