4. Regulation of Glycolysis in the Liver

Metabolic Valves

Additional Metabolic Valves in Glycolysis

The previous video covered the metabolic valve at step 3: F6P->F16P.

There are two more valves: Step 1 (Gly->G6P) and Step 10 (PEP->Pyruvate).

The Step 1 Valve

For all cells except the liver, the conversion of Glu -> G6P is catalyzed by Hexokinase.

The ways in which hexokinase is regulated varies by cell type, as the need for glycolysis vary by tissue. These variations in behavior are reflected in the different isomers of Hexokinase that exist.

Two essential isomers of Hexokinase

There are five isoforms of Hexokinase. Two are important here.

M-isoform is found in the muscle/brain. It has a strong affinity for glucose (low Km).

L-isoform (a.k.a, Glucokinase, a.k.a., Hexokinase IV) is found in the liver. It has a lower affinity for Glu (high Km). When [Glu] is low, the enzyme gets sequestered in nucleus.  This means that when [Glu] is low, the liver defers Glucose consumption to the muscle and brain–the brain and muscle are “privileged consumers” of Glucose. This also means that under these conditions, the M-isoform operates at Vmax.

Liver starts consuming when [Glu] in the blood is high. In this case, the [G6P] in muscle is also high. Why?

First off, in non-liver cells, G6P is an allosteric inhibitor of hexokinase.

Second, a high level of blood glucose indicates that cells are at a high energy state and thus ATP is in abundance. Since ATP inhibits PFK-1, F6P will slow its conversion to F16P. Because G6P <–> F6P is reversible and because F6P –> F16P is stalled, then [G6P] will start to rise.

Okay, so now we have a ton of G6P in the muscle cells. Now what?

Because G6P is a hexokinase inhibitor, Glucose will stop getting imported into these cells. As such, the [Glu] in the blood will start to rise.  Fortunately, the L-isoform of hexokinase–glucokinase–is not inhibited by G6P.

Yet, ATP is still high and thus glycolysis is inhibited. The solution is a re-route:

In the liver, excess Glucose is converted to glycogen and fat. This is why carb-rich diets can lead to obesity.

Glu -> G6P -> G1P -> UPD-Glucose

UPD-Glucose—(glycogen synthase)—> Glycogen chain (recall the complex carbs lecture)

UPD-Glucose –>…—> fatty acids: lipids

glycogen synth

 

The regulation of Hexokinase affects other pathways too, such as the Pentose Phosphate Pathway that leads to the production of Ribose-5-Phosphate, which produces nucleotides and cofactors like NAD+, FAD+ and coQ.

This is why the regulation of PFK-1 is critical to glycolysis. The conversion of F6P->F16P is the first irreversible or “committed step” in glycolysis.

The Step 10 Valve

The last step is also regulated too:

Phosphoenolpyruvate (PEP) —(Pyrovatekinase)–> Pyruvate, gain: ATP

Pyruvate kinase (Pk) is an enzyme that phosphorylates proteins. It’s a reaction running in reverse actually! In vitro, its runs the other way. Under physiologic conditions (pH = 7.4), it proceeds toward production of Pyruvate and produces ATP.

NOTE: A reaction that’s reversible has a ∆G = 0. Why? The reverse of an exogenic reaction is endogenic and vice versa. Thus Gibbs Free Energy has to be zero.

Pk regulation

Pk is responsive to the levels of various metabolites, but there’s tissue-specific regulation too. In the liver, there’s an L isoform and in the muscle and brain, there’s an M isoform. Just like Hexokinase.

Both isoforms are allosteric enzymes that experience cooperative binding of their substrate (PEP).

Both are controlled by three effectors:

  1. PFK-1: When PFK-1 is open, F16P is produced and activates Pk. That is, glycolysis steps downstream from Step 3 will be pushed forward.
  2. ATP: ATP inhibits PFK-1 and Pk. That is high [ATP] can close two of three MVs that control Glycolysis.
  3. Alanine: High [Alanine] => [Pyruvate] is also high => other pathways leading to the synthesis of ATP => [ATP] is high => high energy state. Thus it’s an inhibitor as well. See this article on the Cahill Cycle for more on the relationship between Alanine and Pyruvate.

Difference between the L and M isoforms of Pk

The L isoform is controlled by reversible phosphorylation:

When [Glu] is low, glucagon is produced => liver receptors kick of a cascade and activate Protein Kinase A (PKA). The PKA phosphorylates the Pk (L isoform of Pk, that is (since we’re in the liver)). This inhibits Pk.

Important! Muscle and Brain cells do not have glucagon receptors. This means this pathway inhibition doesn’t occur. Why? Because Brain and Muscle need the energy.

Sidebar on PKA and cAMP

PKA is a family of enzymes whose activity depends on the concentration of cyclic AMP (cAMP). Specifically:

  • a hormone like glucagon wakes up a G protein-coupled receptor that causes the conversion of GDP to GTP.
  • The GTP activates the enzyme adenylyl cyclase, which catalyzes the conversion of ATP into cAMP.
  • 4 cAMP are needed to bind to PKA to wake it up, two to each of its regulatory subunits
  • These two regulatory subunits detach from the enzymes, exposing the two catalytic subunits of PKA, thus putting them to work.
  • As they phosphorylate proteins, a substrate is released that converts cAMP back to ATP, providing a negative feedback mechanism.

Summary

  • There are L and M isoforms for both Hexokinase and Pyruvate Kinase (Pk)
  • Differences in regulation between liver and the muscle (and brain)
  • Muscles consume glucose
  • Liver helps maintain blood glucose levels–homeostasis

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