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Fluorescent Hexose Conjugates Establish Stringent Stereochemical Requirement by GLUT5 for Recognition and Transport of Monosaccharides.
- Source :
-
ACS chemical biology [ACS Chem Biol] 2017 Apr 21; Vol. 12 (4), pp. 1087-1094. Date of Electronic Publication: 2017 Mar 02. - Publication Year :
- 2017
-
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.
- Subjects :
- Biological Transport
Carbon-13 Magnetic Resonance Spectroscopy
Cell Line, Tumor
Hexoses chemistry
Humans
Protein Binding
Proton Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Spectroscopy, Fourier Transform Infrared
Stereoisomerism
Glucose Transporter Type 5 metabolism
Hexoses metabolism
Monosaccharides metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1554-8937
- Volume :
- 12
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- ACS chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 28205432
- Full Text :
- https://doi.org/10.1021/acschembio.6b01101