Citric acid cycle

Definitions & Key takeaways

The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a series of chemical reactions in aerobic organisms' cells. The TCA cycle generates energy in the form of ATP from nutrients able to give acetyl-CoA molecules. These include carbohydrates, lipids, alcohol, and ketogenic amino acids. Molecules.

The citric acid cycle begins with pyruvate oxidation to acetyl-CoA by the enzyme pyruvate dehydrogenase. Acetyl-CoA is then transported into the mitochondrial matrix and enters the TCA cycle, where it is oxidized by succinyl-CoA synthase to succinyl-CoA, which is then oxidized by Succinate dehydrogenase to fumarate. Fumarate is then hydrated by fumarase to malate, and malate is oxidized by malate dehydrogenase to oxaloacetate. Oxaloacetate is then reduced by phosphoenolpyruvate carboxykinase to phosphoenolpyruvate. Phosphoenolpyruvate is then dehydrogenated by pyruvate kinase to pyruvate.

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For cells to perform any function, any work, they must have energy. You can’t go jogging or lifting weights if you’re tired, because a cell won’t work without the help of chemical energy.
The main energy currency in the cells is adenosine triphosphate, or ATP, but any nucleoside triphosphate, like guanosine triphosphate, GTP, will do.
For cells to make ATP, a process generating electricity has to take place in our mitochondria. Electricity is power!
And thanks to this electricity, ATP is made. Now to create electricity, electron rich molecules must deliver electrons to a chain of complexes, the electron transport chain, which move them to a final acceptor, a molecule of oxygen.
And there are two electron donor molecules: nicotinamide adenine dinucleotide, or NADH, and flavin adenine dinucleotide, or FADH2.
But of course, the cell has to produce NADH and FADH2 in the first place, and they’re produced by critical enzymes called dehydrogenases.
Dehydrogenases are the main enzymes found in the citric acid cycle or Kreb’s cycle. In fact, the citric acid cycle is a set of 8 enzymatic reactions that start with a molecule called acetyl-CoA, and four of the enzymes, half of them, are dehydrogenases.
And in this process, AcetylCoA gets converted into carbon dioxide. Acetyl-CoA comes from various sources depending on whether you’ve just eaten or are starving.
Let’s say that you’re hungry and a bit angry - so you’re feeling hangry. That’s when stress hormones like glucagon, epinephrine, and cortisol start to rise.
In this hangry state, fatty acids from triglycerides become the primary source of acetyl-CoA. Now, let’s say you have a bowl of delicious French onion soup, everything changes - insulin is plentiful and you have plenty of acetyl-CoA from breaking down glucose, fructose, and galactose -with glucose playing the biggest role.
Now, alcohol is also a source of Acetyl-CoA in the liver where it’s metabolized. In addition, proteins can also help contribute to acetyl-CoA production.
But in the case of glucose, after a meal, one glucose, a 6-carbon molecule, splits into two 3 carbon pyruvate molecules through glycolysis, which occurs in the cytoplasm of the cell.
Each of the pyruvate molecules then enter the mitochondria. In the mitochondria, an enzyme called pyruvate dehydrogenase snatches an electron and a carbon and two oxygens, from pyruvate, and adds coenzyme A, making acetyl-CoA.
The electron goes to a nearby NAD+, making NADH, while the carbon and two oxygens are released to form carbon dioxide or CO2.
This step links glycolysis to the citric acid cycle, but really isn’t considered part of either process. Yet, it is a source of NADH and CO2 and shares some similarity with enzymes of the citric acid cycle.
As we go through the citric acid cycle, we’ll keep track of our total GTP, NADH, FADH2, and CO2 count with these energy counters.
And remember that this cycle has many dehydrogenases. Okay, citric acid cycle starts when acetyl-CoA is joined to a 4-carbon molecule called oxaloacetate by an enzyme called citrate synthase, making a 6-carbon molecule - citrate.
