Despite the high sequence similarity among GLUT members, known inhibitors of other GLUT proteins (for example cytochalasin B, phloretin, or forskolin) do not affect GLUT5, suggesting that subtle differences may be responsible for ligand specificity among GLUT family members (this work, 17, 18). Nonetheless, selective and potent inhibitors for GLUT5 have not been described.
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Given the medical importance of GLUT5, its inhibitors could potentially serve as therapeutics for the treatment and management of cancer or diabetes. GLUT5 is upregulated in some diabetic patients and this expression is reversible with diabetes management treatment 16. In normal tissue, the expression of GLUT5 is upregulated by fructose 15 and may be the underlying mechanism linking GLUT5 with metabolic disorders 8.
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Consequently, GLUT5 activity is being explored as a marker for cancer, and development of fluorinated fructose analogs for use in positron emission tomography (PET) cancer diagnosis in GLUT5-overexpressing tumors is underway 14. Pancreatic cancer cells prefer fructose in their nucleic acid synthesis, thus fructose promotes pancreatic cancer proliferation 13. Also, abolishing GLUT5 expression in breast cancer cells inhibited tumor proliferation 12. Additionally, in vitro studies linked fructose exposure to modification of the glycan structures on the cell surface that enhance cancer cell invasiveness and proliferation 11. For example, GLUT5 is not normally present in mammalian breast cells, but the breast carcinoma cell lines MCF7 and MDA-MB-231 exhibit elevated GLUT5 mRNA level and show high rates of fructose transport 10. GLUT5 is frequently overexpressed in cancer cells (~27% of analyzed tumors) 9. GLUT5 is expressed in intestinal epithelia, sperm, brain, fat, skeletal muscle and kidney cells 8.Ĭancer cells require more energy for their uncontrolled growth and usually exhibit increased rates of carbohydrates transport, compared to normal cells. Among the 14 members of human GLUT protein family, only GLUT5 is fructose specific and lacks the ability to transport other carbohydrates such as glucose and galactose 5, 6, 7. Some studies also link a fructose-rich diet with hypertension 3, 4.įructose transport across cell membranes is carried out by members of the facilitated glucose transporter (GLUT, SLC2) family. Unlike glucose, fructose in serum is not regulated by insulin, and high levels of fructose consumption can cause dyslipidemia, impair glucose homeostasis and increase insulin resistance 2. Recent studies indicate that fructose consumption increased by almost 50% among US adults in the last 40 years, with fructose accounting for at least 10% of daily calories on average 1. During our evolution, humans have consumed relatively small amounts of fructose mostly from fruits. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity.įructose is one of the most common dietary carbohydrates.
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Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a K I of 3.2 ± 0.4 μM. MSNBA inhibition was specific to GLUT5 this inhibitor did not affect the fructose transport of human GLUT2 or the glucose transport of human GLUT1-4 or bacterial GlcP Se. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. GLUT5, a fructose-transporting member of the facilitative glucose transporter (GLUT, SLC2) family, is a therapeutic target for diabetes and cancer but has no potent inhibitors.