title: Selective inhibition of beta-1,4- and alpha-1,3-galactosyltransferases: donor sugar-nucleotide based approach.
abstract: A combined rational and library approach was used to identify bisphosphonates (IC50 = 20 microM) and galactose type 1-N-iminosugar (IC50=45 microM) as novel motifs for selective inhibition of beta-1,4-galactosyltransferase (beta-1,4-GalT) and alpha-1,3-galactosyltransferase (alpha-1,3-GalT), respectively. Our results demonstrate that, though these two galactosyltransferases both utilize the same donor sugar-nucleotide (UDP-Gal), the difference in their mechanisms can be utilized to design donor sugar or nucleotide analogues with inhibitory activities selective for only one of the galactosyltransferases. Investigation of beta-1,4-GalT inhibition using UDP-2-deoxy-2-fluorogalactose (UDP-2-F-Gal), UDP, and bisphosphonates, also led to the observation of metal dependent inhibition of beta-1,4-GalT. These observations and the novel inhibitor motifs identified in this study pave the way for the design and identification of even more potent and selective galactosyltransferase inhibitors.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: S
authors.initials: S
authors.lastname: Takayama
authors.forename: S J
authors.initials: SJ
authors.lastname: Chung
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi
authors.forename: Y
authors.initials: Y
authors.lastname: Ichikawa
authors.forename: A
authors.initials: A
authors.lastname: Sepp
authors.forename: R I
authors.initials: RI
authors.lastname: Lechler
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: T
authors.initials: T
authors.lastname: Hayashi
authors.forename: G
authors.initials: G
authors.lastname: Siuzdak
authors.forename: C H
authors.initials: CH
authors.lastname: Wong
mesh_terms: D000818:Animals; D002417:Cattle; D004164:Diphosphonates / Q000737:chemistry; D004926:Escherichia coli / Q000378:metabolism; D005700:Galactosyltransferases / Q000037:antagonists & inhibitors*; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D014531:Uridine Diphosphate Galactose / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D014531:Uridine Diphosphate Galactose; D005700:Galactosyltransferases