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JOHN ESSIGMANN: Let's
Look at Storyboard 17,

00:00:22.980 --> 00:00:27.030
Panel A. So far in 5.07,
we've looked in detail

00:00:27.030 --> 00:00:29.430
at carbohydrate
catabolism, we've

00:00:29.430 --> 00:00:31.620
seen that the
complete catabolism

00:00:31.620 --> 00:00:35.200
of a molecule of glucose by
way of glycolysis, pyruvate,

00:00:35.200 --> 00:00:37.860
dehydrogenase, and
the TCA cycle results

00:00:37.860 --> 00:00:42.324
in the generation of about
36 to 38 molecules of ATP.

00:00:42.324 --> 00:00:43.740
At this point,
we're going to turn

00:00:43.740 --> 00:00:47.130
to catabolism of another
metabolic fuel, lipids.

00:00:47.130 --> 00:00:48.900
As we'll see
lipids, because they

00:00:48.900 --> 00:00:51.660
contain more energy per
gram, because they're

00:00:51.660 --> 00:00:53.940
more highly reduced
than carbohydrates,

00:00:53.940 --> 00:00:56.880
will produce much
more ATP pundit weight

00:00:56.880 --> 00:00:58.320
than carbohydrates.

00:00:58.320 --> 00:01:01.160
For example, if we were to
metabolize hexanoic acid,

00:01:01.160 --> 00:01:04.690
the six carbon hydrocarbon,
the same number of carbons

00:01:04.690 --> 00:01:08.130
as glucose, we'd get
over 50 ATPs rather than

00:01:08.130 --> 00:01:10.860
about 35 ATPs per
molecule, which

00:01:10.860 --> 00:01:13.150
we would have got from glucose.

00:01:13.150 --> 00:01:15.000
Now let's look at
Panel B. Lipids

00:01:15.000 --> 00:01:18.160
have many roles in
biological systems.

00:01:18.160 --> 00:01:20.190
The first that will be
relevant to this lecture

00:01:20.190 --> 00:01:22.740
is that there are
primary energy reserve.

00:01:22.740 --> 00:01:27.480
In fact about 80% of our stored
energy is in the form of lipid.

00:01:27.480 --> 00:01:29.940
Second, as JoAnne
taught us, lipids

00:01:29.940 --> 00:01:32.540
are key components of
biological membranes,

00:01:32.540 --> 00:01:34.710
and thus, they
contribute in a major way

00:01:34.710 --> 00:01:36.780
to the
compartmentalisation that's

00:01:36.780 --> 00:01:40.410
critical for normal
biological functions.

00:01:40.410 --> 00:01:44.580
And the third role is that some
lipids are signaling molecules.

00:01:44.580 --> 00:01:46.980
The one I've pictured
here is Estradiol.

00:01:46.980 --> 00:01:50.220
While Estradiol may not
look like a typical lipid

00:01:50.220 --> 00:01:51.030
it actually is.

00:01:51.030 --> 00:01:54.660
Indeed, it's made by a lipid
biosynthetic pathway that

00:01:54.660 --> 00:01:57.570
starts with Acetyl
Coenzyme A. And we'll

00:01:57.570 --> 00:01:59.940
see later that Acetyl
CoA also serves

00:01:59.940 --> 00:02:04.850
as the precursor for the
canonical lipid fatty acid.

00:02:04.850 --> 00:02:07.350
Fatty acids are
the classic lipid.

00:02:07.350 --> 00:02:11.580
They're hydrocarbon chains that
are fully saturated or contain

00:02:11.580 --> 00:02:15.800
a small number of double
bonds and sometimes branches.

00:02:15.800 --> 00:02:18.380
Sometimes the fatty acid
moiety is esterified

00:02:18.380 --> 00:02:20.360
to the backbone of glycerol.

00:02:20.360 --> 00:02:24.250
If you have three fatty acids
on a glycerol backbone, one

00:02:24.250 --> 00:02:26.180
to each of the
hydroxyl groups, that's

00:02:26.180 --> 00:02:28.160
called a triacylglyceride.

00:02:28.160 --> 00:02:32.030
That's our primary
storage form of energy.

