The TCA Cycle

In my last post for BIOC3004, I wrote about glycolysis: the process in which glucose is broken down to pyruvate. That post did not cover the stuff that happens before and after this process: the breakdown of glycogen into glucose, and the entrance of pyruvate into the citric acid cycle.

Describe the reactions of the TCA cycle, where they occur within the cell and the regulation of the pathways.

From Glycolysis to Acetyl CoA formation

After glycolysis, which occurs in the cytosol, pyruvate enters the mitochondria where it is irreversibly converted to acetyl CoA with the help of pyruvate dehydrogenase, producing a little NADH along the way. Pyruvate dehydrogenase is actually a large complex made up of three subunits, each of which catalyses a single step in this reaction. Pyruvate dehydrogenase can exist in a phosphorylated (active) and dephosphorylated (less active) form. It is held in place by negative feedback mechanisms: when acetyl CoA, NADH and ATP levels increase, they can inhibit the phosphorylation of pyruvate dehydrogenase.

If pyruvate dehydrogenase is deficient, this can cause a condition called lactic acidosis, which may result in neurological defects and death. This is because pyruvate cannot become acetyl CoA, so it gets converted into lactate instead. Sometimes, this condition can be managed by eating fewer carbohydrates so that less pyruvate will build up.

The TCA Cycle

Enter long chain of reactions! All of these happen in the mitochondria.

1. Acetyl CoA and oxaloacetate (a four-carbon molecule) combine to form citrate. Requires citrate synthase.
2. Citrate forms isocitrate with the help of aconitase.
3. Isocitrate forms α-ketoglutarate with the help of isocitrate dehydrogenase. Forms NADH and CO₂.
4. α-ketoglutarate forms succinyl CoA with the help of α-ketoglutarate dehydrogenase. Also forms NADH and CO₂.
5. Succinyl-CoA forms succinate with the help of succinyl-CoA synthetase. Forms GTP.
6. Succinate forms fumarate with the help of succinate dehydrogenase. Forms FADH₂.
7. Fumarate forms malate with the help of fumarase.
8. Malate forms oxaloacetate with the help of malate dehydrogenase. Forms NADH.

Aaaand we're back to the beginning of the cycle!

It should be noted that this cycle is not strictly a cycle: some things can enter at different spots along the way, and some of the substances in the cycle can leave and do their own thing.

It should also be noted that NADH, FADH₂ and GTP don't come out of nowhere. NAD⁺, FAD and GDP are also required for the cycle, providing another mechanism through which the TCA cycle can be regulated.

Electrons carried by NADH and FADH₂ can then enter the electron transport chain in the inner mitochondrial membrane, but that's a subject for a later post.

Draw Pyruvate & Acetyl group of Acetyl CoA.

We have to draw these? I DID NOT SIGN UP FOR THIS SHIT >_>

Drew these on ChemDoodle, with a bit of wrestling with my computer. Enjoy.

Understand the energetics of aerobic metabolism.

Aerobic metabolism produces a net ATP yield of 38 molecules. You see, each molecule of NADH yields 3 ATP after going through the electron transport chain (which I'll talk about in a later post), whereas each molecule of FADH₂ forms 2 molecules of ATP. Hence you get the following:

• Glycolysis: 2 ATP + 2 NADH (x3 = 6ATP) = 8 ATP
• Pyruvate to acetyl CoA: 1 NADH (x3 = 6 ATP) = 3 ATP x 2 (because you get 2 molecules of pyruvate for every molecule of glucose) = 6 ATP
• TCA cycle: 3 NADH (x 3 = 9 ATP) + 1 FADH2 (x 2 = 2 ATP) + 1GTP (=1 ATP) = 12 ATP x 2 = 24 ATP
• 8 + 6 + 24 = total yield of 38 ATP

Know the pathway of glycogen breakdown.

Glycogen can be broken down to glucose in the process of glycogenolysis. I've covered this in more detail in an earlier post: Carbohydrates- Metabolism of Glycogen.