Feedforward activation

Pyruvate kinase the last enzyme in aerobic glycolysis, it catalyzes a substrate-level phosphorylation of ADP using the high-energy substrate phosphoenolpyruvate (PEP). Pyruvate kinase is activated by fructose 1,6-bisphosphate from the PFK-1 reaction (feedforward activation). 

The control via activation or inhibition of the rate(s) of an enzyme-catalyzed reaction(s). This control includes the increase or decrease in the stability or half-life of the enzyme(s). There are many different means by which control can be achieved. These include 1. Substrate availability and reaction conditions (e.g., pH, temperature, ionic strength, lipid interface activation) 2. Magnitude of Vraax sud valucs) 3. Activation (particularly, feedforward activation) 4. Isozyme formation 5. Com-partmentalization and channeling 6. Oligomerization/ polymerization 7. Feedback inhibition and cooperativity (particularly, allosterism and/or hysteresis) 8. Covalent modification and 9. Gene regulation (induction repression)... 

Pyruvate kinase is also stimulated by fructose 1,6-bisphosphate (see Topic J3 feedforward activation) so that its activity rises when needed, as glycolysis speeds up. 

The last enzyme in glycolysis, pyruvate kinase, is also subject to allosteric regulation. In this case, fructose-l,6-bisphosphate is the allosteric activator. It is interesting that fructose-l,6-bisphosphate is the product of the reaction catalyzed by phosphofructokinase. Thus, activation of phosphofructokinase results in the activation of pyruvate kinase. This is an example of feedforward activation because the product of an earlier reaction causes activation of an enzyme later in the pathway... 

Explain the feedforward activation mechanism that results in the activation of pyruvate kinase. 

After mention of feedback inhibition and activation, as well as feedforward inhibition, it will be evident that there is a fourth possibility—feedforward activation. This is also rare, but, significantly, when it does occur it is sometimes in pathways that are not demand-driven. We shall meet an example of this shortly when we consider glycogen production in the liver. 

Pyruvate kinase is inhibited by ATP, activated by fructose-1,6-bisphosphate (feedforward activation), and inhibited by acetyl-CoA. It is also responsive to hormonally-regulated phosphorylation in the liver -the phosphorylated form of the enzyme is less active. Alanine is also an inhibitor of the enzyme. 

This complicated commensalistic system is shown to be less stable, with limit-cycle response occurring after dilution rate changes, as would be expected from a model with more parameters. Though virtually any feedback from the dependent to the independent species will cause some overshoot after a step change in D, the most pronounced oscillatory behavior is caused by feedback inhibition and feedforward activation. Limited agreement with experimental data was obtained even though the analysis was somewhat limited due to the complexity of the system and the large number of differential equations. Similar results were obtained by Sheintuch (1980), who examined the dynamics of commensalistic systems with self- and cross-inhibition. Multiplicity of steady states was observed as well as oscillatory states with these complex kinetics and in the case of a reactor with biomass recirculation. Stability and dynamics are summarized in a qualitative phase plane by this author. 

The terminology of electromechanical systems has been appropriated to describe both feedback inhibition and feedforward activation as servomechanisms, or automatic devices which control the flow of large amounts of energy with the expenditure of only a minute amount of energy. Implicit in the servomechanism concept is the capacity to sense and correct errors, such capability being automatic, constant, and immediate. 

Acetyl-CoA carboxylase from animal tissues requires a hydroxy tricarboxylic acid, such as citrate or isocitrate, for its catalytic activity. Because citrate is a precursor of acetyl-CoA, it functions as a positive feedforward activator. Fatty acyl-CoAs which can be regarded as end products of fatty acid synthesis, act as negative feedback inhibitors. 

---