00:02:32.030 --> 00:02:34.670
With phospholipids, one
of the hydroxyl groups

00:02:34.670 --> 00:02:38.330
of the glycerol backbone is
esterified to either phosphate

00:02:38.330 --> 00:02:40.880
or some kind of
decorated phosphate

00:02:40.880 --> 00:02:45.020
where the decoration could be
a sugar or some other moiety.

00:02:45.020 --> 00:02:47.460
As was seen in JoAnne's
lecture's, phospholipids

00:02:47.460 --> 00:02:51.320
are the key building blocks
of biological membrane.

00:02:51.320 --> 00:02:53.600
Now take a look at Panel
D. The rest of this lecture

00:02:53.600 --> 00:02:56.660
will deal with the details of
how fatty acids are broken down

00:02:56.660 --> 00:02:59.630
to carbon dioxide with the
intermediate production

00:02:59.630 --> 00:03:03.200
of reducing equivalents in
the form of NADH and FADH-2

00:03:03.200 --> 00:03:06.890
and ultimately energy
equivalence in the form of ATP.

00:03:06.890 --> 00:03:08.960
Cells can acquire
lipids directly

00:03:08.960 --> 00:03:12.410
from the blood where typically
they're transported by albumin.

00:03:12.410 --> 00:03:15.980
They can come directly from
our diet or from other organs

00:03:15.980 --> 00:03:18.410
or from breakdown
of triacylglycerides

00:03:18.410 --> 00:03:20.390
within our cells.

00:03:20.390 --> 00:03:22.160
We're going to be
looking at four

00:03:22.160 --> 00:03:25.010
steps in fatty acid catabolism.

00:03:25.010 --> 00:03:28.010
The first step involves the
appearance of the fatty acid

00:03:28.010 --> 00:03:29.790
in the cytoplasm of the cell.

00:03:29.790 --> 00:03:32.400
The fatty acid can come
in either from breakdown

00:03:32.400 --> 00:03:35.450
of a triacylglyceride
stored in the cytoplasm,

00:03:35.450 --> 00:03:37.940
or the fatty acid could
appear from transport

00:03:37.940 --> 00:03:39.920
across the membrane
from the blood.

00:03:39.920 --> 00:03:41.970
In the cytoplasm,
the fatty acid,

00:03:41.970 --> 00:03:43.730
which is technically
a carboxylic acid,

00:03:43.730 --> 00:03:48.960
will be thioesterified to
form a fatty Acyl Coenzyme A.

00:03:48.960 --> 00:03:51.290
The second step of
fatty acid catabolism

00:03:51.290 --> 00:03:55.490
involves the transport of the
fatty Acyl Coenzyme A ester

00:03:55.490 --> 00:03:57.950
into the mitochondrion,
which is the site

00:03:57.950 --> 00:03:59.990
of fatty acid oxidation.

00:03:59.990 --> 00:04:02.270
The third step in
fatty acid catabolism

00:04:02.270 --> 00:04:05.750
involves the actual
oxidation process itself.

00:04:05.750 --> 00:04:09.020
The series of reactions
is called beta oxidation.

00:04:09.020 --> 00:04:11.480
Beta oxidation results
in the conversion

00:04:11.480 --> 00:04:17.180
of the carboxylic acid starting
material to Acetyl Coenzyme A.

00:04:17.180 --> 00:04:19.940
There can be several
fates to the Acetyl

00:04:19.940 --> 00:04:22.490
CoA produced by beta oxidation.

00:04:22.490 --> 00:04:24.740
But the one we're
going to be looking at

00:04:24.740 --> 00:04:28.430
is its entry into the TCA
cycle, where the Acetyl CoA is

00:04:28.430 --> 00:04:31.460
metabolized to carbon dioxide
with the generation of reducing

00:04:31.460 --> 00:04:32.480
equivalents.

00:04:32.480 --> 00:04:35.240
Those reduced electron
carriers have the potential

00:04:35.240 --> 00:04:39.340
to be converted into energy
currency in the form of ATP.

