Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants
1993
Takeda, J. | Gidh-Jain, M. | Xu, L.Z. | Froguel, P. | Velho, G. | Vaxillaire, M. | Cohen, D. | Shimada, F. | Makino, H. | Nishi, S.
Glucokinase plays a key role in the regulation of glucose metabolism in insulin-secreting pancreatic beta-cells and in the liver. Recent studies have shown that mutations in this enzyme can lead to the development of a form of non-insulin-dependent diabetes mellitus that is characterized by an autosomal dominant mode of inheritance and onset during childhood. Here, we report the catalytic properties of five additional missense mutations associated with diabetes (Glu70 leads to Lys, Ser131 leads to Pro, Ala188 leads to Thr, Trp257 leads to Arg and Lys414 leads to Glu), one polymorphism present in both normal and diabetic subjects (Asp4 leads to Asn), and three site-directed mutations (Glu177 leads to Lys, Glu256 leads to Ala, and Lys4l4 leads to Ala). The Trp257 leads to Arg mutation generated an enzyme that had an activity that was less than 0.5% of that for native human beta-cell glucokinase. By contrast, the Glu70 leads to Lys, Ser131 leads to Pro, Ala188 leads to Thr, and Lys414 leads to Glu mutations had a Vmax that was 20-100% of normal but a K,. for glucose that was 8-14-fold greater than the native enzyme. There was no effect of the Asp4 leads to Asn polymorphism or the Glu 177 leads to Lys substitution on glucokinase activity. The Lys414 leads to Ala substitution had no effect on Vmax but increased the Km for glucose 2-fold and the Glu256 leads to Ala substitution caused a approximately 200-fold decrease in Vmax. These studies have led to the identification of additional residues involved in glucokinase catalysis and substrate binding.
Show more [+] Less [-]AGROVOC Keywords
Bibliographic information
This bibliographic record has been provided by National Agricultural Library