Evolution of glucose utilization: Glucokinase and glucokinase regulator protein

- Hexokinases are essential for mammalian glucose metabolism.
- Glucokinase evolved from a larger ancestral protein.
- GCKR allowed glucokinase to evolve tissue-specific enzymatic roles.
- Parallel loss of GCKR occurred in response to change in diet.

Glucose is an essential nutrient that must be distributed throughout the body to provide energy to sustain physiological functions. Glucose is delivered to distant tissues via be blood stream, and complex systems have evolved to maintain the levels of glucose within a narrow physiological range. Phosphorylation of glucose, by glucokinase, is an essential component of glucose homeostasis, both from the regulatory and metabolic point-of-view. Here we review the evolution of glucose utilization from the perspective of glucokinase. We discuss the origin of glucokinase, its evolution within the hexokinase gene family, and the evolution of its interacting regulatory partner, glucokinase regulatory protein (GCKR). Evolution of the structure and sequence of both glucokinase and GCKR have been necessary to optimize glucokinase in its role in glucose metabolism.