Theoretical Study of the Relative Stability of Rotational Conformers of α and β-<scp>d</scp>-Glucopyranose in Gas Phase and Aqueous Solution

Corchado, J. C.; Sánchez, M. Luz; Aguilar, M.

doi:10.1021/ja0398767

Cited by 77 publications

(88 citation statements)

References 93 publications

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“…The locations of amino acids with similar selectivity to the above were obtained using docking studies with D-glucose, D-galactose, D-mannose, and D-fructose ligands on the GLUT1 three-dimensional template. In aqueous solution, hexoses coexist as ␣-and ␤-anomers in a 34:66% ratio, respectively (39). ␤-DGlucose is transported faster than ␣-D-glucose by human erythrocytes (40).…”

Section: Resultsmentioning

confidence: 99%

Docking Studies Show That D-Glucose and Quercetin Slide through the Transporter GLUT1

Cunningham

Afzal-Ahmed

Naftalin

2006

Journal of Biological Chemistry

101

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On a three-dimensional templated model of GLUT1 (Protein Data Bank code 1SUK), a molecular recognition program, AUTODOCK 3, reveals nine hexose-binding clusters spanning the entire "hydrophilic" channel. Five of these cluster sites are within 3-5 Å of 10 glucose transporter deficiency syndrome missense mutations. Another three sites are within 8 Å of two other missense mutations. D-Glucose binds to five sites in the external channel opening, with increasing affinity toward the pore center and then passes via a narrow channel into an internal vestibule containing four lower affinity sites. An external site, not adjacent to any mutation, also binding phloretin but recognizing neither D-fructose nor L-glucose, may be the main threading site for glucose uptake. Glucose exit from human erythrocytes is inhibited by quercetin (K i ‫؍‬ 2.4 M) but not anionic quercetin-semiquinone. Quercetin influx is retarded by extracellular D-glucose (50 mM) but not by phloretin and accelerated by intracellular D-glucose. Quercetin docking sites are absent from the external opening but fill the entire pore center. In the inner vestibule, Glu 254 and Lys 256 hydrogen-bond quercetin (K i ≈ 10 M) but not quercetin-semiquinone. Consistent with the kinetics, this site also binds D-glucose, so quercetin displacement by glucose could accelerate quercetin influx, whereas quercetin binding here will competitively inhibit glucose efflux. ␤-D-Hexoses dock twice as frequently as their ␣-anomers to the 23 aromatic residues in the transport pathway, suggesting that endocyclic hexose hydrogens, as with maltosaccharides in maltoporins, form -bonds with aromatic rings and slide between sites instead of being translocated via a single alternating site.The glucose uniporter GLUT1 (SLC2A1), a member of the major facilitator superfamily of solute transporters, has to date not been crystallized, but its three-dimensional structure has been modeled by templating it to that of Lac Y permease and glycerol 3-phosphate antiporter (GlpT) from Escherichia coli (1-3). The 12 transmembrane ␣-helical domains of the monomeric GLUT protein are arranged around a central water-filled pore lined predominantly with uncharged hydrophilic and hydrophobic amino acids. The 15-Å-long, 8-Å-wide channel narrows near its midpoint (1, 2). Molecular dynamic simulations show that glucose binds close to this position within the pore, as expected of lactose binding to Lac Y permease (2). Glucose docks additionally in a cavity at the external entrance of the pore (3).GLUTs transport other substrates besides hexoses (e.g. dehydroascorbate (4, 5) via GLUT1, -3, and -4 and glucosamine (6) via GLUT2). The flavonone, quercetin, is transported via GLUT4. Quercetin influx into GLUT4 is inhibited by high glucose or cytochalasin B concentrations (7). Conversely, quercetin inhibits glucose and ascorbate transport via GLUT1, -2, -3, and -4 (8 -10).This present study demonstrates that quercetin is also transported via GLUT1, and its uptake is accelerated by exchange with intracellular glucose. Our...

