Fatty acid oxidation
Definitions & Key takeaways
Fatty acid oxidation is the process your body uses to break down and uses fatty acids for energy. This process occurs in the mitochondria of your cells. During fatty acid oxidation, a fatty acid is broken down into two molecules of acetyl coenzyme A (CoA). These molecules are then used by the mitochondria to produce energy.
Our bodies are capable of surviving without food for long periods of time, at least 3-4 weeks with hydration! The reason we can do that is that we can store our dietary fuels, and then break them down when needed to make energy in the form of adenosine triphosphate, or ATP.
Fat is one of the most important ways we store energy and the term “burning fat”, actually refers to fatty acid oxidation.
In fact, if two individuals were stranded in the Andes mountains with no food, the person with more fat content would survive longer - yet another reason to avoid working out.What makes fat such a great source of energy are fatty acids, which are the simplest form of fats, composed of long chains of carbon and hydrogens.
The transfer of electrons in the form of hydrogen from these fatty acids to certain molecules, can then be used to generate ATP.
Fatty acid oxidation primarily takes place in the mitochondria of heart, skeletal muscle, and liver cells. Before we can oxidize fat, it needs to be moved from storage sites to the cells that can use it.
Fat is stored in adipocytes or fat cells as triglycerides, which are 3 fatty acids attached to a glycerol molecule. Triglycerides can be broken down by the enzyme hormone sensitive lipase, into free fatty acids and glycerol.
So if you’re starving in the Andes, first your blood glucose level falls. In response, the pancreas secretes a hormone called glucagon which increases the activity of hormone sensitive lipase, and increases the breakdown of triglycerides.
Now, the free fatty acids can leave the fat cell, and enter the bloodstream, where they bind to a protein called albumin.
Albumin carries the fatty acids to target cells, like liver cells, that are capable of fatty acid oxidation. First, the free fatty acid dissociates from albumin and diffuses into the cell.
Once inside the cell, a cytosolic enzyme called fatty acyl-CoA synthetase adds a coenzyme A molecule to the end of the fatty acid, turning it into a metabolically active fatty acyl-CoA.
This process requires 2 ATP molecules - so it takes a little energy to make energy, but it’s totally worth it in the end.Now the mitochondria is composed of two membranes - an outer membrane and an inner membrane, with a small space in between - and the mitochondrial matrix at the core.
The enzymes required for beta oxidation are located in the mitochondrial matrix - however, the fatty acid can’t cross the inner mitochondrial membrane when CoA is attached to it.
To get around this problem, we need to free the CoA from the fatty acid. An enzyme within the outer mitochondrial membrane called carnitine palmitoyltransferase 1, or CPT1 replaces the CoA with a carnitine, making fatty acyl-carnitine and a free CoA, both of which can easily cross the inner mitochondrial membrane.
We can also get more carnitine from our diet, mainly from meat products. Finally, the carnitine shuttle can be regulated by a product of fatty acid synthesis called malonyl-CoA, which specifically inhibits CPT1 slowing down fatty acid oxidation.
After all, you don’t want to make and break fatty acids at the same time.Okay, so fatty acid chains can vary in length, from short, medium, long and very long fatty acids, but the process of fatty acid oxidation is the same for any length.
We’ll explain fatty acid oxidation with an example of a long chain fatty acid: the 16-carbon long palmitoyl-CoA. The enzymatic modifications that take place in fatty acid oxidation happen on the 2nd and 3rd carbon of the chain, also called the alpha and beta carbons, respectively.
Each of those carbons enters fatty acid oxidation with 2 hydrogens bound to it. First, an enzyme called acyl-CoA dehydrogenase removes 1 hydrogen from the 2nd carbon, and one hydrogen from the 3rd.
The same enzyme then gives those 2 hydrogens to a nearby flavin adenine dinucleotide molecule, or FAD, making FADH2, and converting the palmitoyl-CoA to enoyl-CoA in the process.
Enoyl-CoA has only 1 hydrogen on each of the alpha and beta carbons. This is the first oxidation step.
