Structural requirements for binding to the sugar-transport system of the human erythrocyte.
The structural requirements for binding to the glucose/sorbose-transport system in the human erythrocyte were explored by measuring the inhibition constants, K(i), for specifically substituted analogues of d-glucose when l-sorbose was the penetrating sugar. Derivatives in which a hydroxyl group in the d-gluco configuration was inverted, or replaced by a hydrogen atom, at C-1, C-2, C-3, C-4 or C-6 of the d-glucose molecule, all bound to the carrier, confirming that no single hydroxyl group is essential for binding to the carrier. The binding and transport of 1-deoxy-d-glucose confirmed that the sugars bind in the pyranose form. The relative inhibition constants of d-glucose and its deoxy, epimeric and fluorinated analogues are consistent with the combination of beta-d-glucopyranose with the carrier by hydrogen bonds at C-1, C-3, probably C-4, and possibly C-6 of the sugar. Both polar and non-polar substituents at C-6 enhance the affinity of d-glucose derivatives relative to d-xylose, and d-galactose derivatives relative to l-arabinose, and it is suggested that the carrier region around C-6 of the sugar may contain both hydrophobic and polar binding groups. The spatial requirements at C-1, C-2, C-3, C-4 and C-6 were explored by comparing the relative binding of d-glucose and its halogeno and O-alkyl substituents. The carrier protein closely approaches the sugar except at C-3 in the d-gluco configuration, C-4 and C-6. d-Glucal was a good inhibitor, showing that a strict chair form is not essential for binding. 3-O-(2',3'-Epoxypropyl)-d-glucose, a potential substrate-directed alkylating agent, bound to the carrier, but did not inactivate it.
D001665:Binding Sites; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism*; D002247:Carbon Isotopes; D002352:Carrier Proteins / Q000378:metabolism; D002854:Chromatography, Paper; D002855:Chromatography, Thin Layer; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D004988:Ethers, Cyclic / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008433:Mathematics; D008954:Models, Biological; D008968:Molecular Conformation; D011487:Protein Conformation; D013013:Sorbose / Q000097:blood* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013997:Time Factors; D014316:Tritium
D001786:Blood Glucose; D002247:Carbon Isotopes; D002352:Carrier Proteins; D004988:Ethers, Cyclic; D014316:Tritium; D005947:Glucose; D013013:Sorbose