00:04:39.340 --> 00:04:41.550
The fourth topic or
stage in fatty acid

00:04:41.550 --> 00:04:44.540
catabolism that we'll deal with
concerns specialized endings

00:04:44.540 --> 00:04:47.060
of the catabolic pathway.

00:04:47.060 --> 00:04:48.970
The first problem that
we'll look at concerns

00:04:48.970 --> 00:04:52.330
the fact that some fatty acids
have an odd number of carbons

00:04:52.330 --> 00:04:56.080
in them, whereas the classical
fatty acid beta oxidation

00:04:56.080 --> 00:05:00.040
system was primarily designed
to process fatty acids with even

00:05:00.040 --> 00:05:02.770
numbers of carbon units.

00:05:02.770 --> 00:05:04.360
The second problem
that we'll look

00:05:04.360 --> 00:05:06.820
at as an ending of
fatty acid oxidation

00:05:06.820 --> 00:05:10.000
concerns the fact that some
of the fatty acids in our diet

00:05:10.000 --> 00:05:12.490
have a double bond that is
either in the wrong stereo

00:05:12.490 --> 00:05:15.940
chemistry or is
in the wrong place

00:05:15.940 --> 00:05:18.490
to enable easy metabolism.

00:05:18.490 --> 00:05:21.430
Nature has worked out ways
to reposition the double bond

00:05:21.430 --> 00:05:23.740
to facilitate the
entry of the molecule

00:05:23.740 --> 00:05:27.480
into classical beta
oxidation schemes.

00:05:27.480 --> 00:05:30.390
Let's look now at
Panel E. The first step

00:05:30.390 --> 00:05:33.990
in fatty acid catabolism
involves thioesterification

00:05:33.990 --> 00:05:37.320
of the carboxylate
residue of the fatty acid.

00:05:37.320 --> 00:05:39.390
We're going to see in
a couple of minutes

00:05:39.390 --> 00:05:42.900
that placing a Coenzyme A
moiety on the carboxylate

00:05:42.900 --> 00:05:45.750
is going to enable chemistry
at the beta carbon.

00:05:45.750 --> 00:05:48.800
Without the Coenzyme A group,
chemistry at the beta carbon

00:05:48.800 --> 00:05:50.960
would be impossible.

00:05:50.960 --> 00:05:54.470
The enzyme involved is
called Fatty Acyl Coenzyme

00:05:54.470 --> 00:05:57.670
A synthetase, sometimes
called ligase.

00:05:57.670 --> 00:06:01.490
And it additionally goes by the
more common name Thiokinase.

00:06:01.490 --> 00:06:04.400
This enzyme uses
ATP to adenalate

00:06:04.400 --> 00:06:06.740
the carboxalate residue.

00:06:06.740 --> 00:06:11.270
And then it allows Coenzyme
A to replace the AMP residue

00:06:11.270 --> 00:06:14.240
with the resulting product
being a fatty Acyl Coenzyme

00:06:14.240 --> 00:06:19.180
A. This reaction happens in
the cytoplasm of the cell.

00:06:19.180 --> 00:06:21.790
Beta oxidation however,
is going to occur

00:06:21.790 --> 00:06:23.210
in the mitochondrial matrix.

00:06:23.210 --> 00:06:27.220
So we have to find a way to get
this fatty Acetyl Coenzyme A

00:06:27.220 --> 00:06:30.720
into the mitochondrial matrix.

00:06:30.720 --> 00:06:34.120
Let's go now to Storyboard
18, Panel A. Panel A

00:06:34.120 --> 00:06:37.650
shows the cytoplasm, the
mitochondrial outer membrane,

00:06:37.650 --> 00:06:40.650
the intermembrane space,
the inner membrane,

00:06:40.650 --> 00:06:42.240
and the mitochondrial matrix.

00:06:42.240 --> 00:06:43.890
As I just said,
the matrix is going

00:06:43.890 --> 00:06:47.490
to be the site at which
beta oxidation occurs.

00:06:47.490 --> 00:06:51.570
The intermembrane space
contains a small alcohol

00:06:51.570 --> 00:06:53.220
called Carnitine.

00:06:53.220 --> 00:06:54.900
And the mitochondrial
outer membrane

00:06:54.900 --> 00:06:58.260
contains an enzyme called
Carnitine Acyl Transferase I

00:06:58.260 --> 00:07:00.090
or CAT-I.

