Mutations in exons 10 and 11 of human glucokinase result in conformational variations in the active site of the structure contributing to poor substrate binding - explains hyperglycemia in type 2 diabetic patients.
Mutations in the glucokinase (GK) gene play a critical role in the establishment of type 2 diabetes. In our earlier study, R308K mutation in GK in a clinically proven type 2 diabetic patient showed, structural and functional variations that contributed immensely to the hyperglycemic condition. In the extension of this work, a cohort of 30 patients with established type 2 diabetic condition were chosen and the exons 10 and 11 of GK were PCR-amplified and sequenced. The sequence alignment showed A379S, D400Y, E300A, E395A, E395G, H380N, I348N, L301M, M298I, M381G, M402R, R308K, R394P, R397S, and S398R mutations in 12 different patients. The structural analysis of these mutated GKs, showed a variable number of β-α-β units, hairpins, β-bulges, strands, helices, helix-helix interactions, β-turns, and γ-turns along with the RMSD variations when compared to wild-type GK. Molecular modeling studies revealed that the substrate showed variable binding orientations and could not fit into the active site of these mutated structures; moreover, it was expelled out of the conformations. Therefore, these structural variations in GK due to mutations could be one of the strongest reasons for the hyperglycemic levels in these type 2 diabetic patients.
a Division of Animal Biotechnology, Department of Zoology , Sri Venkateswara University , Tirupati , Andhrapradesh 517502 , India.
Nandakumar
N
Yellapu
Manoj Kumar
MK
Mahto
Koteswara Rao
KR
Valasani
P V G K
PV
Sarma
Bhaskar
B
Matcha
D020134:Catalytic Domain; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D056726:Genetic Association Studies; D005941:Glucokinase / Q000737:chemistry / Q000235:genetics*; D005947:Glucose / Q000737:chemistry; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000235:genetics; D062105:Molecular Docking Simulation; D020125:Mutation, Missense; D011485:Protein Binding
D005941:Glucokinase; D005947:Glucose
glucokinase; molecular docking; molecular dynamics; mutations