Inhibitions of sugar transport produced by ligands binding at opposite sides of the membrane. Evidence for simultaneous occupation of the carrier by maltose and cytochalasin B

Carruthers, Anthony; Helgerson, Amy L.

doi:10.1021/bi00230a015

Cited by 85 publications

(97 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…70, No. 1, 1998 KINETICS OF HUMAN BRAIN GLUCOSE UPTAKE 405 carrier (Carruthers and Helgerson, 1991). Furthermore, by comparing our measurements of brain glucose levels over an extended range of plasma glucose levels with those previously reported over a much narrower plasma glucose level range (Gruetter et al, 1992a), we obtained apparent Michaelis-Menten constants Tmax and K, that are in excellent agreement and thus appear to be independent of the range of glucose levels studied.…”

supporting

confidence: 74%

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

Gruetter¹,

Uğurbil

Seaquist³

1998

Journal of Neurochemistry

233

280

View full text Add to dashboard Cite

Understanding the mechanism of brain glucose transport across the blood-brain barrier is of importance to understanding brain energy metabolism. The specific kinetics of glucose transport have been generally described using standard Michaelis-Menten kinetics. These models predict that the steady-state glucose concentration approaches an upper limit in the human brain when the plasma glucose level is well above the Michaelis-Menten constant for half-maximal transport, K~. In experiments where steady-state plasma glucose content was varied from 4 to 30 mM, the brain glucose level was a linear function of plasma glucose concentration. At plasma concentrations nearing 30 mM, the brain glucose level approached 9 mM, which was significantly higher than predicted from the previously reported Kõf --'4 mM (p < 0.05). The high brain glucose concentration measured in the human brain suggests that ablumenal brain glucose may compete with lumenal glucose for transport. We developed a model based on a reversible MichaelisMenten kinetic formulation of unidirectional transport rates. Fitting this model to brain glucose level as a function of plasma glucose level gave a substantially lower Kõ f 0.6 ±2.0 mM, which was consistent with the previously reported millimolar Km of GLUT-i in erythrocyte model systems. Previously reported and reanalyzed quantification provided consistent kinetic parameters. We conclude that cerebral glucose transport is most consistently described when using reversible Michaelis-Men±en kinetics. Key Words: NMR-Glucose transport-ln vivo studies-Spectroscopy-Human. J. Neurochem. 70, 397-408 (1998).Knowledge of the specific mechanism of glucose transport across the blood-brain barrier is important for understanding cerebral carbohydrate metabolism, which is the major source of energy for ATP production. Glucose transport across the blood-brain barrier occurs by facilitated diffusion mediated by specific transporter proteins. Glucose extraction is a saturable process in the brain/ (Crone, 1965) and erythrocytes (Le Fevre, 1961)atid is mediated by facilitated diffusion that has been well-established to be stereospecific and substrate-specific. Standard Michaelis-Menten models for glucose transport kinetics have since been used almost exclusively in most studies of the brain (for reviews, see, e.g., Lund-Andersen, 1979;Pardridge, 1983;Gjedde, 1992), with one exception .Many elegant techniques have been applied to study brain glucose uptake. The indicator-dilution techniques sample tracer extraction with a single pass across the capillary bed at a very high time resolution but with a somewhat limited spatial resolution (Knudsen et al., 1990). On the other hand, state-of-the art tracer techniques, such as positron emission tomography (PET), can provide a high spatial resolution (Svarer et al., 1996). However, the information on cerebral glucose content is indirect because the active metabolism of labeled glucose implies substantial label accumulation in metabolic products that cannot be distinguished fr...

show abstract

supporting

confidence: 74%

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

Gruetter¹,

Uğurbil

Seaquist³

1998

Journal of Neurochemistry

233

280

View full text Add to dashboard Cite

show abstract

“…The inhibitors likely cannot make similar hydrophobic or π-π interactions with Trp388 when the hGLUT transporters are in outward-open conformations because in the outward-open conformation of the closely related hGLUT3, the face of the Trp388 indole ring is inaccessible (14). It is widely accepted that cytochalasin B binds only to inward-open conformations of hGLUT1 (12).…”

Section: Discussionmentioning

confidence: 99%

“…Previous biochemical studies have shown that cytochalasin B and forskolin inhibit hGLUT1-mediated sugar transport in RBCs by binding at or close to the hGLUT1 sugar export site (11,12). Recent structural studies on hGLUTs have been focused toward elucidating the glucose-binding site.…”

mentioning

confidence: 99%

Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides

Kapoor

Finer-Moore

Pedersen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

180

220

View full text Add to dashboard Cite

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, and two previously undescribed Phe amide-derived inhibitors. Despite very different chemical backbones, all three compounds bind in the central cavity of the inward-open state of hGLUT1, and all binding sites overlap the glucose-binding site. The inhibitory action of the compounds was determined for hGLUT family members, hGLUT1-4, using cell-based assays, and compared with homology models for these hGLUT members. This comparison uncovered a probable basis for the observed differences in inhibition between family members. We pinpoint regions of the hGLUT proteins that can be targeted to achieve isoform selectivity, and show that these same regions are used for inhibitors with very distinct structural backbones. The inhibitor cocomplex structures of hGLUT1 provide an important structural insight for the design of more selective inhibitors for hGLUTs and hGLUT1 in particular.X-ray structure | glucose facilitator | human MFS transporter | cytochalasin B | GLUT inhibitor

show abstract

“…Several specific inhibitors of glucose transport in cells of eukaryotes have been described. Phloretin, cytochalasin B and maltose have all been shown to inhibit glucose transport in human erythrocytes (Carruthers & Helgerson, 1991). Also, by setting various extracellular glucose concentrations, the glucose transport activity can be specifically modulated.…”

Section: Introductionmentioning

confidence: 99%

Strategies to determine the extent of control exerted by glucose transport on glycolytic flux in the yeast Saccharomyces bayanus

et al. 1999

View full text Add to dashboard Cite

The extent to which the transport of glucose across the plasma membrane of the yeast Saccharomyces bayanus controls the glycolytic flux was determined. The magnitude of control was quantified by measuring the effect of small changes in the activity of the glucose transport system on the rate of glucose consumption. Two effectors were used to modulate the activity of glucose transport : (i) maltose, a competitive inhibitor of the glucose transport system in S. bayanus (as well as in Saccharomyces cerevisiae) and (ii) extracellular glucose, the substrate of the glucose transport system. Two approaches were followed to derive from the experimental data the flux control coefficient of glucose transport on the glycolytic flux : (i) direct comparison of the steadystate glycolytic flux with the zero trans-influx of glucose and (ii) comparison of the change in glycolytic flux with the concomitant change in calculated glucose transport activity on variation of the extracellular glucose concentration. Both these approaches demonstrated that in cells of S. bayanus grown on glucose and harvested at the point of glucose exhaustion, a high proportion of the control of the glycolytic flux resides in the transport of glucose across the plasma membrane.

show abstract

Inhibitions of sugar transport produced by ligands binding at opposite sides of the membrane. Evidence for simultaneous occupation of the carrier by maltose and cytochalasin B

Cited by 85 publications

References 7 publications

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

Steady‐State Cerebral Glucose Concentrations and Transport in the Human Brain

Mechanism of inhibition of human glucose transporter GLUT1 is conserved between cytochalasin B and phenylalanine amides

Strategies to determine the extent of control exerted by glucose transport on glycolytic flux in the yeast Saccharomyces bayanus

Contact Info

Product

Resources

About