Sulfotransferase structural biology and inhibitor discovery

The carbohydrate sulfotransferases, which are emerging drug targets, are likely to be amenable to enzyme specific small molecule inhibitors through exploitation of the differences at both the cofactor-and substrate-binding sites. Sulfotransferases catalyze the transfer of a sulfuryl group from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to proteins, carbohydrates and small molecules. The sulfotransferases comprise cytosolic and Golgi-resident enzymes; Golgi-resident enzymes represent fertile territory for identifying pharmaceutical targets. Structure-based sequence alignments indicate that the structural fold, and the PAPS-binding site, is conserved between the two classes. Initial efforts to identify sulfotransferase inhibitors by screening kinase inhibitor libraries yielded competitive inhibitors of PAPS with μM IC 50 values. Within particular classes of Golgi-resident sulfotransferases that show tight in vitro specificity, the substrate-binding site might be a suitable drug target, although sulfotransferases are generally assumed to be difficult to inhibit as a result of the expected size and chemical character of the substrate-binding site.