Comparative stereochemical analysis of glucose-binding proteins for rational design of glucose-specific agents

Abstract

There is a need for synthesizing glucose-sensitive molecules which can be used in glucosesensors and self-regulating insulin delivery devices. Currently, glucose-sensitive proteins, such as glucoseoxidase and concanavalin A (Con-A), are used for detecting glucose molecules. For long-term in vivoapplications, it is necessary to synthesize non-proteineous glucose-sensitive molecules which are biocompatible,nontoxic, cost-effective, and independent of environmental factors such as pH, ionic strength, orthe presence of divalent cations. As a first step toward synthesizing glucose sensitive molecules, we have compared glucose-bindingsites of four different types of glucose-binding proteins. They are human β-cell glucokinase, D-xyloseisomerase, lectins (Lathyrus ochrus isolectin I and Con-A), and glucose/ galactose binding protein. Analysisof the glucose-binding sites of their 3-dimensional crystal structures showed that the hydrogen bondsbetween the hydroxyl groups of glucose and a few types of amino acid residues of proteins provided themain attraction. In some cases, the same atom was involved in multiple hydrogen bonds. Hydrophobicinteractions between the pyranose ring of glucose and aromatic rings of hydrophobic amino acid residuesalso played an important role in the glucose specificity. A sandwich geometry was observed among thehydrophobic groups. This comparative stereochemical analysis suggests that a possible glucose bindingsite can be made by placing Asp and Asn around glucose for hydrogen bonding and Phe on both sidesof glucose for hydrophobic interaction.