Characterization of glucokinase mutations associated with maturity-onset diabetes of the young type 2 (MODY-2): different glucokinase defects lead to a common phenotype
| Autor: | Elizabeth J. Karschnia, Graeme I. Bell, David C. LaPorte, Gulshan R. Anand, Stephen P. Miller, Alex J. Lange |
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| Rok vydání: | 1999 |
| Předmět: |
medicine.medical_specialty
Hot Temperature Endocrinology Diabetes and Metabolism Mutant MODY 2 Biology medicine.disease_cause Maturity onset diabetes of the young Islets of Langerhans Drug Stability Reference Values Internal medicine Glucokinase Escherichia coli Internal Medicine medicine Humans Missense mutation Glucose homeostasis Age of Onset Enzyme Inhibitors Adaptor Proteins Signal Transducing Mutation Palmitoyl Coenzyme A Proteins medicine.disease Glucose binding Kinetics Phenotype Endocrinology Diabetes Mellitus Type 2 Carrier Proteins |
| Zdroj: | Diabetes. 48:1645-1651 |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | Glucokinase (GK) is expressed in the pancreatic beta-cells and liver, and plays a key role in the regulation of glucose homeostasis. The enzymatic activity and thermal stability of wild-type (WT) GK and several mutant forms associated with maturity-onset diabetes of the young type 2 (MODY-2) were determined by a steady-state kinetic analysis of the purified expressed proteins. The eight MODY-2 mutations studied were Ala53Ser, Val367Met, Gly80Ala, Thr168Pro, Arg36Trp, Thr209Met, Cys213Arg, and Val226Met. These missense mutations were shown to have variable effects on GK kinetic activity. The Gly80Ala and Thr168Pro mutations resulted in a large decrease in Vmax and a complete loss of the cooperative behavior associated with glucose binding. In addition, the Gly80Ala mutation resulted in a sixfold increase in the half-saturating substrate concentration (S0.5) for ATP, and Thr168Pro resulted in eight- and sixfold increases in the S0.5 values for ATP and glucose, respectively. The Thr209Met and Val226Met mutations exhibited three- and fivefold increases, respectively, in the S0.5 for ATP, whereas the Cys213Arg mutation resulted in a fivefold increase in the S0.5 for glucose. These mutations also led to a small yet significant reduction in Vmax. Of all the mutations studied, only the Cys213Arg mutation had reduced enzymatic activity and decreased thermal stability. Two mutants, Ala53Ser and Val367Met, showed kinetic and thermal stability properties similar to those of WT. These mutants had increased sensitivities to the known negative effectors of GK activity, palmitoyl-CoA, and GK regulatory protein. Taken together, these results illustrate that the MODY-2 phenotype may be linked not only to kinetic alterations but also to the regulation of GK activity. |
| Databáze: | OpenAIRE |
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