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JOHN ESSIGMANN: Let's Look at Storyboard 17,
Panel A. So far in 5.07, we've looked in detail
at carbohydrate catabolism, we've
seen that the complete catabolism
of a molecule of glucose by way of glycolysis, pyruvate,
dehydrogenase, and the TCA cycle results
in the generation of about 36 to 38 molecules of ATP.
At this point, we're going to turn
to catabolism of another metabolic fuel, lipids.
As we'll see lipids, because they
contain more energy per gram, because they're
more highly reduced than carbohydrates,
will produce much more ATP pundit weight
than carbohydrates.
For example, if we were to metabolize hexanoic acid,
the six carbon hydrocarbon, the same number of carbons
as glucose, we'd get over 50 ATPs rather than
about 35 ATPs per molecule, which
we would have got from glucose.
Now let's look at Panel B. Lipids
have many roles in biological systems.
The first that will be relevant to this lecture
is that there are primary energy reserve.
In fact about 80% of our stored energy is in the form of lipid.
Second, as JoAnne taught us, lipids
are key components of biological membranes,
and thus, they contribute in a major way
to the compartmentalisation that's
critical for normal biological functions.
And the third role is that some lipids are signaling molecules.
The one I've pictured here is Estradiol.
While Estradiol may not look like a typical lipid
it actually is.
Indeed, it's made by a lipid biosynthetic pathway that
starts with Acetyl Coenzyme A. And we'll
see later that Acetyl CoA also serves
as the precursor for the canonical lipid fatty acid.
Fatty acids are the classic lipid.
They're hydrocarbon chains that are fully saturated or contain
a small number of double bonds and sometimes branches.
Sometimes the fatty acid moiety is esterified
to the backbone of glycerol.
If you have three fatty acids on a glycerol backbone, one
to each of the hydroxyl groups, that's
called a triacylglyceride.
That's our primary storage form of energy.
With phospholipids, one of the hydroxyl groups
of the glycerol backbone is esterified to either phosphate
or some kind of decorated phosphate
where the decoration could be a sugar or some other moiety.
As was seen in JoAnne's lecture's, phospholipids
are the key building blocks of biological membrane.
Now take a look at Panel D. The rest of this lecture
will deal with the details of how fatty acids are broken down
to carbon dioxide with the intermediate production
of reducing equivalents in the form of NADH and FADH-2
and ultimately energy equivalence in the form of ATP.
Cells can acquire lipids directly
from the blood where typically they're transported by albumin.
They can come directly from our diet or from other organs
or from breakdown of triacylglycerides
within our cells.
We're going to be looking at four
steps in fatty acid catabolism.
The first step involves the appearance of the fatty acid
in the cytoplasm of the cell.
The fatty acid can come in either from breakdown
of a triacylglyceride stored in the cytoplasm,
or the fatty acid could appear from transport
across the membrane from the blood.
In the cytoplasm, the fatty acid,
which is technically a carboxylic acid,
will be thioesterified to form a fatty Acyl Coenzyme A.
The second step of fatty acid catabolism
involves the transport of the fatty Acyl Coenzyme A ester
into the mitochondrion, which is the site
of fatty acid oxidation.
The third step in fatty acid catabolism
involves the actual oxidation process itself.
The series of reactions is called beta oxidation.
Beta oxidation results in the conversion
of the carboxylic acid starting material to Acetyl Coenzyme A.
There can be several fates to the Acetyl
CoA produced by beta oxidation.
But the one we're going to be looking at
is its entry into the TCA cycle, where the Acetyl CoA is
metabolized to carbon dioxide with the generation of reducing
equivalents.
Those reduced electron carriers have the potential
to be converted into energy currency in the form of ATP.
The fourth topic or stage in fatty acid
catabolism that we'll deal with concerns specialized endings
of the catabolic pathway.
The first problem that we'll look at concerns
the fact that some fatty acids have an odd number of carbons
in them, whereas the classical fatty acid beta oxidation
system was primarily designed to process fatty acids with even
numbers of carbon units.
The second problem that we'll look
at as an ending of fatty acid oxidation
concerns the fact that some of the fatty acids in our diet
have a double bond that is either in the wrong stereo
chemistry or is in the wrong place
to enable easy metabolism.
Nature has worked out ways to reposition the double bond
to facilitate the entry of the molecule
into classical beta oxidation schemes.
Let's look now at Panel E. The first step
in fatty acid catabolism involves thioesterification
of the carboxylate residue of the fatty acid.
We're going to see in a couple of minutes
that placing a Coenzyme A moiety on the carboxylate
is going to enable chemistry at the beta carbon.
Without the Coenzyme A group, chemistry at the beta carbon
would be impossible.
The enzyme involved is called Fatty Acyl Coenzyme
A synthetase, sometimes called ligase.
