Dual allosteric activation mechanisms in monomeric human glucokinase.

Cooperativity in human glucokinase (GCK), the body's primary glucose sensor and a major determinant of glucose homeostatic diseases, is fundamentally different from textbook models of allostery because GCK is monomeric and contains only one glucose-binding site. Prior work has demonstrated that millisecond timescale order-disorder transitions within the enzyme's small domain govern cooperativity. Here, using limited proteolysis, we map the site of disorder in unliganded GCK to a 30-residue active-site loop that closes upon glucose binding.

Small-Molecule Allosteric Activation of Human Glucokinase in the Absence of Glucose.

Synthetic allosteric activators of human glucokinase are receiving considerable attention as potential diabetes therapeutic agents. Although their mechanism of action is not fully understood, structural studies suggest that activator association requires prior formation of a binary enzyme-glucose complex. Here, we demonstrate that three previously described activators associate with glucokinase in a glucose-independent fashion.

Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties.

The tatanans are members of a novel class of complex sesquilignan natural products recently isolated from the rhizomes of Acorus tatarinowii Schott plants. Tatanans A, B and C have previously been reported to have potent glucokinase-activating properties that exceed the in vitro activity of known synthetic antidiabetic agents. Here, using a series of sequential [3,3]-sigmatropic rearrangements, we report the total synthesis of tatanan A in 13 steps and 13% overall yield.