The conservation of such ligand-gated conformational changes-albeit triggered in different loops-suggests that these decorating loops evolve independently of the barrel providing a starting point for the emergence and divergence of new enzyme activities. In addition, TrpF, for example, has been shown to be highly tolerant of variations in loop 6 sequence, such that grafting sequences from related enzymes such as TrpA, HisA and PriA onto the TrpF scaffold did not abolish activity. 103 This is significant considering the high evolvability of this scaffold, and the wide range of chemistry it supports, which makes it very desirable as a starting point for protein engineering efforts. In addition, it could be argued that the real-time evolution experiment that bestowed PRA-isomerization activity to HisA 46 effectively performed "natural" loop-engineering by altering the conformations of key active site loops. Our work suggests therefore that, more broadly, loop grafting and engineering is a powerful tool for generating novel enzymes with tailored activities and specificities, even in complex systems with multiple highly mobile and interdependent catalytic loops.