title: Controlling Sulfuryl-Transfer Biology.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Cook
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Chemical Biology Core Facility, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA.
authors.forename: Felix
authors.initials: F
authors.lastname: Kopp
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461-1926, USA. Electronic address: tsleyh@gmail.com.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Leyh
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000378:metabolism; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D013461:Sulfur Oxides / Q000378:metabolism*
chemical_list: D011960:Receptors, Estrogen; D013461:Sulfur Oxides; D015238:Sulfotransferases; C028152:alcohol sulfotransferase; C011118:sulfur trioxide
keywords: derivatives; estrogen receptor; inhibition; mechanism; raloxifene; selectivity; structure; sulfation; sulfonation; sulfotransferase; synthesis