Synergistic investigations of the reactions catalyzed by several members of an enzyme superfamily provide a more complete understanding of the relationships between structure and function than is possible from focused studies of a single enzyme alone. The crotonase (or enoyl-CoA hydratase) superfamily is such an example whereby members catalyze a wide range of metabolic reactions but share a common structural solution to a mechanistic problem. Some enzymes in the superfamily have been shown to display dehalogenase, hydratase, and isomerase activities. Others have been implicated in carbon-carbon bond formation and cleavage as well as the hydrolysis of thioesters. While seemingly unrelated mechanistically, the common theme in this superfamily is the need to stabilize an enolate anion intermediate derived from an acyl-CoA substrate. This apparently is accomplished by two structurally conserved peptidic NH groups that provide hydrogen bonds to the carbonyl moieties of the acyl-CoA substrates and form an "oxyanion hole".