AssessmentsCitric acid cycle
Citric acid cycle
Content Reviewers:Rishi Desai, MD, MPH
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.
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.
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 a carbon and two oxygens, from pyruvate, and adds coenzyme A, making acetyl-CoA.
In the process two electrons are also transferred to a nearby NAD+, in the form of a hydride ion, making NADH, while the carbon and two oxygens are released to form carbon dioxide or CO2.
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 a carbon and two oxygens from isocitrate.
In the process two electrons are also transferred to a nearby NAD+, in the form of a hydride ion, 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.
Generates energy in the form of GTP, NADH, and FADH2
Occurs in mitochondria
Starts with acetyl-CoA → CO2
Acetyl-CoA + oxaloacetate (via citrate synthase) → citrate + CoA
Citrate (via aconitase) → isocitrate
Isocitrate + NAD+ (via isocitrate dehydrogenase) → α-ketoglutarate + NADH + CO2
- Rate-limiting step
α-ketoglutarate + NAD+ + CoA-SH (α-ketoglutarate dehydrogenase) → succinyl-CoA + NADH + CO2
- Requires five cofactors: thiamine, lipoic acid, CoA, FAD+, NAD+
Succinyl-CoA + phosphate + GDP (via succinate thiokinase) → succinate + GTP
Succinate + FAD+ (via succinate dehydrogenase) → fumarate + FADH2
Fumarate + H2O (via fumarase) → malate
Malate + NAD+ (via malate dehydrogenase) → oxaloacetate + NADH
- Oxaloacetate then enters next cycle
Generates one GTP molecule, three NADH molecules, one FADH2 molecule