Tunable GLUT–Hexose Binding and Transport via Modulation of Hexose C‐3 Hydrogen‐Bonding Capabilities

Kondapi, Venkata Pavan Kumar; Soueidan, Mohamad; Cheeseman, Chris I.; West, F. G.

doi:10.1002/chem.201701329

Cited by 9 publications

(14 citation statements)

References 33 publications

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“…Fructose transporter photolabels, based on the 2,5-anhydro-D-mannitol core structure, interact well with GLUT5 [228]. Fluorescent GLUT5 probes based on the 2,5 anhydro-mannitol ring have also recently been designed [17,126]. 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 fructose transport into tumour cells.…”

Section: Glut Specificity For Substrates and Inhibitorsmentioning

confidence: 99%

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Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Holman

2020

Pflugers Arch - Eur J Physiol

128

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The SLC2 genes code for a family of GLUT proteins that are part of the major facilitator superfamily (MFS) of membrane transporters. Crystal structures have recently revealed how the unique protein fold of these proteins enables the catalysis of transport. The proteins have 12 transmembrane spans built from a replicated trimer substructure. This enables 4 trimer substructures to move relative to each other, and thereby alternately opening and closing a cleft to either the internal or the external side of the membrane. The physiological substrate for the GLUTs is usually a hexose but substrates for GLUTs can include urate, dehydro-ascorbate and myo-inositol. The GLUT proteins have varied physiological functions that are related to their principal substrates, the cell type in which the GLUTs are expressed and the extent to which the proteins are associated with subcellular compartments. Some of the GLUT proteins translocate between subcellular compartments and this facilitates the control of their function over long-and shorttime scales. The control of GLUT function is necessary for a regulated supply of metabolites (mainly glucose) to tissues. Pathophysiological abnormalities in GLUT proteins are responsible for, or associated with, clinical problems including type 2 diabetes and cancer and a range of tissue disorders, related to tissue-specific GLUT protein profiles. The availability of GLUT crystal structures has facilitated the search for inhibitors and substrates and that are specific for each GLUT and that can be used therapeutically. Recent studies are starting to unravel the drug targetable properties of each of the GLUT proteins.

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Section: Glut Specificity For Substrates and Inhibitorsmentioning

confidence: 99%

“…Interestingly, replacement of the C3-OH with a fluorine group (Fig. 3i), that can function only as a hydrogen bond acceptor, resulted in selective recognition by GLUT1 rather than GLUT5 [126].…”

Section: Glut Specificity For Substrates and Inhibitorsmentioning

confidence: 99%

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Holman

2020

Pflugers Arch - Eur J Physiol

128

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“…GLUT5 is known to be up-regulated in cancer of some tissues [ 109 , 116 , 117 ] and fructose (derived from all the sucrose we consume) probably does more harm than good in the body as it can contribute toward non-alcoholic fatty liver disease [ 118 ]. In addition, fructose is more rapidly converted to advanced glycation end products than glucose, but the significance of this fructation is debated [ 119 ].…”

Section: Looking To the Future Of Chemical Biology Approaches To Studmentioning

confidence: 99%

“…Fluorescent GLUT5 probes based on the 2,5-anhydro-mannitol ring have also recently been designed [ 121 ]. The potential for targeting the unique specificity of the fructose transporters is therefore good [ 108 , 116 ]; particularly now there are good crystal structures of GLUT5 [ 61 ]. Detailed modelling may be required to design fructose analogues that are transported only by GLUT5 and not by GLUT2 (which has significant affinity for fructose) [ 122 , 123 ].…”

Section: Looking To the Future Of Chemical Biology Approaches To Studmentioning

confidence: 99%

Chemical biology probes of mammalian GLUT structure and function

Holman

2018

Biochemical Journal

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The structure and function of glucose transporters of the mammalian GLUT family of proteins has been studied over many decades, and the proteins have fascinated numerous research groups over this time. This interest is related to the importance of the GLUTs as archetypical membrane transport facilitators, as key limiters of the supply of glucose to cell metabolism, as targets of cell insulin and exercise signalling and of regulated membrane traffic, and as potential drug targets to combat cancer and metabolic diseases such as type 2 diabetes and obesity. This review focusses on the use of chemical biology approaches and sugar analogue probes to study these important proteins.

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“…Aryl conjugates of 1-amino-2,5-deoxy- d -mannitol (1-AM) show high affinity and specificity towards GLUT5 with NBD conjugate of 1-AM working as fluorescent GLUT5 reporter [ 31 , 32 ]. Interestingly, epimers or regio-isomers of NBDM were shown to gain uptake through glucose GLUTs with loss of uptake through the fructose GLUTs [ 33 , 34 ]. While NBDM provided feasibility for discriminating between normal and cancer cells on the basis of the uptake through GLUT5 [ 32 ], the probe had limited accumulation in cells (uptake saturation was measured at 50 µM concentration), resulting in the unfavorable background fluorescence.…”

Section: Introductionmentioning

confidence: 99%

Metabolism-Driven High-Throughput Cancer Identification with GLUT5-Specific Molecular Probes

et al. 2018

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Point-of-care applications rely on biomedical sensors to enable rapid detection with high sensitivity and selectivity. Despite advances in sensor development, there are challenges in cancer diagnostics. Detection of biomarkers, cell receptors, circulating tumor cells, gene identification, and fluorescent tagging are time-consuming due to the sample preparation and response time involved. Here, we present a novel approach to target the enhanced metabolism in breast cancers for rapid detection using fluorescent imaging. Fluorescent analogs of fructose target the fructose-specific transporter GLUT5 in breast cancers and have limited to no response from normal cells. These analogs demonstrate a marked difference in adenocarcinoma and premalignant cells leading to a novel detection approach. The vastly different uptake kinetics of the analogs yields two unique signatures for each cell type. We used normal breast cells MCF10A, adenocarcinoma cells MCF7, and premalignant cells MCF10AneoT, with hepatocellular carcinoma cells HepG2 as the negative control. Our data indicated that MCF10AneoT and MCF7 cells had an observable difference in response to only one of the analogs. The response, observed as fluorescence intensity, leads to a two-point assessment of the cells in any sample. Since the treatment time is 10 min, there is potential for use in rapid on-site high-throughput diagnostics.

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Tunable GLUT–Hexose Binding and Transport via Modulation of Hexose C‐3 Hydrogen‐Bonding Capabilities

Cited by 9 publications

References 33 publications

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Structure, function and regulation of mammalian glucose transporters of the SLC2 family

Chemical biology probes of mammalian GLUT structure and function

Metabolism-Driven High-Throughput Cancer Identification with GLUT5-Specific Molecular Probes

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