The many levels of glycolytic flux regulation

Glycotic Flux
The regulatory unit of the glycolytic pathway composed of the fructose steps at the interface between the initial step of glucose trapping in the cell through phosphorylation and the conditioning of the glucose molecule for catabolism.

Glycolysis is a fundamental metabolic pathway that is critical for the production of energy. Glycolytic flux, or the rate at which molecules proceed through the glycolytic pathway, is tightly regulated in response to the cellular environment. In a recent minireview in the Journal of Biological Chemistry, Sigurd Lenzen of the Hannover Medical School in Germany describes the complex regulatory mechanisms underlying glycolytic flux.
 
Glycolytic flux is regulated during the initial steps of glycolysis, including glucose uptake and phosphorylation. Phosphorylation of glucose is carried out by hexokinases. While all cells express at least one hexokinase with extremely high affinity for glucose, select cell types, including liver and pancreatic β cells, also express glucokinase, which has a much lower affinity for glucose. The unique kinetic properties of glucokinase allow it to act as a glucose sensor and translate changes in blood-glucose levels into changes in glycolytic flux.
 
It long has been thought that glucokinase function is weakly regulated. However, in the past few decades, a number of studies have begun to demonstrate that glucokinase activity is not only regulated, but it is regulated differently in different cell types. For example, in the liver, glucokinase is inhibited by GRP, a nuclear protein that selectively binds and inactivates glucokinase during starvation. Glucokinase also is inhibited in β cells, although that is done by ubiquitin and ubiquitin-binding proteins, as GRP is not expressed in those cells.
 
While glucokinase activity is important for initiating flux, the most crucial steps in glycolytic-flux regulation are the two fructose steps. These steps, which are carried out by phosphofructokinase/fructobisphosphatase isoenzymes to produce fructose ester products, form a regulatory unit. Both the enzymes that participate in these steps and the products that are formed influence glycolytic flux at multiple levels. For example, the activity of PFK1 is responsible for establishing the glycolytic oscillations that drive insulin secretion. Additionally, the fructose ester products are allosteric regulators of glycolysis, as they can inhibit the FBPases and promote glucose catabolism.
 
As research in the past 30 years has continued to demonstrate, the mechanisms of regulation of glycolysis are more complex than initially thought. Significantly, movement through the glycolytic pathway is regulated on multiple levels by the enzymes that function in the pathway and by the glycolytic intermediates as well as by regulatory proteins.

Photo of Kathleen McCannKathleen McCann (Kathleen.mccann
@yale.edu) is a graduate student in the genetics department at Yale University.