00:07:00.090 --> 00:07:04.470
CAT-I removes the Acyl group
from the Fatty Acyl Coenzyme

00:07:04.470 --> 00:07:07.050
A in the cytoplasm
and transfers it

00:07:07.050 --> 00:07:09.450
to the alcoholic
residue in the center

00:07:09.450 --> 00:07:11.850
of the carnitine
molecule forming

00:07:11.850 --> 00:07:14.820
an ester of the fatty
acid with carnitine.

00:07:14.820 --> 00:07:17.850
This ester is
delivered to CAT-II,

00:07:17.850 --> 00:07:22.750
which is embedded in the inner
membrane on the matrix side.

00:07:22.750 --> 00:07:26.210
CAT-II will then transfer
the Acyl functionality

00:07:26.210 --> 00:07:31.370
to a Coenzyme A, restoring the
fatty Acyl Coenzyme A molecule.

00:07:31.370 --> 00:07:35.000
Thus, CAT-I and CAT-II
working in a concerted way,

00:07:35.000 --> 00:07:38.930
result in the effective transfer
of a fatty Acyl Coenzyme A

00:07:38.930 --> 00:07:42.200
from the cytoplasm into
the mitochondrial matrix,

00:07:42.200 --> 00:07:44.700
the site of beta oxidation,
which will be our next step.

00:07:49.190 --> 00:07:53.480
Let's now look at Panel B.
This panel shows an inset

00:07:53.480 --> 00:07:56.480
with the mitochondrial inner
membrane, the electron transfer

00:07:56.480 --> 00:08:00.110
complex, and ETFP, the
electron transferring

00:08:00.110 --> 00:08:03.200
flavor protein, which
is going to be the entry

00:08:03.200 --> 00:08:06.770
point of electrons from the
initial step of oxidation

00:08:06.770 --> 00:08:11.640
of the Fatty Acyl CoA into
the electron transport chain.

00:08:11.640 --> 00:08:14.060
We also see in this
panel, the fatty acid

00:08:14.060 --> 00:08:18.500
polmitate the C-16 Straight
Chain Carboxylic Acid.

00:08:18.500 --> 00:08:22.010
The hydrogen beta to
the Coenzyme A ester

00:08:22.010 --> 00:08:25.070
is relatively acidic,
therefore this hydrogen

00:08:25.070 --> 00:08:27.680
will be taken off
to form an alkene.

00:08:27.680 --> 00:08:30.080
And the hydride
will be transferred

00:08:30.080 --> 00:08:34.490
from the beta carbon, the
third carbon from the right.

00:08:34.490 --> 00:08:36.500
Those electrons are
transferred to a flavin

00:08:36.500 --> 00:08:40.970
in the electron transferring
flavor protein, ETFP.

00:08:40.970 --> 00:08:43.820
Eventually, those electrons
are transferred to Coenzyme Q

00:08:43.820 --> 00:08:47.660
to form the reduced form of
Coenzyme Q. Those electrons

00:08:47.660 --> 00:08:50.410
then travel along through
the electron transport chain.

00:08:50.410 --> 00:08:52.520
The Organic product
of this reaction

00:08:52.520 --> 00:08:56.050
is a trans enoyl Coenzyme A.

00:08:56.050 --> 00:08:59.500
Now let's take a look at
Panel C. In the next step,

00:08:59.500 --> 00:09:03.580
water is added to the 3 Carbon
of the enoyl Coenzyme A.

00:09:03.580 --> 00:09:07.675
Resulting product is a 3
Hydroxy Fatty Acyl Coenzyme

00:09:07.675 --> 00:09:11.530
A. We've seen oxidation of
alcohols that looks something

00:09:11.530 --> 00:09:12.850
like this many times.

00:09:12.850 --> 00:09:15.860
For example, malate
being oxidized by malate

00:09:15.860 --> 00:09:19.150
dehydrogenase to oxaloacetate.

00:09:19.150 --> 00:09:22.090
And as we have seen
before, the hydroxyl group

00:09:22.090 --> 00:09:24.930
is converted to a
keto functionality.

