title: Fluorescent Hexose Conjugates Establish Stringent Stereochemical Requirement by GLUT5 for Recognition and Transport of Monosaccharides.
abstract: The specificity characteristics of transporters can be exploited for the development of novel diagnostic therapeutic probes. The facilitated hexose transporter family (GLUTs) has a distinct set of preferences for monosaccharide substrates, and while some are expressed ubiquitously (e.g., GLUT1), others are quite tissue specific (e.g., GLUT5, which is overexpressed in some breast cancer tissues). While these differences have enabled the development of new molecular probes based upon hexose- and tissue-selective uptake, substrate design for compounds targeting these GLUT transporters has been encumbered by a limited understanding of the molecular interactions at play in hexose binding and transport. Four new fluorescently labeled hexose derivatives have been prepared, and their transport characteristics were examined in two breast cancer cell lines expressing mainly GLUTs 1, 2, and 5. Our results demonstrate, for the first time, a stringent stereochemical requirement for recognition and transport by GLUT5. 6-NBDF, in which all substituents are in the d-fructose configuration, is taken up rapidly into both cell lines via GLUT5. On the other hand, inversion of a single stereocenter at C-3 (6-NBDP), C-4 (6-NBDT), or C-5 (6-NDBS) results in selective transport via GLUT1. An in silico docking study employing the recently published GLUT5 crystal structure confirms this stereochemical dependence. This work provides insight into hexose-GLUT interactions at the molecular level and will facilitate structure-based design of novel substrates targeting individual members of the GLUT family and forms the basis of new cancer imaging or therapeutic agents.
authors.affiliation: Department of Chemistry, University of Alberta , 11227 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2G2.|Department of Physiology, University of Alberta , 7-55 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Olivier-Mohamad
authors.initials: OM
authors.lastname: Soueidan
authors.affiliation: Department of Chemistry, University of Alberta , 11227 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Scully
authors.affiliation: Department of Oncology, University of Alberta , Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2.
authors.forename: Jatinder
authors.initials: J
authors.lastname: Kaur
authors.affiliation: Department of Biochemistry, University of Alberta , 451 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Panigrahi
authors.affiliation: Department of Chemistry, University of Alberta , 11227 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Belovodskiy
authors.affiliation: Department of Physiology, University of Alberta , 7-55 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Victor
authors.initials: V
authors.lastname: Do
authors.affiliation: Department of Chemistry, University of Alberta , 11227 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: Carson D
authors.initials: CD
authors.lastname: Matier
authors.affiliation: Department of Biochemistry, University of Alberta , 451 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: M Joanne
authors.initials: MJ
authors.lastname: Lemieux
authors.affiliation: Department of Oncology, University of Alberta , Cross Cancer Institute, Edmonton, Alberta, Canada T6G 1Z2.
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.affiliation: Department of Physiology, University of Alberta , 7-55 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7.
authors.forename: Chris
authors.initials: C
authors.lastname: Cheeseman
authors.affiliation: Department of Chemistry, University of Alberta , 11227 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2G2.
authors.forename: F G
authors.identifier: 0000-0001-7419-2314
authors.initials: FG
authors.lastname: West
mesh_terms: D001692:Biological Transport; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D051296:Glucose Transporter Type 5 / Q000378:metabolism*; D006601:Hexoses / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009005:Monosaccharides / Q000378:metabolism*; D011485:Protein Binding; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism
chemical_list: D051296:Glucose Transporter Type 5; D006601:Hexoses; D009005:Monosaccharides; C495726:SLC2A5 protein, human