This process also releases coenzyme A. Next, another enzyme, aconitase, rearranges the chemical shape of citrate to make its isomer, isocitrate, without adding or removing any carbon molecules.
So far we haven’t made anything related to energy. But here comes the first dehydrogenase, called isocitrate dehydrogenase, which removes an electron and a carbon and two oxygens from isocitrate.
The electron goes to a nearby NAD+, making our first NADH, and the carbon and oxygens give us our first CO2, leaving us with a 5-carbon molecule called alpha ketoglutarate.
High levels of ATP and NADH in the cell can inhibit isocitrate dehydrogenase, signaling the cycle to slow down since the cell has plenty of energy.
On the other hand, high levels of ADP, an ATP precursor, stimulate this enzyme, signaling the cycle to speed up since the cell needs more energy.
In fact, isocitrate dehydrogenase is considered the rate-limiting step of the cycle! And you remember that jogging we wanted to do?
Well, calcium levels rise during muscle contraction, and contraction is work and requires energy. And as it turns out - calcium also activates the enzyme isocitrate dehydrogenase.
Next, another dehydrogenase called alpha ketoglutarate dehydrogenase converts the 5-carbon alpha-ketoglutarate to the 4-carbon succinyl-CoA, releasing our 2nd molecule of NADH and CO2 in the process.
Now, this enzyme requires 5 sidekicks called cofactors to function. You can remember them by the first letters of mnemonic: T-rex Loves and Cares For Nachos.
“T” for thiamine, or vitamin B1. “L” for lipoic acid.
“C” for coenzyme A also called vitamin B5 or pantothenate. “F” for FAD+ also called vitamin B2 or riboflavin, and “N” for NAD+ also called vitamin B3 or niacin.
`So adequate intake of these vitamins is essential, because deficiencies can disrupt the citric acid cycle, and impact overall health as a consequence.
For example, thiamine deficiency can lead to a disease called beriberi, in which the central nervous system and then the heart can’t work properly.
Likewise, niacin deficiency can cause a disease called pellagra, characterized by 4 “D”s: diarrhea, dermatitis, dementia and, if the deficiency isn’t corrected, it can cause death.
Yikes. But let’s say that the cycle is working properly, then the next step is that an enzyme called succinate thiokinase removes the CoA from succinyl CoA, turning it into a 4-carbon succinate molecule.
It also uses couples a phosphate and GDP molecule to the reaction, making making GTP. Alright, next, the enzyme succinate dehydrogenase takes an electron from succinate and gives it to FAD+, making fumarate and FADH2 in the process.
This time, we’re using FAD+ instead of NAD+ because succinate is kind of greedy and holds onto its electron tightly. Luckily for our cycle, FAD+ fights harder for the electron than NAD+, and is able to snag those powerful electrons.
Also, it’s worth knowing that succinate dehydrogenase is already part of the electron transport chain, and it goes by the name Complex II.
Next, an enzyme called fumarate hydrase or simply fumarase adds a water molecule to fumarate, making malate. Malate is then converted to oxaloacetate by the enzyme malate dehydrogenase, making our 3rd and final NADH in the process.
So now we’ve come full circle, Oxaloacetate can then join up with another new acetyl-CoA molecule that’s just hanging around waiting to begin a new cycle.
The control of the citric acid cycle is based on energy level of the cell. It has to run all the time!
So when it needs more energy, it speeds up, and when it has enough energy, it slows down. Hormones don’t play a role in its regulation.
Alright, a quick recap. So in the end, from one acetyl-CoA molecule, we’ve made three NADH, one FADH2, one GTP and two CO2.
The CO2s leave the cell and are transported in the blood as bicarbonate thanks to enzymes called carbonic anhydrases. They’re exhaled by the lungs.
In the electron transport chain, each NADH makes 3 ATPs, and each FADH2 makes 2 ATPs. Our 1 GTP yields the energy equivalent of 1 ATP.
And so, we make a total of 12 ATP molecules per acetyl-CoA. And since one glucose molecule splits into 2 pyruvates, each glucose molecule yields 24 ATP in the citric acid cycle.