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Controlling Sulfuryl-Transfer #MMPMID27203377
Cook I; Wang T; Wang W; Kopp F; Wu P; Leyh TS
Cell Chem Biol 2016[May]; 23 (5): 579-86 PMID27203377show ga
In humans, the cytosolic sulfotransferases (SULTs) catalyze regiospecific transfer of the sulfuryl-moiety (?SO3) from PAPS to thousands of metabolites, including numerous signaling small molecules, and thus regulates their activities and half-lives. Imbalances in the in vivo set-points of these reaction leads to disease. Here, with the goal of controlling sulfonation in vivo, molecular ligand-recognition principles in the SULT and nuclear-receptor families are integrated in creating a strategy that can prevent sulfonation of a compound without significantly altering its receptor affinity, or inhibiting SULTS. The strategy is validated by using it to control the sulfonation and estrogen-receptor (ER) activating activity of raloxifene (an FDA-approved SERM) and its derivatives. Preventing sulfonation is shown to enhance ER-activation efficacy 104-fold in studies using Ishikawa cells. The strategy offers the opportunity to control sulfuryl-transfer on a compound-by-compound basis, to enhance the efficacy of sulfonated drugs, and to explore the biology of sulfuryl-transfer with unprecedented precision.