Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis.

The cytosolic sulfotransferases (SULTs) are dimeric enzymes that help maintain homeostasis through the modulation of hormone and drug activity by catalyzing their transformation into hydrophilic sulfate esters and increasing their excretion. Each of the thirteen active human SULT isoforms displays a unique substrate specificity pattern that underlies its individual role in our bodies. These specificities have proven to be complex, in some cases masking the biological role of specific isoforms. The first part of this review offers a short summary of historical underpinnings of human SULTs, primarily centered on the characterization of each isoform's kinetic and structural properties. Recent structural investigations have revealed each SULT has an active site "lid" that undergoes restructuring once the cofactor/sulfonate donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), binds to the enzyme. This structural rearrangement can alter substrate-binding profiles, therefore complicating enzyme/substrate interactions and making substrate/cosubstrate concentrations and binding order important considerations in enzyme functionality. Molecular dynamic simulations have recently been employed to describe this restructuring in an attempt to offer insight to its effects on substrate selectivity. In addition to reviewing new data on SULT molecular dynamics, we will discuss the contribution of PAPS concentrations and SULT dimerization in the regulation of SULT activity within the human body.