Abstract
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. We virtually screened a library of 6 million chemicals onto a GLUT5 model and identified N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) as an inhibitor of GLUT5 fructose transport in proteoliposomes. 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 GlcPSe. In MCF7 cells, a human breast cancer cell line, MSNBA competitively inhibited GLUT5 fructose uptake with a KI of 3.2 ± 0.4 μM. Ligand docking, mutagenesis and functional studies indicate that MSNBA binds near the active site and inhibitor discrimination involves H387 of GLUT5. Thus, MSNBA is a selective and potent inhibitor of fructose transport via GLUT5, and the first chemical probe for this transporter. Our data indicate that active site differences in GLUT members could be exploited to further enhance ligand specificity.
Highlights
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
The top ranked 175 in silico hits were tested for inhibition of fructose transport by human GLUT5 in proteoliposomes, and we found that N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA, SMILES: [S](= O)(= O)(C)c1cc(c(cc1)Nc2cc3c(cc2)OCO3)[N+ ](= O)[O−]) inhibited GLUT5
There is significant variation in the soluble loops depending upon the starting model, but the transmembrane substrate cavity in all GLUT5 homology models was invariable, consistent with the similarity of the crystal structures (Supplementary Fig. S1); the root-meansquare deviations for the superposition in the transmembrane helices was less than 1.5 Å for hGLUT5 models constructed from GlcPSe, hGLUT1 and bGLUT5 structures, as calculated with Superpose[24]
Summary
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. Fructose transport across cell membranes is carried out by members of the facilitated glucose transporter (GLUT, SLC2) family. 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]. 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]. Abolishing GLUT5 expression in breast cancer cells inhibited tumor proliferation[12]. GLUT5 is upregulated in some diabetic patients and this expression is reversible with diabetes management treatment[16]
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