Fatty acid synthesis
converted to acetyl-CoA by an enzyme called
 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.
 Lipids come in many forms, including cholesterol,
glycerol, phospholipids, and fatty acids.
 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.
 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
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 citratelyase,
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
 “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.
1. 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.
2. Allosteric regulation: 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.
 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 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.