Allosterism in glucokinase

Glucokinase is a hexokinase isoenzyme mainly expressed in liver and pancreas. it is also called hexokinase IV and hexokinase D. As all hexokinases, it catalyses phosphorylation of glucose at the expense of ATP hydrolysis. However, glucokinase is characterised by being efficient only when glucose concentration is high. For this reason, it has a key role in regulation of glycemia.

Some synthetic compounds have been developed (like MRK, shown in the figure) which are able to bind glucokinase and enhance its activity. They are collectively called GKA (glucokinase activators).

Observe the conformational transition:

The closed and semiclosed forms in the model have one glucose molecule bound (substrate) and one molecule of an allosteric effector (MRK and RO-28-1675, respectively)
These ligands and the substrate, when not bound, are displayed apart from the protein.

of the protein.

between all three conformations.

This conformational change is an example of allosterism, since it involves a change in catalytic activity as a consequence of ligand binding far away from the active site. In the case of glucokinase, MRK binding prevents the superopen conformation, so the equilibrium is shifted towards the closed conformation of the protein, with higher enzymatic activity; furthermore, the kinetics is modified, changing from sigmoidal to hyperbolic:

activity (mmol min⁻¹ g⁻¹)

[glucose] (mM)

with 30 µM effector

without effector