And it additionally goes by the more common name Thiokinase.
This enzyme uses ATP to adenalate
the carboxalate residue.
And then it allows Coenzyme A to replace the AMP residue
with the resulting product being a fatty Acyl Coenzyme
A. This reaction happens in the cytoplasm of the cell.
Beta oxidation however, is going to occur
in the mitochondrial matrix.
So we have to find a way to get this fatty Acetyl Coenzyme A
into the mitochondrial matrix.
Let's go now to Storyboard 18, Panel A. Panel A
shows the cytoplasm, the mitochondrial outer membrane,
the intermembrane space, the inner membrane,
and the mitochondrial matrix.
As I just said, the matrix is going
to be the site at which beta oxidation occurs.
The intermembrane space contains a small alcohol
called Carnitine.
And the mitochondrial outer membrane
contains an enzyme called Carnitine Acyl Transferase I
or CAT-I.
CAT-I removes the Acyl group from the Fatty Acyl Coenzyme
A in the cytoplasm and transfers it
to the alcoholic residue in the center
of the carnitine molecule forming
an ester of the fatty acid with carnitine.
This ester is delivered to CAT-II,
which is embedded in the inner membrane on the matrix side.
CAT-II will then transfer the Acyl functionality
to a Coenzyme A, restoring the fatty Acyl Coenzyme A molecule.
Thus, CAT-I and CAT-II working in a concerted way,
result in the effective transfer of a fatty Acyl Coenzyme A
from the cytoplasm into the mitochondrial matrix,
the site of beta oxidation, which will be our next step.
Let's now look at Panel B. This panel shows an inset
with the mitochondrial inner membrane, the electron transfer
complex, and ETFP, the electron transferring
flavor protein, which is going to be the entry
point of electrons from the initial step of oxidation
of the Fatty Acyl CoA into the electron transport chain.
We also see in this panel, the fatty acid
polmitate the C-16 Straight Chain Carboxylic Acid.
The hydrogen beta to the Coenzyme A ester
is relatively acidic, therefore this hydrogen
will be taken off to form an alkene.
And the hydride will be transferred
from the beta carbon, the third carbon from the right.
Those electrons are transferred to a flavin
in the electron transferring flavor protein, ETFP.
Eventually, those electrons are transferred to Coenzyme Q
to form the reduced form of Coenzyme Q. Those electrons
then travel along through the electron transport chain.
The Organic product of this reaction
is a trans enoyl Coenzyme A.
Now let's take a look at Panel C. In the next step,
water is added to the 3 Carbon of the enoyl Coenzyme A.
Resulting product is a 3 Hydroxy Fatty Acyl Coenzyme
A. We've seen oxidation of alcohols that looks something
like this many times.
For example, malate being oxidized by malate
dehydrogenase to oxaloacetate.
And as we have seen before, the hydroxyl group
is converted to a keto functionality.
Hydride transfer goes to NAD+ to form NADH.
The enzyme that does this conversion
is 3 Hydroxy Fatty Acyl Coenzyme A Dehydrogenase.
At this point, we have generated one FADH-2 and one NADH
in the overall process of the beta oxidation scheme.
The 3 Keto Acyl Coenzyme A is now
set up to release a first molecule of Acetyl Coenzyme
A. The enzyme beta ketothiolase has a cystine on it.
The thiol of the cystine will attack
the carbon that has the keto group
and release Acetyl Coenzyme A. The residue is
a thioester in which the residual 14
carbons of the polmitate that we started with
are now connected to beta-ketothiolase.
Lastly, beta-ketothiolase will transfer this residual 14
carbons to a Coenzyme A molecule,
forming the Fatty Acyl Coenzyme A
that will be 14 carbons long, that is,
it's two carbons shorter than the 16 carbons of polmitate
that we started with.
Overall, this process is called beta oxidation.
The system is now set up to allow the 14 carbon
molecule to go to 12 to 10 and so on, until the entire 16
carbon hydrocarbon has been reduced through seven
rounds of beta oxidation to eight molecules of Acetyl
Coenzyme A. If these eight molecules of Acetyl CoA
are further oxidized by the TCA cycle,
you'll get 96 ATP molecules.
And of course, along the way, in each round of beta oxidation,
you will also produce seven FADH-2s.
The seven FADH-2s will be converted into 14 ATPs.
You will also get seven NADHs, and they
will be converted into 21 ATPs.
So the full conversion of the 16 carbon hydrocarbon polmitate
will result in a total of 131 ATPs.
In order to put together a full balance sheet,
however, keep in mind that we needed
to use several ATPs early in the process in order
to prime the system.
That is Fatty Acyl Coenzyme A synthetase used 2 high energy
phosphate bonds in order to prime the fatty acid
for production of the Coenzyme A intermediate
that's necessary for beta oxidation.