Energy is essential to cellular function and we can get this energy by metabolizing carbohydrates, proteins, and fats. The Kreb's Cycle (also known as the TCA Cycle & Citric Acid Cycle) is a critical component for macronutrient metabolism and energy conversion for all 3 of these nutrients. The complete metabolism for each of them must, at some point, go through the Kreb's Cycle. For a more indepth discussion of this pathway, keep reading.
The Kreb's cycle takes place in the mitochondria of the cell. It was named for the chemist and Nobel Prize winner (1953), Hans Krebs. This cycle is a series of chemical intermediates that are transformed to another intermediate by enzymes specific to that step in the cycle. Each step is catalyzed by a specific enzyme. The cycle starts with oxaloacetate and ends with oxaloacetate. The cycle produces 1 ATP, 3 NADH, and 1 FADH2 per turn. If you recall from glycolysis, two pyruvates are produced per molecule of glucose. Pyruvate is converted to acetyl CoA which enters the Kreb's cycle. Therefore, one molecule of glucose eventually creates 2 turns of the krebs cycle.
Some amino acids can enter at different steps in the Kreb's cycle. During the metabolism of odd chain fatty acids, one three carbon molecule remains at the end. It enters the Kreb's cycle at the Succinyl CoA step. Thus, the Kreb's cycle is very important for energy production from all food supplies.
Also, keep in mind that I have divided these steps based on a number of sources. Different sources divide these steps differently. They may even add other intermediates. I have tried to keep these steps as simple as possible and only expand on the areas that are important in understanding the process. Others may argue that other areas are also important and they may be right but this is my site and not theirs. Again, I hope this helps.
The first step in the Krebs Cycle is the formation of citrate from the combination of oxaloacetate and Acetyl CoA. The acetyl group from acetyl CoA is added to oxaloacetate forming citrate via the enzyme citrate synthase. The CoA from acetyl CoA leaves as CoASH. Not much else occurs at this step. Citrate inhibits citrate synthase (product inhibition). So does succinyl CoA by competitive inhibition.
Citrate is converted to isocitrate by the action of aconitase. Again, not much occurs here.
Isocitrate DH acts on isocitrate, converting it to α-ketoglutarate, producing an NADH and CO2 in the process. The carbon that forms CO2 comes from the acetyl group that enters the cycle. This is our first yield from the Kreb's cycle. The removal of carbon dioxide is termed oxidative decarboxylation (if anyone cares!).
NADH inhibits isocitrate DH (product inhibition). NADH product inhibition provides control over three steps in the Kreb's cycle. Since there are only 4 controlled steps in Kreb's, NADH is an important control mechanism. This step is also controlled (enhanced) by increased ADP and calcium.
This is a pretty big and important step. The α-ketoglutarate DH complex acts upon α-ketoglutarate ultimately forming Succinyl CoA. This enzyme complex is described in fair detail in the pyruvate to acetyl CoA step. However, it should be noted that the α-ketoglutarate DH complex is just one of a family of enzymes that oxidatively decarboxylate these a-keto acids. There is an oxidative decarboxylation occuring here (the 2nd carbon from the acetyl entering the Kreb's). In other words, CO2 is released. CoASH is needed and NADH is also produced. Some amino acids (BCAA's) and the 3-carbon molecule remaining after beta oxidation of odd chain fatty acids enter the Kreb's Cycle at this step by being acted upon by this enzyme complex.
NADH inhibits this enzyme complex (as described previously). As NADH concentrations increase, the Kreb's cycle slows down.
All of the remaining intermediates in the Kreb's cycle are four carbon molecules.
This step produces NADH and allows other energy sources (such as AA's and fatty acids) to enter here.
The CoASH that went into step 4 comes off here. Succinate thiokinase acts upon succinyl CoA removing the CoASH and forming succinate. The energy from its release fuels the formation of GTP. Some would say that the GTP fuels the conversion of ADP to ATP (that's where we get the ATP discussed in the overview).
Two pairs of electrons from the acetyl group of acetyl CoA remain even though the carbons have been removed as carbon dioxide. The remaining steps in the Kreb's cycle are transferred to NAD+ and FAD and ultimately reforming oxaloacetate.
In this step, succinate DH acts upon succinate forming fumarate and converting FAD to FADH2. The FAD accepts one of the pairs of electrons that remain. Now only one pair of electrons from the original acetyl group remain in fumarate.
Succinate DH resides within the inner mitochondrial membrane. It binds FAD fairly tightly. All of the other enzymes involved in the Kreb's cycle are located in the mitochondrial matrix.
The only thing that happens in this step is that water is added to fumarate. The enzyme fumarase adds a hydroxyl group and a proton (from the water) to fumarate converting it to malate.
This is the final step of the Kreb's cycle. It is the final step because the intermediate that we added acetyl CoA to, oxaloacetate, is reformed. The final pair of electrons from the original acetyl group are donated to NAD+ forming NADH. The enzyme that catalyzes the reaction is malate DH.
NADH inhibits this step.
In case I haven't mentioned it earlier, there are five co-enzymes needed for the Kreb's cycle to function properly. They have been mentioned in the steps but I didn't specifically point them out (as I will do now). They are: NAD+, FAD, thiamine pyrophosphate, lipoate (lipoic acid), and CoA.
As mentioned earlier, other molecules (such as fats and amino acids) can enter the Kreb's cycle at different locations to produce energy. For example, during periods of long-duration, low to moderate-intensity exercise (aerobic), beta-oxidation of odd-chain fatty acids may enter the Kreb's at the alpha-ketoglutarate DH step. However, when these products must be synthesized, these intermediates have to be pulled out of the cycle. Citrate and malate may be pulled out of the cycle for product synthesis. This would result in a deficiency of the 4-carbon intermediates. Fortunately, there are reactions that re-supply these intermediates. They are called anaplerotic reactions. An example of one of these reactions is the conversion of pyruvate and carbon dioxide to form oxaloacetate. The enzyme that catalyzes this reaction is pyruvate carboxylase. This enzyme must have biotin in order for it to function properly.