Structural instability of mutant beta-cell glucokinase: implications for the molecular pathogenesis of maturity-onset diabetes of the young (type-2).
The catalytic function and thermal stability of wild-type and mutant recombinant human pancreatic beta-cell glucokinase was investigated. The mutants E70K and E300K, which are thought to be the cause of impaired insulin production by the pancreatic beta-cell and decreased glucose uptake by the liver of patients with maturity-onset diabetes of the young, were found to be functionally indistinguishable from the wild-type, i.e. their kcat.S0.5, inflection point and h were normal. However, these two mutants showed markedly reduced stability under a variety of test conditions. Glucokinase instability, not low enzyme catalytic activity, may be the cause of diabetes mellitus with E70K and E300K mutants.
Kesavan
P
P
Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia 19104-6015, USA.
Wang
L
L
Davis
E
E
Cuesta
A
A
Sweet
I
I
Niswender
K
K
Magnuson
M A
MA
Matschinsky
F M
FM
D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000209:etiology* / Q000235:genetics*; D004795:Enzyme Stability; D005941:Glucokinase / Q000737:chemistry* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007515:Islets of Langerhans / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D009154:Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
D011994:Recombinant Proteins; D005941:Glucokinase