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-GlcNAc) 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-GlcNAc 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-GlcNAc to the dimer (the smallest unit for catalyzing the substrate) that UDP-GlcNAc is bound to the interface of the dimer by 12 hydrogen bonds. On the basis of the docking results, a binding pocket of human GFAT1 dimer for UDP-GlcNAc 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.
Chou
Kuo-Chen
KC
Gordon Life Science Institute, San Diego, CA 92130, USA. kchou@san.rr.com
D000595:Amino Acid Sequence; D001665:Binding Sites; D003198:Computer Simulation; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D019281:Dimerization; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D005947:Glucose / Q000378:metabolism; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000737:chemistry*
D014537:Uridine Diphosphate N-Acetylglucosamine; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D005947:Glucose