title: Small molecule inhibitors of mucin-type O-linked glycosylation from a uridine-based library.
abstract: The polypeptide N-acetyl-alpha-galactosaminyltransferases (ppGalNAcTs, also abbreviated ppGaNTases) initiate mucin-type O-linked glycosylation and therefore play pivotal roles in cell-cell communication and protection of tissues. In order to develop new tools for studying mucin-type O-linked glycosylation, we screened a 1338 member uridine-based library to identify small molecule inhibitors of ppGalNAcTs. Using a high-throughput enzyme-linked lectin assay (ELLA), two inhibitors of murine ppGalNAcT-1 (K(I) approximately 8 microM) were identified that also inhibit several other members of the family. The compounds did not inhibit other mammalian glycosyltransferases or nucleotide sugar utilizing enzymes, suggesting selectivity for the ppGalNAcTs. Treatment of cells with the compounds abrogated mucin-type O-linked glycosylation but not N-linked glycosylation and also induced apoptosis. These uridine analogs represent the first generation of chemical tools to study the functions of mucin-type O-linked glycosylation.
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Hang
authors.forename: Chong
authors.initials: C
authors.lastname: Yu
authors.forename: Kelly G
authors.initials: KG
authors.lastname: Ten Hagen
authors.forename: E
authors.initials: E
authors.lastname: Tian
authors.forename: Katharine A
authors.initials: KA
authors.lastname: Winans
authors.forename: Lawrence A
authors.initials: LA
authors.lastname: Tabak
authors.forename: Carolyn R
authors.initials: CR
authors.lastname: Bertozzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004800:Enzymes, Immobilized; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D051379:Mice; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009077:Mucins / Q000737:chemistry / Q000378:metabolism*; D017350:N-Acetylgalactosaminyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D014529:Uridine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D004800:Enzymes, Immobilized; D009077:Mucins; D004317:Doxorubicin; D017350:N-Acetylgalactosaminyltransferases; D014529:Uridine