Lecture 28 Summary

The regulation of of glycolytic pathway also has a logic, one that is context-dependent. We finish our study of glycolysis with a look at some control issues. In order to fully understand the regulation of glycolysis, we must know a little bit about its alter-ego pathway, gluconeogenesis.

Control of glycolysis and allosteric regulation of PFK

Control of glycolysis illustrates a key principle: the flux through a pathway is regulated at steps that are associated with a significant drop in free energy, i.e. at exergonic steps. The first significantly exergonic step that is unique to a given pathway is referred as the committed step of that pathway. The most important point of control of glycolysis is held to be at the reaction catalyzed by phosphofructokinase (PFK EC 2.7.1.1]. The reaction catalyzed by PFK is the committed step of glycolysis, and it would seem to be a logical choice for regulation, and indeed PFK displays allosteric regulation. ATP is an inhibitor (as well as a substrate!) of PFK, and a "side" metabolite of glycolysis, fructose 2,6-bisphosphate, activates the enzyme. Furthermore, fructose 2,6-bisphosphate relieves the inhibitory effect of ATP. The committed step of glycolysis is the step catalyzed by phosphofructokinase [PFK, EC 2.7.1.1], and it is the major control point of this pathway. PFK is regulated allosterically, and levels of an allosteric activator of PFK - fructose 2,6-bisphosphate - are controlled by covalent modification (phosphorylation) of a bifunctional enzyme responsible for its production as well as its breakdown.

Other regulatory features: Hexokinase : . Pyruvate kinase: Feed-forward activation by FBP; product inhibition by ATP. cellular glucose uptake by transporters. Glycolysis vs. gluconeogenesis; Substrate cycles.

Substrate cycles

If the rates of two directly opposing reactions, the phosphofructokinase reaction of glycolysis and that of the fructose 1,6-bisphosphatase reaction of gluconeogenesis are measured (with the help, say, of isotope-labeled substrates) it is found that both reactions can and do take place at the same time. Since the net result of this substrate cycle is simply the hydrolysis of ATP, it was believed at one time that this was a wasteful "futile cycle". Subsequently, it was discovered that substrate cycles can provide an effective means to create large changes in metabolic flux.

Learning objectives

Page updated 12-18-06

References

1. Berg, Tymoczko, and Stryer. Biochemistry (BTS): 6th edition (2007, Freeman) pp.383-388