Last couple of weeks, we had really long articles on the metabolic pathway of glycolysis. Yeah, kind of dry, too. It’s important to understand, though, because that is sort of the foundation that a lot of our pathways are built off of. We’re going to keep exploring those, this time with gluconeogensis!

Gluconeogenesis is actually going to not result in energy like glycoysis. In fact, it’s almost going to follow the exact same path as glycolysis but backwards, meaning we’re going to end up with glucose when we’re done. This way, we can use things like lactate, glycerol, glucogenic amino acids, and oxalocetate to give us an energy source we can use. In this way, we can avoid things like hypoglycemia.

This is mostly happening in our liver and a little bit in our kidneys, during a fasted state. Fasted state just means we’re low on energy, so this can come about from not eating in awhile or intense physical exertion. Either way, we’re running out of energy and need to get some made.

Alright, so let’s just use lactate. Wherever it comes from, it’s going to get transported to the liver and converted to pyruvate. That’s down through a process called the Cori Cycle. If you’re a med student, maybe look this up but it doesn’t seem to be too high yield at the writing of this article. Just know the enzyme is lactate dehydrogenase. Another common one in text books is alanine being converted to pyruvate.

To use amino acids, other than leucine and lysine, we just have to knock off that amine group, either through transamination or deamination. Then they essentially go in as pyurvate or oxaloacetate. They can also be incorporated into the citric acid cycle.

Okay, so we’re in the liver, and we’re in the mitochondria. Oxaloacetate is decarboxylated (remove a -CO2 group) and then phosphorylated (add a -PO3). This gives us phophoenolpyruvate, which if you remember, is the last step of glycolysis before making pyruvate. It was one of the reversible steps that we’re now reversing, essentially. The enzyme doing this is phosphoenolpyruvate carboxykinase and it’s going to cost us one energy in the form of GTP.

Now we just follow glycolysis backwards! PEP leads to 2-phosphoglycerate to 3-phosphyglycerate to 1,3-biphosphoglycerate to glyceraldehyde-3-P to fructose-1, 6-biphosphate.

Here we need an enzyme, though. We use fructose-1, 6-bisphophatase to converte fructose-1, 6-biphosphate to just regular old fructose 6-phosphate. We’re going to release a phosphate and use up a water molecule. This is an important step to keep in mind because this is the rate-limiting step.

Then fuructose 6-phosphate is turned into glucose 6-phosphate by phosphoglucoisomerase. From here, we can use glucose 6 phosphate in things like glycogenesis/glycogenolysis or the HMP shunt. We can also dephosphorylate it to make glucose. That happens using…yep, glucose 6-phosphatase but make note that it happens in the endoplasmic reticulum. Once its formed and free, we roll out to the cytosol!

Not terrible, right? And if you have glycolysis down, you should be pretty set to go for learning gluconeogenesis!