Next, an enzyme called enoyl-CoA hydratase transfers a hydroxyl group, which is an oxygen linked with a hydrogen, from a water molecule on to the beta carbon of enoyl CoA, making beta-hydroxyacyl-CoA.The second oxidation step involves a similar hydrogen transaction mediated by another dehydrogenase called beta-hydroxyacyl-dehydrogenase.
Beta-hydroxyacyl-dehydrogenase removes two hydrogens from the beta carbon, and transfers one of them to a nicotinamide adenine dinucleotide molecule, or NAD+, making NADH and beta-ketoacyl-CoA in the process, and releasing the other hydrogen.
And because this oxidation step occurs at the beta-carbon, fatty acid oxidation is also sometimes called beta-oxidation.Finally, an enzyme called beta-ketothiolase cleaves those 2 alpha and beta carbons off the fatty acid chain, making a 2-carbon acetyl-CoA molecule in the process.
This leaves us with a 14-carbon acyl CoA that can enter another cycle of beta-oxidation. So the longer the fatty acid chain, the more cycles, and the more energy we make.
And in one cycle of beta-oxidation, we made 1 NADH, 1 FADH2 and 1 acetyl-CoA. NADH and FADH2 are now full of electrons, and can enter a mitochondrial pathway called the electron transport chain, where those electrons can be used to make ATP.
1 NADH molecule makes roughly 3 ATPs, while 1 FADH2 molecule makes roughly 2 ATPs. On the other hand, acetyl-CoA can enter the citric acid cycle - which is another metabolic pathway in the mitochondria that burns acetyl-coA to make more NADH and FADH2, which then enter the electron transport chain, yielding a total of 12 ATPs per acetyl-CoA.
So from a 16-carbon palmitoyl-CoA molecule, we make a total of 7 NADH, 7 FADH2 and 8 acetyl-CoA molecules. If we calculate the total ATP yield, we make 131 ATPs.
But remember we consumed 2 ATPs when we first activated fatty-acyl CoA. So per palmitoyl-CoA, we made a net worth of 129 ATP molecules.
That’s a lot of ATP. Told you it was worth it.Now that’s straightforward enough for a fatty acid chain that has an even number of carbons, but the oxidation of a fatty acid with an odd number of carbons can be somewhat different.
So let’s say we’re dealing a 13-carbon fatty acid. Initially, the process of oxidation goes exactly the same, until we reach a 3-carbon fragment called propionyl-CoA.
This is when it gets a bit awkward for the prototypical oxidation enzymes, so to get the job done, we’ll need 3 other enzymes to break it down.
3 reactions for the 3-carbon molecule. First, an enzyme called propionyl-CoA carboxylase adds a carboxyl group to propionyl-CoA, making methylmalonyl-CoA.This enzyme requires 3 cofactors, which can be remembered with a simple “ABC” mnemonic.
“A” for ATP, “B” for biotin, or vitamin B7 and “C” for carbon dioxide, which is the carboxyl group source in this reaction.
Next, an enzyme called methylmalonyl-CoA mutase rearranges the carbons on methylmalonyl-CoA to make succinyl-CoA. This enzyme requires vitamin B12 as a cofactor.
Succinyl-CoA can then enter the citric acid cycle, or it can be used for the synthesis of heme, which is the oxygen binding element in hemoglobin.
Finally, for really long fatty acid molecules that are 22-carbons long or longer, specific organelles called peroxisomes may be needed.
Peroxisomal oxidation works the same way as mitochondrial oxidation, but just has different enzymes that are capable of degrading the long fatty acid chain until it’s under 22 carbons - and then the fatty acids are sent back to the mitochondria to take over.
Alright, a quick recap. Fatty acids are one of the main sources of energy in the body, especially during the fasting state.
Fatty acid oxidation occurs in 3 steps: activation, then transport through the carnitine shuttle, and finally beta-oxidation in the mitochondrial matrix.
energy in the body, especially during the fasting State fatty acid, oxidation to cousin three steps activation and transport through the carnitine Shuffle and finally Pizza oxidation in
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