The suicide inhibitory mechanism of serine protease inhibitors of the serpin superfamily depends heavily on their structural flexibility, which is controlled in large part by the breach and shutter regions of the central Abeta-sheet. We examined codon usage by the highly conserved residues, Ser-53 and Ser-56, of the shutter region and found a TCN-AGY usage dichotomy for Ser-56 that remarkably is linked to the protostome-deuterostome split. Our results suggest that serpin evolution was driven by phylogenetic speciation and not pressure to fulfill new physiologic functions mitigating against coevolution with the family of serine proteases they inhibit.