Fatty acid synthesis
Definitions & Key takeaways
Fatty acids are one of the essential forms of energy storage. The biosynthesis of fatty acids is a multi-step process in the cytoplasm, mainly of the liver and fat cells. The process takes place in three major steps: the citrate shuttle, acetyl-CoA carboxylase (the rate-limiting step), and fatty acid synthase complex.
In addition to carbohydrates and proteins, lipids are the third main macromolecule we consume in our diet. Fatty foods include red meat, dairy products, and even peanut butter.
And lipids come in many forms, including cholesterol, glycerol, phospholipids, and fatty acids. Of these, fatty acids are the simplest form of lipids - they’re basically just long chains of carbon and hydrogen, that are grouped by length into short, medium, long and very long chain fatty acids.
Fatty acids can also combine with glycerol to make triacylglycerides, which is made of 3 fatty acids attached to a glycerol molecule, and is the main storage form of fat in our body.
Now, short and medium-chain fatty acids are primarily obtained from the diet, but the liver and fat cells can synthesize long chain fatty acids.
This occurs by combining lots of 2-carbon molecules, called acetyl-coenzyme A or acetyl-CoA, into a single 16-carbon, long chain fatty acid called palmitoyl-coenzyme A, or palmitoyl-CoA.
Palmitoyl-CoA can then serve as a precursor to even longer chain fatty acids. To make palmitoyl-CoA, acetyl-CoA provides the carbon atoms, and nicotinamide adenine dinucleotide phosphate, or NADPH provides the hydrogen atoms.
As it turns out, most of the acetyl-CoA used to make fatty acids comes from carbohydrate metabolism - specifically glucose, which is a 6-carbon sugar molecule.
After eating a glucose-rich dinner, like cake and cookies, glucose levels in the blood rise quickly. In response, the pancreas secretes insulin, a hormone which makes our cells take in and process a lot more glucose.
Inside the cells, glucose can enter glycolysis where it’s broken down into two 3-carbon pyruvate molecules, and that yields a bit of energy in the form of adenosine triphosphate - or ATP.
Pyruvate then moves into the mitochondria, and is converted to acetyl-CoA by an enzyme called pyruvate dehydrogenase. Inside the mitochondria, acetyl CoA enters the citric acid cycle by combining with a molecule called oxaloacetate, to form citrate.
Citrate can then continue in the citric acid cycle, which generates electron carriers that can join the electron transport chain and oxidative phosphorylation.
All of this leads to the formation of a lot more ATP. So the math is simple - more glucose, more ATP.
Well, ATP inhibits some enzymes in the citric acid cycle, slowing it down overall, and that means that extra acetyl-CoA can be used to make fatty acids instead.
However, the enzymes required for fatty acid synthesis are all in the cytoplasm, so in order to start fatty acid synthesis, acetyl-CoA needs to get out of the mitochondria.
Unfortunately, acetyl-CoA cannot cross the mitochondrial membrane - so to get to the cytoplasm, it combines with oxaloacetate to form citrate, just as it would to enter the citric acid cycle.
So when there’s a lot of ATP around, citrate crosses the mitochondrial membrane and enters the cytoplasm. In the cytoplasm, an enzyme called citrate lyase, cleaves citrate back into acetyl-CoA and oxaloacetate.
This process of conversion and reconversion is called the citrate shuttle. In the meantime, oxaloacetate is recycled and goes back into the mitochondria so it can be available the next incoming acetyl-CoA.
But we have another problem; oxaloacetate can’t cross the membrane either. So an enzyme called malic enzyme, converts oxaloacetate into pyruvate, forming NADPH from NADP+ in the process.
Now, pyruvate can cross the mitochondrial membrane, and an enzyme called pyruvate carboxylase converts it back into oxaloacetate, which can begin a new cycle.
High levels of acetyl-CoA also increase the activity of pyruvate carboxylase, so that oxaloacetate is made available. With acetyl-CoA in the cytoplasm, all we need to begin fatty acid synthesis is NADPH to provide the hydrogens.
Once there’s enough NADPH, acetyl-CoA can begin its journey towards palmitoyl-CoA. Ok, so first, a carboxyl group is added to acetyl-CoA by an enzyme called acetyl-CoA carboxylase, converting it to the 3-carbon malonyl-CoA.
This enzyme requires 3 cofactors, which can be easily remembered with the mnemonic, ABC. “A” is for ATP, “B” is for biotin, or vitamin B7, and “C” is for carbon dioxide, or CO2, which is the carboxyl group source.
