The (βα)8-barrel is the most frequent and most versatile fold among enzymes [Höcker et al., Curr. Opin. Biotechnol. 12 (2001) 376–381; Wierenga, FEBS Lett. 492 (2001) 193–198]. Structural and functional evidence suggests that (βα)8-barrels evolved from an ancestral half-barrel, which consisted of four (βα) units stabilized by dimerization [Lang et al., Science 289 (2000) 1546–550; Höcker et al., Nat. Struct. Biol. 8 (2001) 32–36; Gerlt and Babbitt, Nat. Struct. Biol. 8 (2001) 5–7]. Here, by performing a comprehensive database search, we detect a striking and unexpected structural and amino acid sequence similarity between (βα)4 half-barrels and members of the (βα)5 flavodoxin-like fold. These findings provoke the hypothesis that a large fraction of the modern-day enzymes evolved from a basic structural building block, which can be identified by a combination of sequence and structural analyses.
