A common evolutionary origin of two elementary enzyme folds

The (betaalpha)(8)-barrel is the most frequent and most versatile fold among enzymes [Hocker et al., Curr. Opin. Biotechnol. 12 (2001) 376-381; Wierenga, FEBS Lett. 492 (2001) 193-198]. Structural and functional evidence suggests that (betaalpha)(8)-barrels evolved from an ancestral half-barrel, which consisted of four (betaalpha) units stabilized by dimerization [Lang et al., Science 289 (2000) 1546-550; Hocker 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 (betaalpha)(4) half-barrels and members of the (betaalpha)(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. (C) 2002 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.