title: Tunable GLUT-Hexose Binding and Transport via Modulation of Hexose C-3 Hydrogen-Bonding Capabilities.
abstract: The importance of the hydrogen bonding interactions in the GLUT-hexose binding process (GLUT=hexose transporter) has been demonstrated by studying the binding of structurally modified d-fructose analogues to GLUTs, and in one case its transport into cells. The presence of a hydrogen bond donor at the C-3 position of 2,5-anhydro-d-mannitol derivatives is essential for effective binding to GLUT5 and transport into tumor cells. Surprisingly, installation of a group that can function only as a hydrogen bond acceptor at C-3 resulted in selective recognition by GLUT1 rather than GLUT5. A fluorescently labelled analogue clearly showed GLUT-mediated transport and low efflux properties of the probe. This study reveals that a single positional modification of a 2,5-anhydro-d-mannitol derivative is sufficient to switch its binding preference from GLUT5 to GLUT1, and uncovers general scaffolds that are suitable for the potential selective delivery of molecular payloads into tumor cells via GLUT transport machinery.
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr., Edmonton, AB, CA, T6G 2G2, Canada.|Department of Physiology, University of Alberta, Medical Sciences Building, Edmonton, AB, CA, T6G 2H7, Canada.
authors.forename: Venkata Pavan
authors.initials: VP
authors.lastname: Kumar Kondapi
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr., Edmonton, AB, CA, T6G 2G2, Canada.|Department of Physiology, University of Alberta, Medical Sciences Building, Edmonton, AB, CA, T6G 2H7, Canada.
authors.forename: Olivier-Mohamad
authors.initials: OM
authors.lastname: Soueidan
authors.affiliation: Department of Physiology, University of Alberta, Medical Sciences Building, Edmonton, AB, CA, T6G 2H7, Canada.
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Cheeseman
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Dr., Edmonton, AB, CA, T6G 2G2, Canada.
authors.forename: Frederick G
authors.identifier: http://orcid.org/0000-0001-7419-2314
authors.initials: FG
authors.lastname: West
mesh_terms: D000818:Animals; D001692:Biological Transport; D045744:Cell Line, Tumor; D051272:Glucose Transporter Type 1 / Q000737:chemistry / Q000378:metabolism*; D051296:Glucose Transporter Type 5 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006601:Hexoses / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006860:Hydrogen Bonding; D008353:Mannitol / Q000031:analogs & derivatives / Q000737:chemistry; D051379:Mice; D018613:Microscopy, Confocal; D009004:Monosaccharide Transport Proteins / Q000737:chemistry / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D051296:Glucose Transporter Type 5; D006601:Hexoses; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D008353:Mannitol; C031765:2,5-anhydromannitol
keywords: GLUT; hexose; hydrogen bonding; structure-activity relationships; transport mechanisms