4. Regulation of Glycolysis in the Liver

Homeostasis

Allosteric control refers to a type of enzyme regulation involving the binding of a non-substrate molecule, known as the allosteric effector, at locations on the enzyme other than the active site. —Wiki

These types of enzymes play a key role in metabolic pathways.

They also help organisms achieve homeostasis. This is a steady-state, not an equilibrium.

These allosteric enzymes control the flux of molecules through a particular pathway.

Homeostasis is the balance between the influx of energy/nutrients with the efflux of waste products.

This is achieved by the constant activation and inhibition of metabolic pathways. That is, a disturbance in the steady-state leads to regulation response in one or more pathways until steady-state is achieved again.

Equilibrium is far less desirable. Cells at equilibrium are dead cells–no gradients, potentials, etc.

Types of Metabolic Enzymes

Substrate-limited reactions (SLR)

  • At equilibrium
  • Substrates rapidly converted to products

Enzyme-limited reactions (ELR)

  • Far from equilibrium
  • Activity is low
  • Enzyme activated by effectors

Example of an ELR

Glycolysis step 3: F6P —(PFK1)—> F1,6P, cost: ATP

The enzyme here PFK1 is Phosphofructokinase-1. It’ll be the star of many future videos, by the way, so remember this one.

The Mass-Action Ratio (MAR: compare to the equilibrium constant) in this reaction is defined as:

[F16P][ADP]
—————-
[F6P][ATP]

Under normal cell conditions, the MAR above is 0.04. That is, [Product] << [Substrate]. In vitro, however, this ratio is 250 (which then is the equilibrium constant). So in cells, PFK1 is relatively inactive. Therefore, PFK1 regulates an ELR and as such is called a Metabolic Valve (MV) for the pathway. It reduces the glycolytic flux. When active, it increases the flux of glycolysis.

More generally, not all enzymes in a pathway act as MVs. But in these types of pathways, the product of each step becomes the substrate for the step that follows. The points in the pathway with ELRs are also called rate-limiting steps. Here, effectors bind to the regulatory subunits.

Forms of metabolic regulation

Allosteric regulation

  • Allosteric regulators usually reflect cell metabolic state
  • Fast regulation (a few milliseconds)

Reversible covalent modification

  • Can either activate or inhibit an enzyme, e.g., phosphorylation
  • Slower than allosteric (a few seconds)

Transcriptional regulation

  • Slowest form of regulation
  • Change in expression of enzymes: inhibitors of gene expression
  • Long-term metabolic adaption usually achieved by stable changes to gene expression mediated by transcriptional regulators.

 

 

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