Fatty acid synthesis

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.

Some of that NADPH is generated by malic enzyme when it converts oxaloacetate to pyruvate.

And the rest comes from the metabolism of the excess glucose in a pathway called the pentose-phosphate pathway.

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.