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Section: Resultsmentioning

confidence: 99%

Docking Studies Show That D-Glucose and Quercetin Slide through the Transporter GLUT1

Cunningham

Afzal-Ahmed

Naftalin

2006

Journal of Biological Chemistry

101

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“…42-48) including carbohydrate structure and dynamics (49 -52) and carbohydrate reactivity (see for instance Refs. [53][54][55][56][57][58].…”

Section: Methodsmentioning

confidence: 99%

Substrate Distortion in the Michaelis Complex of Bacillus 1,3–1,4-β-Glucanase

Biarnés

Nieto

Planas

et al. 2006

Journal of Biological Chemistry

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The structure and dynamics of the enzyme-substrate complex of Bacillus 1,3-1,4-␤-glucanase, one of the most active glycoside hydrolases, is investigated by means of Car-Parrinello molecular dynamics simulations (CPMD) combined with force field molecular dynamics (QM/MM CPMD). It is found that the substrate sugar ring located at the ؊1 subsite adopts a distorted 1 S 3 skew-boat conformation upon binding to the enzyme. With respect to the undistorted 4 C 1 chair conformation, the 1 S 3 skew-boat conformation is characterized by: (a) an increase of charge at the anomeric carbon (C1), (b) an increase of the distance between C1 and the leaving group, and (c) a decrease of the intraring O5-C1 distance. Therefore, our results clearly show that the distorted conformation resembles both structurally and electronically the transition state of the reaction in which the substrate acquires oxocarbenium ion character, and the glycosidic bond is partially broken. Together with analysis of the substrate conformational dynamics, it is concluded that the main determinants of substrate distortion have a structural origin. To fit into the binding pocket, it is necessary that the aglycon leaving group is oriented toward the ␤ region, and the skew-boat conformation naturally fulfills this premise. Only when the aglycon is removed from the calculation the substrate recovers the all-chair conformation, in agreement with the recent determination of the enzyme product structure. The QM/MM protocol developed here is able to predict the conformational distortion of substrate binding in glycoside hydrolases because it accounts for polarization and charge reorganization at the ؊1 sugar ring. It thus provides a powerful tool to model E⅐S complexes for which experimental information is not yet available. Glycoside hydrolases (GHs)2 are the enzymes responsible for the hydrolysis of glycosidic bonds and play important biological functions such as glycan processing in glycoproteins, remodeling the cell walls, and polysaccharide modification and degradation. The reaction mechanism, a classical textbook example of enzymatic reaction, has attracted much interest because genetically inherited disorders of glycoside hydrolysis often occur and because inhibitors of these enzymes can act as new therapeutic agents for the treatment of viral infections (1, 2). Despite the large number of GHs known, classified into more than 90 families (1), the catalytic mechanism is similar. They typically operate by means of acid/base catalysis with retention or inversion of the anomeric configuration, although a different mechanism has recently been proposed for the GH family 4 (3). The acid/base reaction is assisted by two essential residues: a proton donor and a nucleophile or general base residue (4). Inverting enzymes operate by a single nucleophilic substitution, whereas retaining glycosidases follow a double displacement mechanism via formation and hydrolysis of a covalent glycosyl-enzyme intermediate. Both steps involve oxocarbenium ion-like transition states (F...

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“…4 Thus, it is crucial to select a target proton in the D-(+)-glucose for this study. 18 which is mainly related to the interaction between the solvent and the free-electron pair of the anomeric oxygen, 19 monitoring either α-C1 proton at 5.21 ppm or β-C1 proton at 4.64 ppm, but not both protons, was sufficient to quantitate D-(+)-glucose in D2O by qNMR. As shown in Fig.…”

Section: Optimization Of Dosy Acquisition Conditionsmentioning

confidence: 99%

Quantitative Analysis of D-(+)-Glucose in Fruit Juices Using Diffusion Ordered-1H Nuclear Magnetic Resonance Spectroscopy

et al. 2014

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Theoretical Study of the Relative Stability of Rotational Conformers of α and β-d-Glucopyranose in Gas Phase and Aqueous Solution

Cited by 77 publications

References 93 publications

Docking Studies Show That D-Glucose and Quercetin Slide through the Transporter GLUT1

Docking Studies Show That D-Glucose and Quercetin Slide through the Transporter GLUT1

Substrate Distortion in the Michaelis Complex of Bacillus 1,3–1,4-β-Glucanase

Quantitative Analysis of D-(+)-Glucose in Fruit Juices Using Diffusion Ordered-1H Nuclear Magnetic Resonance Spectroscopy

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