Energy metabolism Part 13 - How does the body synthesize fatty acids?
Have you ever wondered how and why all that sugar in cake lands as fat on your hips?
Well, this deposit of fat serves well as an energy store, because fats have the highest
energy density.
Namely, fat weighs significantly less compared to carbohydrates in terms of storing an identical
amount of energy.
That's why it makes sense to convert excess carbohydrates into fats, mainly palmitic and
stearic acid.
Fatty acid synthesis can occur in almost all of the body’s cells when there’s excess
energy.
However, it primarily takes place in the liver, adipose tissue, and during lactation as well
as in mammary glands.
At a molecular level, excess energy is a surplus of acetyl-CoA or citrate.
Do you remember episode 6 of our energy metabolism course?
Here's a quick reminder: Acetyl-CoA is formed by the breakdown of fats and sugars and is
converted to citrate in the first step of the citric acid cycle.
The following reaction step, the conversion of citrate into isocitrate, is the bottleneck
of the citric acid cycle.
That's why an excess of energy leads to an accumulation of citrate and subsequently,
of acetyl-CoA.
In terms of glucose metabolism, episode 10 of this course showed us that gluconeogenesis
isn’t just the reversal of glycolysis.
The same applies to fatty acid synthesis.
It’s not catalyzed by the enzymes of beta-oxidation, so it isn’t merely the inversion of it.
Both metabolic pathways differ through a few important aspects:
The first difference lies in the site of metabolism.
Fatty acid degradation occurs mainly in the mitochondrial matrix, whereas fatty acid synthesis
takes place in the cytosol.
Consequently, excess acetyl-CoA or citrate from the citric acid cycle needs to be transported
from the mitochondria to the cytosol.
This transport is mediated by the citrate shuttle in the inner mitochondrial membrane.
In the cytosol, acetyl-CoA is restored from citrate.
However, the energy required per acetyl-CoA molecule is one ATP, which we’ll add to
the energy balance.
The second difference concerns the molecular units used in metabolism.
Beta-oxidation forms acetyl-CoA, a two carbon unit.
In fatty acid synthesis, acetyl-CoA only functions as a starter molecule.
For extending the fatty acid chain, the C3 unit malonyl-CoA is used.
The required conversion of acetyl-CoA to malonyl-CoA is catalyzed by acetyl-CoA carboxylase.
In this two-step reaction, the C1 unit carbon dioxide, or more precisely the carbonate formed
from it, is initially activated by ATP and then bound to the C2 unit acetyl-CoA.
Let’s include this additional ATP molecule in the energy balance.
At this stage, there are two important points to remember: First, malonyl-CoA inhibits carnitine
palmitoyltransferase 1, which is part of the carnitine shuttle and plays an important role
in fatty acid degradation.
This prevents the breakdown of newly formed fatty acids.
Second, the formation of malonyl-CoA by acetyl-CoA carboxylase is the rate-limiting step in fatty
acid synthesis.
The enzyme is subject to hormonal and allosteric regulation: Glucagon, epinephrine in carbohydrate
deficiency or increased physical activity, and palmitoyl-CoA as an indicator of an adequate
supply of free fatty acids inhibit acetyl-CoA carboxylase.
Yet, citrate indicates an excess of energy and, therefore, acts as an activator.
The third characteristic of fatty acid synthesis is that all reaction steps are performed by
only one enzyme complex, fatty acid synthase.
The growing fatty acid chain remains anchored to the enzyme during the entire process.
This ensures that fatty acid build-up doesn’t stop before reaching the desired chain length.
At the beginning of the process, each malonyl unit used to build the fatty acid is attached
to an acyl carrier protein, abbreviated ACP.
This, in turn, binds to fatty acid synthase.
Now, let’s move on to a rough description of the steps of fatty acid synthesis.
If you’d like to see molecular structures with the names of the substances, click on
Dieter’s red molecule.
You can hide the structures at any time by clicking on the molecule again.
At the beginning of fatty acid synthesis, an acetyl unit is attached to the enzyme as
a starter molecule.
Malonyl units are bound to it via four steps each.
