5. Regulation of Blood Sugar in the Liver

Gluconeogenesis

Motivation

The brain consumes an average of 120g/day of Glucose. Incoming monosaccharides aren’t enough. The brain needs an anabolic pathway to synthesis the glucose it needs.

Gluconeogenesis

Gluconeogenesis is that pathway. It’s not just the reverse of glycolysis though. Recall that  three metabolic valves of glycolysis also represent three irreversible steps. To sidebar on this, glycolysis can be described as:

Three enzyme-limited steps

  • three steps in glycolysis (1,3,10)
  • highly exergonic
  • irreversible
  • reactions not at equilibrium

Seven substrate-limited steps

  • easily reversible
  • reactions at equilibrium

So to handle the path back to glucose, gluconeogenesis relies on three bypass reactions to deal with the irreversible reactions. The other seven can proceed in reverse. These bypass reactions rely on other enzymes.

The First Bypass: Pyruvate -> PEP

The last step of glycolysis is the first step in gluconeogenesis. This is one of glycolysis’s metabolic valves and thus requires bypass. This bypass is a multi-step process, the details of which vary depending on the precursors involved.

The first precursor is alanine. Here, both alanine and Pyruvate are transported from the cytoplasm into the mitochondria–alanine converts to pyruvate via a process called transamination.

Once in the mitochondria, pyruvate is converted into oxaloacetate by binding a Biotin molecule to the enzyme pyruvate carboxylase. The cost is 1 ATP.

Note that the conversion of pyruvate to oxaloacetate also provides a way to replenish the citric acid cycle. See past lecture on that detail.

Since oxaloacetate can not cross the mitochondrial membrane, it’s reduced to malate, which can cross. In the cytosol, malate is re-oxidized to oxaloacetate. Then it gets oxidatively decaroboxylated to PEP by phosphoenolpyruvate carboxykinase.

During a later step, G13BP –> G3P, which consumes 1 NADH and occurs in the cytoplasm. The ratio of NADH/NAD+ in the cytoplasm is far less than the same ratio in the mitochondrion though. 10^5 lower in fact! Thus the synthesis of G3P contributes to the deficit of NADH in the cytoplasm. Unfortunately, this can’t be overcome by the export of NADH from the mitochondria since the IM of mito is impermeable to NADH. Thus, the above mitochondrial step allows for net movement of reduction equivalent from the mito to cytoplasm. Specifically, the mito step of Oxal->Malate uses NADH, but there’s plenty to be had there.  Once transported back to the cytoplasm, the conversion back of Malate->Oxal produces a needed NADH. So it’s a win.

Summary of Reactions:

Pyruvate + ATP + GTP + HCO3- —> PEP + ADP + GDP +Pi +CO2

Note that at standard conditions, this is endogenic. But because [PEP] is low in a cell, it gets consumed rapidly. This pushes it into the realm of spontaneous.

Two high energy phosphate groups are expended (ATP, GTP) to phosphorylate Pyruvate in PEP. In contrast, in Glycolysis, this step (in the other direction, of course) is coupled with the synthesis of 1 ATP.

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The second precursor for this first step is lactate. This is produced by RBC and muscles and transported to the liver.

In the cytoplasm of liver cells, the conversion of lactate to pyruvate produces NADH. This will compensate for the loss of NADH when G3P is later produced. The pyruvate again moves into the mitochondria, is converted to Oxal and from there into PEP.

The Second Bypass: F16P -> F6P

In glycolysis, this step is catalyzed by PFK-1 (and is irreversible, but you know that by now). In gluconeogenesis, the reverse step is catalyzed by F16Bisphosphatase, also exergonic and irreversible. It is not coupled with the synthesis of ATP.

Newsflash: Gluconeogenesis does not produce ATP

The Third Bypass: G6P -> Glu

Catalyzed by G6Phosphatase, also exergonic and irreversible. This enzyme is only in the livery and kidney, not in the muscle or brain, which prefers to keep glucose trapped in cells, since once the Glucose is synthesized, it can exit the cell.

Summary

The G of glycolysis is -63 kJ/mole

The G of gluconeogenesis is -16 kJ/mole

The difference, 47 kJ/m, represents the cost of producing glucose during gluconeogenesis.