00:09:24.930 --> 00:09:29.740
Hydride transfer goes
to NAD+ to form NADH.

00:09:29.740 --> 00:09:31.420
The enzyme that
does this conversion

00:09:31.420 --> 00:09:36.310
is 3 Hydroxy Fatty Acyl
Coenzyme A Dehydrogenase.

00:09:36.310 --> 00:09:40.360
At this point, we have generated
one FADH-2 and one NADH

00:09:40.360 --> 00:09:44.320
in the overall process of
the beta oxidation scheme.

00:09:44.320 --> 00:09:46.960
The 3 Keto Acyl
Coenzyme A is now

00:09:46.960 --> 00:09:50.560
set up to release a first
molecule of Acetyl Coenzyme

00:09:50.560 --> 00:09:55.510
A. The enzyme beta ketothiolase
has a cystine on it.

00:09:55.510 --> 00:09:57.880
The thiol of the
cystine will attack

00:09:57.880 --> 00:09:59.830
the carbon that
has the keto group

00:09:59.830 --> 00:10:03.580
and release Acetyl
Coenzyme A. The residue is

00:10:03.580 --> 00:10:06.460
a thioester in which
the residual 14

00:10:06.460 --> 00:10:08.830
carbons of the polmitate
that we started with

00:10:08.830 --> 00:10:12.880
are now connected to
beta-ketothiolase.

00:10:12.880 --> 00:10:18.190
Lastly, beta-ketothiolase
will transfer this residual 14

00:10:18.190 --> 00:10:20.950
carbons to a
Coenzyme A molecule,

00:10:20.950 --> 00:10:23.290
forming the Fatty
Acyl Coenzyme A

00:10:23.290 --> 00:10:26.040
that will be 14
carbons long, that is,

00:10:26.040 --> 00:10:29.320
it's two carbons shorter than
the 16 carbons of polmitate

00:10:29.320 --> 00:10:30.580
that we started with.

00:10:30.580 --> 00:10:34.330
Overall, this process is
called beta oxidation.

00:10:34.330 --> 00:10:37.660
The system is now set up
to allow the 14 carbon

00:10:37.660 --> 00:10:42.040
molecule to go to 12 to 10
and so on, until the entire 16

00:10:42.040 --> 00:10:44.980
carbon hydrocarbon has
been reduced through seven

00:10:44.980 --> 00:10:48.250
rounds of beta oxidation to
eight molecules of Acetyl

00:10:48.250 --> 00:10:52.870
Coenzyme A. If these eight
molecules of Acetyl CoA

00:10:52.870 --> 00:10:55.150
are further oxidized
by the TCA cycle,

00:10:55.150 --> 00:10:58.670
you'll get 96 ATP molecules.

00:10:58.670 --> 00:11:02.320
And of course, along the way,
in each round of beta oxidation,

00:11:02.320 --> 00:11:06.110
you will also produce
seven FADH-2s.

00:11:06.110 --> 00:11:10.300
The seven FADH-2s will be
converted into 14 ATPs.

00:11:10.300 --> 00:11:13.300
You will also get
seven NADHs, and they

00:11:13.300 --> 00:11:16.210
will be converted into 21 ATPs.

00:11:16.210 --> 00:11:21.400
So the full conversion of the
16 carbon hydrocarbon polmitate

00:11:21.400 --> 00:11:26.640
will result in a
total of 131 ATPs.

00:11:26.640 --> 00:11:28.900
In order to put together
a full balance sheet,

00:11:28.900 --> 00:11:30.810
however, keep in
mind that we needed

00:11:30.810 --> 00:11:33.990
to use several ATPs early
in the process in order

00:11:33.990 --> 00:11:35.520
to prime the system.

00:11:35.520 --> 00:11:40.110
That is Fatty Acyl Coenzyme A
synthetase used 2 high energy

00:11:40.110 --> 00:11:43.650
phosphate bonds in order
to prime the fatty acid

00:11:43.650 --> 00:11:46.470
for production of the
Coenzyme A intermediate

00:11:46.470 --> 00:11:49.077
that's necessary
for beta oxidation.