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2016 ; 23
(5
): 579-586
Nephropedia Template TP
Cook I
; Wang T
; Wang W
; Kopp F
; Wu P
; Leyh TS
Cell Chem Biol
2016[May]; 23
(5
): 579-586
PMID27203377
show ga
In humans, the cytosolic sulfotransferases (SULTs) catalyze regiospecific
transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate
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 reactions 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 (a US
Food and Drug Administration-approved selective estrogen receptor modulator) and
its derivatives. Preventing sulfonation is shown to enhance ER-activation
efficacy 10(4)-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.
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