title: Structural and chemical profiling of the human cytosolic sulfotransferases.
abstract: The human cytosolic sulfotransfases (hSULTs) comprise a family of 12 phase II enzymes involved in the metabolism of drugs and hormones, the bioactivation of carcinogens, and the detoxification of xenobiotics. Knowledge of the structural and mechanistic basis of substrate specificity and activity is crucial for understanding steroid and hormone metabolism, drug sensitivity, pharmacogenomics, and response to environmental toxins. We have determined the crystal structures of five hSULTs for which structural information was lacking, and screened nine of the 12 hSULTs for binding and activity toward a panel of potential substrates and inhibitors, revealing unique "chemical fingerprints" for each protein. The family-wide analysis of the screening and structural data provides a comprehensive, high-level view of the determinants of substrate binding, the mechanisms of inhibition by substrates and environmental toxins, and the functions of the orphan family members SULT1C3 and SULT4A1. Evidence is provided for structural "priming" of the enzyme active site by cofactor binding, which influences the spectrum of small molecules that can bind to each enzyme. The data help explain substrate promiscuity in this family and, at the same time, reveal new similarities between hSULT family members that were previously unrecognized by sequence or structure comparison alone.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Patricia W
authors.initials: PW
authors.lastname: Pan
authors.forename: Ludmila
authors.initials: L
authors.lastname: Dombrovski
authors.forename: Rafael
authors.initials: R
authors.lastname: Najmanovich
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: Aiping
authors.initials: A
authors.lastname: Dong
authors.forename: Peter
authors.initials: P
authors.lastname: Loppnau
authors.forename: Fernando
authors.initials: F
authors.lastname: Martin
authors.forename: Janet
authors.initials: J
authors.lastname: Thornton
authors.forename: Janet
authors.initials: J
authors.lastname: Thonton
authors.forename: Aled M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Alexey
authors.initials: A
authors.lastname: Bochkarev
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Plotnikov
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D003460:Crystallization; D003600:Cytosol / Q000201:enzymology*; D004795:Enzyme Stability; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010724:Phosphoadenosine Phosphosulfate / Q000737:chemistry; D011485:Protein Binding; D016415:Sequence Alignment; D015238:Sulfotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D010724:Phosphoadenosine Phosphosulfate; D000244:Adenosine Diphosphate; C010840:adenosine 3'-phosphate-5'-phosphate; C479953:SULT4A1 protein, human; C513319:SULT1C2 protein, human; C000591835:SULT1C3 protein, human; D015238:Sulfotransferases