MCAT

Citric Acid Cycle: MCAT

WRITTEN BY
MEDISTUDENTS TEAM
August 31, 2022

The citric acid cycle is one of many MCAT subjects that you need to be aware of for the MCAT exam. It forms part of the Biological and Biochemical Foundations of Living Systems MCAT section and is essential to revise as part of your MCAT preparation. To support you, we’ve prepared a comprehensive overview of the citric acid cycle for the MCAT exam.

How much of the citric acid cycle should you know for the MCAT?

The citric acid cycle plays a critical part in cellular aerobic respiration, converting citric acid to oxaloacetate over a series of 8 steps. Some texts refer to it as the Krebs cycle or the tricarboxylic acid cycle, and its role is to produce NADH and FADH2 for oxidative phosphorylation. As it is a cycle, after one rotation, citric acid is regenerated, allowing for the cycle to start again.

The following sections provide an overview of the key features of the citric acid cycle for the MCAT.

Acetyl CoA for the MCAT

To help you prepare for the citric acid cycle MCAT topic, the following outlines what you need to know about Acetyl-CoA production.

Production of acetyl-CoA starts with the transport of pyruvate from the cytosol of the cell into the intermembrane space across the outer mitochondrial membrane via an intermembrane transporter called porin. Pyruvate is then transported into the mitochondrial matrix across the inner mitochondrial membrane through facilitated diffusion, using a proton symporter called pyruvate translocase. The pyruvate is then converted into acetyl-CoA using a group of 3 enzymes called the pyruvate dehydrogenase complex, first via decarboxylation (producing CO2), followed by an oxidation reaction (reducing NAD+ into NADH), and finally the addition of coenzyme A. This process, in total named the ‘link reaction’, is irreversible and responds to negative feedback when the concentration of acetyl-CoA is increased. The resulting 2-carbon acetyl CoA enters the citric acid cycle, while NADH is used later in aerobic respiration for the electron transport chain.

Reactions of the cycle, substrates, and products

The citric acid cycle has 8 steps, that work as follows:

  1. Acetyl CoA + oxaloacetate ✇ citrate via citrate synthase
  2. Citrate ✇ isocitrate via cis-Aconitase
  3. Isocitrate ✇ α-ketoglutarate via isocitrate dehydrogenase (reduces NAD+ to NADH, produces CO2). This is the rate liselection-centremiting enzyme.
  4. α-ketoglutarate ✇ succinyl-CoA via α-ketoglutarate dehydrogenase (reduces NAD+ to NADH, produces CO2)
  5. Succinyl-CoA ✇ succinate via succinyl-CoA synthetase (phosphorylates GDP to GTP)
  6. Succinate ✇ fumarate via succinate dehydrogenase (reduces FAD to FADH2)
  7. Fumarate ✇ malate via fumarase
  8. Malate ✇ oxaloacetate via malate dehydrogenase (reduces NAD+ to NADH)

Note: NAD+ and FAD are reduced, so the reactions they are involved in are oxidative reactions.  Reactions where carbon dioxide is produced are decarboxylation reactions.

Figure 1. By Narayanese, WikiUserPedia, YassineMrabet, TotoBaggins. Image adapted from Image: Citric acid cycle noi.svg, CC BY-SA 3.0

Regulation of the cycle

Regulation of the citric cycle is another topic that commonly appears in the MCAT. The following is an overview of what you need to know.

An increase in pyruvate results in an increase in activity of the pyruvate dehydrogenase complex, as it inhibits pyruvate dehydrogenase kinase, which itself inhibits pyruvate dehydrogenase. Conversely, as mentioned before, an increased acetyl CoA:coenzyme A ratio allosterically activates pyruvate dehydrogenase kinase, inhibiting the production of acetyl CoA.

Regulation of the citric acid cycle is non-hormonal; therefore, this process relies on regulation by its substrates, enzymes and cofactors, through allosteric regulation.  The previously mentioned isocitrate dehydrogenase is the rate limiting step of the citric acid cycle. As its cofactor is NAD+, this can be inhibited by a high NADH:NAD+ ratio, as well as competitive inhibition by an increase of ATP.  Although this is the main enzyme involved in regulating the cycle, citrate synthase and α-ketoglutarate dehydrogenase have also been found to have important roles in regulation, though the details of these are not required for the MCAT.

A further regulator of both the link reaction and the citric acid cycle is calcium. Its ion, Ca2+, is important for several metabolic processes throughout the body. Of these, calcium can activate pyruvate dehydrogenase phosphatase, as well as acting as an inhibitor for pyruvate dehydrogenase kinase. These actions both increase pyruvate dehydrogenase activity, therefore stimulating the cycle as a whole. Furthermore, calcium can activate two of the rate-limiting enzymes of the citric acid cycle: isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.

Net molecular and energetic results of respiration processes

In this section, you’ll find key nuggets of information relating to the citric acid cycle that are likely to come up in the MCAT, including NADH, the electron transport chain and the mechanism of the citric acid cycle equation.

The principal product of the citric acid cycle is NADH, which is essential for the function of the electron transport chain. For each rotation of the cycle, 3 NAD+ are reduced to form 3 NADH.

Similarly to NADH, FADH₂ is used in the electron transport chain. There is 1 molecule of FADH₂ produced per rotation of the cycle.

GDP gets phosphorylated by succinyl-CoA synthetase to make GTP through the cycle. The structure and function of GTP is very similar to that of ATP, and these two molecules can be easily converted into each other. Furthermore, ATP has been known to be directly produced in place of GTP at this stage. Therefore, several texts will state that one molecule of ATP is produced during each rotation of the cycle.

The final product to consider with the citric acid cycle is carbon dioxide. This is produced at both the isocitrate dehydrogenase and α-ketoglutarate dehydrogenase stages of the cycle.  As this is a waste product of the cycle, after it is produced, it is excreted into the bloodstream and diffuses into the alveoli to be exhaled.

Therefore, the general equation that is used to describe the mechanism of the citric acid cycle is:

Acetyl-CoA + 3NAD+ + FAD + GDP + Pi → 2CO₂ + GTP + 3NADH + FADH₂

Hopefully this guide has given you an overview of what you need to know about the citric acid cycle for the MCAT and has helped support your MCAT prep. To boost your revision further, and help you to achieve the best MCAT score possible, we have blogs covering a wide range of MCAT topics. You can also find everything you need to know about registering, preparing for and completing the MCAT exam in our MCAT Guide and our handy MCAT Checklist.

References

  • Orsay, J. 2007. MCAT Biology. 7th ed. Osote, pp.20,21.
  • NotesMed.  The Citric Acid Cycle: Functions, Reactions, Regulation, Inhibitors. [Online]. [Accessed 28-06-2022]. Available from: https://notesmed.com/citric-acid-cycle-regulation-html/
  • Le, T. 2020. Biochemistry Metabolism. First Aid for the USMLE Step 1. 30 ed.  McGraw Hill, pp.73, 77.
  • Akram, M. 2014. Citric acid cycle and role of its intermediates in metabolism. Cell Biochem Biophys. 68(3), pp.475-478.
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