MCAT Biological and Biochemical Foundations of Living Systems: Passage 14 — Flashcards

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Glucokinase possesses several properties that make it an attractive target for type 2 diabetes therapy, and several activators of the enzyme are currently being developed as potential drug candidates. Although there are numerous treatment options for type 2 diabetes, none of them allow for long-lasting control of blood glucose in most patients. Glucokinase, also known as hexokinase IV, is expressed in the liver and mediates the clearance of glucose from the blood through at least two different mechanisms. First, it catalyzes the phosphorylation of glucose to glucose 6-phosphate. Other forms of hexokinase (hexokinase I, II, III) catalyze the same reaction in other cells of the body, such as muscle cells. Second, glucokinase controls the levels of glucose by regulating the conversion of glucose to the storage form of glycogen. There is also evidence that glucokinase acts as a glucose sensor in pancreatic cells, where it is differentially expressed in response to glucose.

These research observations led to speculation that glucokinase might be an important determinant of the diabetes phenotype. Indeed, family studies in the 1990s revealed that mutations associated with reduced glucokinase activity were associated with a form of diabetes known as maturity onset diabetes of the young (MODY). Furthermore, there is evidence that inactivating mutations act in a dose-dependent fashion: mutations in a single allele are linked to mild hyperglycemia, whereas homozygous mutations are linked to severe permanent diabetes in the neonatal stages. On the other hand, activating mutations have been found to cause hypoglycemia.

The discovery of an allosteric site in glucokinase outside of its active site paved the way for the development of enzymatic activators starting in the early 2000s. In a recent study of patients with type 2 diabetes, one such activator was found to lower blood glucose. To date, numerous glucokinase activators have been developed, and their amino acid sequence may help lead to the identification of endogenous activators of the enzyme. In contrast, there is a physiologic negative allosteric effector of glucokinase, called fructose 6-phosphate, which is a product of the glycolytic pathway downstream of glucose 6-phosphate. Fructose 6-phosphate causes glucokinase to bind more tightly to a regulatory protein that sequesters the enzyme in the nucleus when blood glucose is low. However, when blood glucose is in the normal range, glucokinase dissociates from this regulatory protein, helping to keep the levels of glucose in the appropriate physiological range.