Structural analysis of human glutamine:fructose-6-phosphate amidotransferase, a key regulator in type 2 diabetes.
Glutamine:fructose-6-phosphate amidotransferase (GFAT) is a rate-limiting enzyme in the hexoamine biosynthetic pathway and plays an important role in type 2 diabetes. We now report the first structures of the isomerase domain of the human GFAT in the presence of cyclic glucose-6-phosphate and linear glucosamine-6-phosphate. The C-terminal tail including the active site displays a rigid conformation, similar to the corresponding Escherichia coli enzyme. The diversity of the CF helix near the active site suggests the helix is a major target for drug design. Our study provides insights into the development of therapeutic drugs for type 2 diabetes.
Nakaishi
Yuichiro
Y
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co. Ltd., Kawauchi-cho, Tokushima, Japan. y_nakaishi@research.otsuka.co.jp
Bando
Masahiko
M
Shimizu
Hiroshi
H
Watanabe
Kenji
K
Goto
Fumitaka
F
Tsuge
Hideaki
H
Kondo
Kazumi
K
Komatsu
Makoto
M
D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D015195:Drug Design; D004926:Escherichia coli / Q000235:genetics; D019298:Glucose-6-Phosphate / Q000737:chemistry; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics
D007004:Hypoglycemic Agents; D011994:Recombinant Proteins; D019298:Glucose-6-Phosphate; C497511:GFPT1 protein, human; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing)