%0 Journal Article
%T Structural Variations of Human Glucokinase Glu256Lys in MODY2 Condition Using Molecular Dynamics Study
%A Nanda Kumar Yellapu
%A Kalpana Kandlapalli
%A Koteswara Rao Valasani
%A P. V. G. K. Sarma
%A Bhaskar Matcha
%J Biotechnology Research International
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/264793
%X Glucokinase (GK) is the predominant hexokinase that acts as glucose sensor and catalyses the formation of Glucose-6-phosphate. The mutations in GK gene influence the affinity for glucose and lead to altered glucose levels in blood causing maturity onset diabetes of the young type 2 (MODY2) condition, which is one of the prominent reasons of type 2 diabetic condition. In view of the importance of mutated GK resulting in hyperglycemic condition, in the present study, molecular dynamics simulations were carried out in intact and 256 E-K mutated GK structures and their energy values and conformational variations were correlated. Energy variations were observed in mutated GK (3500£¿Kcal/mol) structure with respect to intact GK (5000£¿Kcal/mol), and it showed increased ¦Ã-turns, decreased ¦Â-turns, and more helix-helix interactions that affected substrate binding region where its volume increased from 1089.152£¿£¿2 to 1246.353£¿£¿2. Molecular docking study revealed variation in docking scores (intact£¿=£¿£¿12.199 and mutated£¿=£¿£¿8.383) and binding mode of glucose in the active site of mutated GK where the involvement of A53, S54, K56, K256, D262 and Q286 has resulted in poor glucose binding which probably explains the loss of catalytic activity and the consequent prevailing of high glucose levels in MODY2 condition. 1. Introduction Type 2 diabetic condition is the increase in blood glucose levels and is due to many reasons; one of the most important factor being MODY2 condition, which is characterized at an early age and is an autosomal dominant inherited disorder [1]. Glucokinase (GK) is one of the potential candidate genes for type 2 diabetes acting through elevated fasting plasma glucose. It is a glucose sensing enzyme that catalyses the formation of glucose-6-phosphate from glucose by utilizing one molecule of ATP and that determines the threshold for glucose-stimulated insulin secretion in islets and controls gluconeogenesis and glycogen synthesis in hepatocytes. It can regulate the insulin secretion and integration of hepatic intermediatory metabolism [2]. GK gene is 52.15 kilo bases (kb) in length and is present on Chromosome 7 p13 with 12 exons and produces a transcript of 2.7£¿kb. A number of reports suggest that the existence of mutations in the coding region of GK is associated with MODY2 [3¨C11]. The mutated structures show variation in the affinity for binding with glucose, which may affect the kinetics of GK [12, 13]. In order to assess the mutations in GK affecting the catalysis process, in silico mutagenic studies will help in revealing the effect of
%U http://www.hindawi.com/journals/btri/2013/264793/