New insights about enzyme evolution from large scale studies of sequence and structure relationships.
Bottom Line: Here, we describe evolution of functionally diverse enzyme superfamilies, each representing a large set of sequences that evolved from a common ancestor and that retain conserved features of their structures and active sites.Using several examples, we describe the different structural strategies nature has used to evolve new reaction and substrate specificities in each unique superfamily.The results provide insight about enzyme evolution that is not easily obtained from studies of one or only a few enzymes.
Affiliation: From the Departments of Bioengineering and Therapeutic Sciences and.Show MeSH
Mentions: The cofactor-dependent “two dinucleotide-binding domains flavoproteins” (tDBDF)2 superfamily is composed of many different reaction families that include several types of monooxygenases, reductases, and dehydrogenases. Comparison of their sequences and structures illustrates how variations in protein-protein interactions can enable a diverse set of overall reactions while the specific organization of the cofactors within the active site is stringently constrained by an active site architecture required for binding the dinucleotide cofactors (28–30). This ensures that all enzymes of the superfamily share a unidirectional electron flow from the re-side to the si-side of the isoalloxazine ring of the FAD cofactor so that electron acceptors unique to each member family access the FAD cofactor from the si-side of the isoalloxazine ring (Fig. 2A). Diversity in the functions of the different reaction families has evolved in part by pairing the delivery of electrons out of the tDBDF member active sites with varied electron acceptors presented via protein-small molecule or protein-protein interactions (Fig. 2B) (29). Many of the penultimate or ultimate acceptor proteins come from different fold classes, resulting in a number of solutions for the evolution of these important oxidation/reduction systems.
Affiliation: From the Departments of Bioengineering and Therapeutic Sciences and.