2016
DOI: 10.1073/pnas.1603735113
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Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides

Abstract: Cancerous cells have an acutely increased demand for energy, leading to increased levels of human glucose transporter 1 (hGLUT1). This up-regulation suggests hGLUT1 as a target for therapeutic inhibitors addressing a multitude of cancer types. Here, we present three inhibitor-bound, inward-open structures of WT-hGLUT1 crystallized with three different inhibitors: cytochalasin B, a nine-membered bicyclic ring fused to a 14-membered macrocycle, which has been described extensively in the literature of hGLUTs, an… Show more

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Cited by 180 publications
(232 citation statements)
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“…GLUT isoform selectivity was determined in the same assay using DLD‐1 cells (express mainly GLUT‐1) and DLD‐1 GLUT1 (−/−) cells (express mainly GLUT‐3) or CHO cells that were stably transfected with hGLUT‐2 or hGLUT‐4. GLUT‐i1 and GLUT‐i2 preferably inhibit GLUT‐1 and GLUT‐4 over GLUT‐2 and GLUT‐3 (Table ) . GLUT‐i1 competes with glucose for the same binding site as determined in glucose competition experiments and crystal structure analysis with hGLUT‐1 (Table ) .…”
Section: Discovery Of the Most Potent Glut Inhibitorsmentioning
confidence: 96%
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“…GLUT isoform selectivity was determined in the same assay using DLD‐1 cells (express mainly GLUT‐1) and DLD‐1 GLUT1 (−/−) cells (express mainly GLUT‐3) or CHO cells that were stably transfected with hGLUT‐2 or hGLUT‐4. GLUT‐i1 and GLUT‐i2 preferably inhibit GLUT‐1 and GLUT‐4 over GLUT‐2 and GLUT‐3 (Table ) . GLUT‐i1 competes with glucose for the same binding site as determined in glucose competition experiments and crystal structure analysis with hGLUT‐1 (Table ) .…”
Section: Discovery Of the Most Potent Glut Inhibitorsmentioning
confidence: 96%
“…reported peptide analogues GLUT‐i1 and GLUT‐i2 (Figure ), with glucose uptake inhibitory activity. The cellular assay that was used monitored ATP depletion of hGLUT‐1‐ and luciferase‐transfected CHO‐K1 cells in the presence of a mitochondrial complex I inhibitor . GLUT‐i1 and GLUT‐i2 inhibit glycolytic ATP production with IC 50 values of 267 and 140 n m , respectively (Table ) .…”
Section: Discovery Of the Most Potent Glut Inhibitorsmentioning
confidence: 99%
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“…A clue that glycogen may be a source of lactate released in excess of glycolytic rate is that cytochalasin B (a glucose transport inhibitor [Jung and Rampal, ; Kapoor et al, ] that also has other effects, such as inhibition of actin polymerization (MacLean‐Fletcher and Pollard, ) was stated to inhibit ∼80% of [ 3 H]DG (and glucose) uptake, whereas this drug only inhibited basal or glutamate uptake–stimulated lactate‐pyruvate release by approximately 50% to 60% (see Methods and Fig. 4 in Pellerin and Magistretti, ).…”
Section: The Anl Shuttle Model Fails Stoichiometric Testsmentioning
confidence: 99%
“…Therefore, interactions of inhibitors with this residue may hinder the movement of the loop that closes the cavity and, therefore, block the flux of glucose through the transporter. 80 …”
Section: Synthetic Glut Inhibitorsmentioning
confidence: 99%