Markers of fitness in a successful enzyme superfamily.

Haloalkanoic acid dehalogenase (HAD) superfamily members serve as the predominant catalysts of metabolic phosphate ester hydrolysis in all three superkingdoms of life. Collectively, the known structural, bioinformatic, and mechanistic data offer a glimpse of the variety of HAD enzymes that have evolved in the service of metabolic expansion. Factors that have contributed to superfamily dominance include a chemically versatile nucleophile, stability of the core superfold, structural modularity of the chemistry and specificity domains, conformational coupling conferred by the topology of the inserted specificity elements, and retention of a conserved mold for stabilization of the trigonal bipyramidal transition state.