However, this additional carbon will not contribute to the fatty acid chain, because it’s lost later on. This is considered the rate-limiting step of fatty acid synthesis.
Which means that the speed of this reaction will determine the overall rate at which all of fatty acid synthesis happens - so acetyl CoA carboxylase is tightly regulated.
There are two types of regulation - hormonal regulation and allosteric regulation. Hormonal regulation involves the pancreatic hormones insulin and glucagon - and they work by adding or removing a phosphate group on acetyl CoA carboxylase.
When insulin is released, like after that cake and cookie bonanza, it activates the enzyme protein phosphatase 2, which removes a phosphate group from acetyl-CoA carboxylase increasing its activity.
On the other hand, when glucagon is released like when you’re fasting, it activates an enzyme called adenosine monophosphate, or AMP-dependent kinase, which adds a phosphate group to acetyl-CoA carboxylase decreasing its activity.
So glucagon basically “handcuffs” the enzyme, and insulin sets it free. This makes sense since you want to break down fatty acids for energy when you’re fasting, not use energy to build them up from scratch.
The other type of regulation is allosteric regulation, and that’s when a molecule increases or decreases the activity of an enzyme by binding to a different site on the enzyme than the site where the substrate binds.
Citrate allosterically increases the activity of acetyl-CoA carboxylase, while fatty acids allosterically inhibit it, signaling that we have enough fatty acids and we don’t need to make more.
Alright, here comes the nitty gritty part. In order to polymerize our acetyl-CoA monomers, we need an enzyme complex called the fatty acid synthase complex.
Overall, the enzyme complex is made up of lots of different enzymes and looks a bit like a kidney bean. The complex has two separate binding domains at each end of the bean; on one end there’s an acyl carrier protein, or ACP, and on the other end there’s an enzyme that has a cysteine amino acid in a very exposed position.
The ACP is where acetyl-CoAs and malonyl-CoAs bind initially, and the cysteine amino acid residue is where they hop on board the growing lipid.
It all starts, when an enzyme that’s part of the fatty acid synthase complex called acetyl-CoA ACP transacylase removes a CoA group from an acetyl-CoA molecule.
The enzyme then attaches the 2-carbon molecule acetate to ACP, and then acetate spontaneously hops on to the cysteine residue.
Now that acetate is bound to the cysteine residue, the ACP residue is empty. So it’s time to bring over that initial malonyl-CoA that we made in the first step of fatty acid synthesis.
Once more, there’s an enzyme that’s part of the fatty acid synthase complex called malonyl-CoA ACP transacylase which removes a CoA group from the malonyl-CoA molecule.
The enzyme then attaches the 3-carbon molecule malonate to the ACP group. So now we have a 2-carbon acetate on the cysteine end, and a 3 carbon malonate on the ACP end.
At this point, another enzyme in the fatty acid synthase complex called 3-ketoacyl-ACP synthase does two important things.
First, it cuts off the carbon that acetyl-CoA carboxylase previously added and releases it as CO2, leaving behind a 2 carbon acetate.
Then, 3-ketoacyl-ACP synthase moves this acetate and condenses it with the acetate molecule attached to the the cysteine group.
2-carbons on top of 2-carbons gives us a 4-carbon fatty acid chain attached to the cysteine group. These two reactions require hydrogen from 2 NADPH molecules.
This cycle repeats again when the next incoming malonyl-CoA molecule attaches to the free ACP group. And it happens for 7 cycles until we’ve got a 16-carbon long fatty acid polymer.
Per cycle, we need 1 acetyl-CoA to be converted to malonyl-CoA, and 2 NADPH molecules. But in the first step, we placed an additional acetate molecule on the ACP group, instead of converting it to malonyl-CoA.
So, summing it up: to make the 16-carbon palmitoyl-CoA, we need a total of 8 acetyl-CoAs and 14 NADPH molecules. Once the fatty acids are made, they’re stored in the liver and fat cells as triacylglycerides, and when they’re needed, they can be broken down in order to make ATP.
Alright, a quick recap. Fatty acids are energy-rich carbon compounds that are synthesized in the cytoplasm of liver and fat cells and are regarded to be one of the main forms of energy storage.
Fatty acid synthesis is the conversion of 2-carbon acetyl-CoA molecules into the 16-carbon palmitoyl-CoA, in the presence of NADPH.
The 3 major steps of fatty acid synthesis are the citrate shuttle, acetyl-CoA carboxylase, which is the rate-limiting enzyme, and finally the fatty acid synthase complex.
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