AssessmentsFatty acid synthesis
Fatty acid synthesis
USMLE® Step 1 style questions USMLE
Biochemistry researchers are studying the pathway of fatty acid synthesis with students in the laboratory. Which of the following is the rate-limiting step of fatty acid synthesis?
Content Reviewers:Rishi Desai, MD, MPH
Fatty foods include red meat, dairy products, and even peanut butter.
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.
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.
All of this leads to the formation of a lot more ATP.
So the math is simple - more glucose, more ATP.
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.
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.