Nakaishi Yuichiro, Bando Masahiko, Shimizu Hiroshi, Watanabe Kenji, Goto Fumitaka, Tsuge Hideaki, Kondo Kazumi, Komatsu Makoto
Medicinal Chemistry Research Institute, Otsuka Pharmaceutical Co. Ltd., Kawauchi-cho, Tokushima, Japan.
FEBS Lett. 2009 Jan 5;583(1):163-7. doi: 10.1016/j.febslet.2008.11.041. Epub 2008 Dec 6.
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.
果糖-6-磷酸酰胺转移酶（GFAT）是己糖胺生物合成途径中的一种限速酶，在2型糖尿病中起重要作用。我们现在报道了在存在环状葡萄糖-6-磷酸和线性氨基葡萄糖-6-磷酸的情况下人GFAT异构酶结构域的首个结构。包括活性位点的C末端尾巴呈现出刚性构象，类似于相应的大肠杆菌酶。活性位点附近CF螺旋的多样性表明该螺旋是药物设计的主要靶点。我们的研究为2型糖尿病治疗药物的开发提供了见解。
