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Evolution of a robust catalytic scaffold for hydrolytic cleavage of phosphate ester metabolites

The Haloalkanoic Acid Dehalogenase (HAD) enzyme superfamily is Natureâ€™s major supplier of organophosphate metabolite phosphohydrolases (phosphatases). The HAD phosphatase catalytic site is housed in the Rossmann‐like fold core domain and is comprised by a Mg2+ cofactor, an Asp nucleophile, an Asp acid/base and two conserved hydrogen bond donors (Thr/Ser and Lys/Arg) which function in collaboration with main chain amide units to bind the substrate phosphoryl group. The phosphoryl group is transferred to the Asp nucleophile to form an aspartylphosphate intermediate, which is subsequently dephosphorylated by attack of an activated water molecule. The catalytic site provides only weak binding interaction with the substrate phosphoryl group in the ground state and reserves strong interaction for stabilization of the trigonal bipyramidal phosphorane‐like transition states. Recent work has revealed a multiplicity of ways in which the basic Rossmann‐like scaffold has been elaborated, through the course of evolution, with sequence inserts that function in substrate recognition. This talk will focus on how the HAD phosphatases have evolved to function in organophosphate metabolite metabolism, phosphoprotein regulation and nucleic acid repair.