Double-duplication evolution

In the 1 September Science Lang et al. argue that two single-domain biosynthetic enzymes appear to have evolved from gene duplication, followed by fusion, followed by a second gene duplication (Science 2000, 289:1546-1550). Both of the proteins, HisA and HisF, can be broken down into two half beta/alpha barrels. The four half barrels can be superimposed on each other, revealing 22% identical or similar residues. As both enzymes bind biphosphate substrates, each half barrel has a phosphate-binding motif, and HisF even exhibits limited HisA catalytic activity. Lang et al. propose that an ancestral protein motif was duplicated and fused to produce the HisA isomerase enzyme, before a second duplication and further evolution yielded the more complex HisF synthase activity.