The underlying reaction strategy of the elongation reflects the reverse steps of beta-oxidation.
These are shown on the right side of the slide for comparison.
So, fatty acid synthesis comprises the addition of the two units, a first reduction from a
ketone to an alcohol, the cleavage of water resulting in the formation of a double bond,
followed by a second reduction of the double bond to a single bond:
During the addition of the malonyl unit, CO2 is cleaved, generating a 3-ketoacyl-ACP intermediate.
As a result, the fatty acid is elongated by only two carbon atoms per condensation step,
despite using a C3 unit.
This explains how palmitic acid, with its 16 carbon atoms, can be one of the main products
of fatty acid synthesis.
To synthesize a fatty acid with an odd number of carbon atoms, propionyl-CoA is used instead
of acetyl-CoA as the starting molecule.
By the way, propionyl-CoA is also the last unit remaining in the breakdown of odd-numbered
fatty acids.
The electrons and protons for the subsequent reduction stem from the reducing equivalent
NADPH and H+.
It functions in the same manner as NADH and H+ and can transfer two protons and two electrons.
The only difference between the two reducing equivalents is a phosphate group in NADPH
and H+, positioned in a part of the molecule not involved in the redox reaction.
To help you tell the two reducing equivalents apart, you can use the following rule of thumb:
NADH and H+ primarily plays a role in catabolic processes, in contrast to NADPH and H+ for
anabolic processes.
Let’s also place NADPH and H+ in our energy balance.
The product of the first reduction is 3-hydroxyacyl-ACP that contains a OH group, which can be cleaved
as part of a water molecule in the next reaction.
A trans-delta-2-enoyl-ACP with a double bond is formed.
Through a second reduction using NADPH and H+, acyl-ACP is formed, elongating the previously
existing molecule by two carbon atoms.
The cycle can now start again in which the continuously growing acyl-ACP chain replaces
the starter molecule.
Please note that the fatty acid synthase reaction doesn’t require ATP.
Yet, each chain elongation by two carbon atoms requires two molecules of ATP; one to translocate
acetyl-CoA to the cytosol and one for the formation of malonyl-CoA.
In addition, two NADPH and H+ are required each for the reduction steps.
Also, a further molecule of ATP is required per fatty acid that is built.
It’s needed for the transport of the starter molecule acetyl-CoA.
So, the most important product of fatty acid synthesis, palmitic acid with its 16 carbon
atoms, requires 15 ATP and 14 NADPH and H+ for transport processes and the reactions
catalyzed by fatty acid synthase.
Usually, food provides a sufficient amount of fatty acids, so the body doesn’t have
to rely on producing them for its requirements.
Therefore, fatty acid synthesis is mostly inhibited.
Though, in times of an increased need for fatty acids, for example, during lactation,
their synthesis is stimulated.
Although the mammary glands synthesize fatty acids, they’re also supplied with fatty
acids from other tissues via the blood.
However, fatty acids are a compact means of storing energy if there’s a caloric surplus.
In lipogenesis, the fatty acids are converted into triglycerides and stored in adipose tissue.
So, that’s how that piece of cake ends up landing on the hips.
Well, that was just a brief overview of fatty acid synthesis.
Let's summarize the most important points again:
Fatty acid synthesis occurs in the cytosol, especially within hepatocytes and adipose
tissue.
In fatty acid synthesis, acetyl-CoA is converted to malonyl-ACP, from which fatty acids, especially
palmitic and stearic acid, are formed.
The malonyl-CoA units are bound to the growing fatty acid chain in a four-step procedure.
The reaction strategy corresponds to reversed beta-oxidation and consists of an addition,
first reduction, dehydration reaction, and second reduction.
Elongation of the fatty acid by two carbon atoms requires a total of 2 ATP and 2 NADPH
and H+.
The rate-limiting step of fatty acid synthesis is the conversion of acetyl-CoA to malonyl-CoA
by acetyl-CoA carboxylase.
It can be inhibited by glucagon, epinephrine, and palmitoyl-CoA, and activated by citrate.
Would you like to test your knowledge of fatty acid synthesis in a quiz?
Then stay put for the next slide.