The Citric Acid Cycle
Have to say, this final CAC lecture was a bit anticlimactic. The animated video provided wasn’t the most illuminating on the subject (IMHO). So, maybe start with this one instead:
The Citric Acid Cycle, a.k.a. Kreb’s Cycle, completes the oxidation of glucose. The major role of CAC is to create a large amount of electron acceptors. It requires oxygen to run.
The cycle is so named because it operates in a loop. Since two pyruvate are generated in glycolysis (thus two Acetyl-CoA), the loop runs twice per original glucose molecule.
- Acetyl-CoA reacts with Oxaloacetate to form Citrate via Citrate synthase. This releases CoA. Oxaloacetate can be converted into one of the 20 amino acids. Citrate synthase is activated by ADP and is inhibited by ATP, NADH, and SCoA. Citrate is a rate-limiting step in glycolysis.
- Citrate isomerizes to Cis-Aconitrate via Acontiase then to Iso-Citrate via iconitase.
- Iso-Citrate is acted on by Isocitrate Dehydrogenase (the removal of hydrogen atoms) to form Oxalosuccinate. In the process NAD picks up two Hydrogen atoms (NADH, H+)–important since they drive the ETC. This is irreversible and is a rate-limiting step for the CAC.
- Oxalosuccinate is acted on by isocitrate dehydrogenase to form Alpha-Ketoglutarate. One molecule of CO2 is produced. This is another TCA intermediate that can be converted into an amino acid– it can be “transaminated” into a glutamate. Any intermediate that can turn into an amino acid can be also be created from that amino acid. So proteins can enter the CAC in some circumstances.
- Alpha-Ketoglutarate is converted via Alpha-Ketogluterate Dehydrogenase Complex into Succinyl-CoA. In this process CoA is added, producing the second CO2 of the cycle. It also produces another NADH molecule and a proton. The Alpha-Ketogluterate Dehydrogenase Complex is inhibited by ATP, GTP, NADH, and Succinyl-CoA. It is activated by calcium. If your muscles contracts, calcium is released, causing the CAC to increase activity to produce the needed energy for those cells. Note that Succinyl-CoA is also a product of (odd chain) FA metabolism and some amino acid metabolism. This provides an alternate way for cells to generate energy, instead of using Glucose to form Acetyl-CoA.
- Succinyl-CoA is acted on by Succinyl-CoA Thiokinase to form Succinate. In the process, GDP picks up a Phosphate to form GTP and the CoA is released.
- Succinate is acted on by Succinate Dehydrogenase to form Fumarate. FAD picks up two protons form FADH2. FADH2 is another critical drivers of the ETC. Succinate Dehydrogenase is the only enzyme in the cycle not found in the mitochondrial matrix. It’s also the only enzyme that participates in both the CAC and the ETC (part of Complex II–explained in the next sections). It’s found in the IMS.
- Fumarate is acted on by Fumarase and converted into L-malate with the consumption of H2O.
- L-malate is acted on by Malate Dehydrogenase to form Oxaloacetate, and thus complete the cycle. This produces the third and final NADH, H+. Note that this is a very energy-intensive (endergonic) step. It’s made possible by coupling this step with Citrate synthase step.
Note that one step is CAC is coupled with the synthesis of GTP by substrate-level phosphorylation. This GTP is later converted into ATP.
Inputs: Acetyl group, 3 NAD+, FAD, ADP, P
Outputs: 2 CO2, 3 NADH, FADH2, ATP, GTP
Mnemonics for CAC:
Mine own attempt:
“Creationists Always Insist On Knowingly Shunning Scientific Facts (on) Man’s Origins”
“Obtuse Creationists Always Insist On Knowingly Shunning Scientifically Factual Material”
Popular mnemonics that skip oxalosuccinate:
“Can I Keep Selling Sex For Money, Officer”
“Our City Is Kept Safe And Sound From Malice”
Word O’ the Day: Anaplerotic— to regenerate CAC intermediates: “to fill up”, as opposed to cataplerotic.
Random MCAT Question…