Molecular therapeutic target for type-2 diabetes

Many lines of evidences indicate that increased flux of glucose through the pathway, in which glutamine: fructose-6-phosphate amidotransferase (GFPT or GFAT) is a key catalyst while uridine-5'-diphosphate-N-acetylglucosamine (UDP-GIcNAc) functions as an energy sensor, can lead to the insulin resistance that is characteristic of Type-2 diabetes. In view of this, GFAT and its interaction mechanism with UDP-GIcNAc may become a novel therapeutic target for the treatment of type 2 diabetes. To stimulate the structure-based drug design, the three-dimensional structures of human GFAT1 monomer and dimer have been developed. It has been found by docking UDP-GIcNAc to the dimer (the smallest unit for catalyzing the substrate) that UDP-GIcNAc is bound to the interface of the dinner by 12 hydrogen bonds. On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GIcNAc is defined. All of these findings can serve as a reference or footing in developing new therapeutic strategy for the treatment of type-2 diabetes.