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BOGDAN FEDELES: Greetings,
and welcome to 5.07

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Biochemistry online.

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00:00:29,300 --> 00:00:31,115
I'm Dr. Bogden Fedeles.

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00:00:31,115 --> 00:00:32,910
Let's metabolize some problems.

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00:00:32,910 --> 00:00:35,320
I have a good problem
for you today.

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00:00:35,320 --> 00:00:38,430
This is problem one,
from problem set nine.

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It is a problem in
which we're going

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to calculate how much energy
we get from metabolizing

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00:00:42,990 --> 00:00:45,690
a molecule of fat,
more specifically,

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00:00:45,690 --> 00:00:48,450
a molecule of triacylglycerol.

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00:00:48,450 --> 00:00:50,640
Here is a structural
representation

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00:00:50,640 --> 00:00:52,770
of the triacylglycerol.

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00:00:52,770 --> 00:00:55,950
Recognize the glycerol
molecule in the middle

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00:00:55,950 --> 00:01:01,080
here, that it's holding
together three fatty acids.

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00:01:01,080 --> 00:01:03,820
Now notice, I picked a
short-chain fatty acid,

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00:01:03,820 --> 00:01:06,310
a long-chain fatty acid,
and a fatty acid that

24
00:01:06,310 --> 00:01:09,430
actually has a double bond.

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00:01:09,430 --> 00:01:11,810
Now when this molecule
gets metabolized,

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00:01:11,810 --> 00:01:15,970
it's going to be acted upon by
an enzyme called the lipase.

27
00:01:15,970 --> 00:01:21,480
It's going to hydrolyze the
molecule into its constituents.

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00:01:21,480 --> 00:01:24,690
Obviously the lipase is
going to use water molecules,

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00:01:24,690 --> 00:01:28,490
and it's going to break it
down into glycerol, shown here.

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00:01:31,110 --> 00:01:31,980
Glycerol.

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00:01:31,980 --> 00:01:36,710
Then, this fatty acid that has
two, four, six, C6 fatty acid.

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00:01:40,480 --> 00:01:44,705
This fatty acid has two, four,
six, eight, 10, 12, 14, 16,

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00:01:44,705 --> 00:01:48,730
C16 fatty acid.

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00:01:48,730 --> 00:01:52,350
And this one, it's an
unsaturated fatty acid,

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00:01:52,350 --> 00:01:54,655
has a double bond, and
if you count the carbons

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00:01:54,655 --> 00:01:56,770
it should add up to 15 carbons.

37
00:01:59,300 --> 00:02:02,660
So not only it
has a double bond,

38
00:02:02,660 --> 00:02:05,480
but also it's an
odd-numbered fatty acid.

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00:02:08,606 --> 00:02:11,230
In order to figure out how much
energy we can get from this one

40
00:02:11,230 --> 00:02:15,100
molecule of fat, we will
look at how much energy

41
00:02:15,100 --> 00:02:18,400
we get from each one
of these constituents--

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00:02:18,400 --> 00:02:21,910
namely, the glycerol and
the three fatty acids--

43
00:02:21,910 --> 00:02:24,430
and calculate what is
the maximum amount of ATP

44
00:02:24,430 --> 00:02:26,530
we can generate
when we metabolize

45
00:02:26,530 --> 00:02:31,180
each one of these molecules
completely to CO2 and water.

46
00:02:31,180 --> 00:02:33,220
In order to keep track
of how much energy we

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00:02:33,220 --> 00:02:35,380
get from each of
the molecules, let's

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00:02:35,380 --> 00:02:38,320
make a handy table right here.

49
00:02:38,320 --> 00:02:44,570
So we're going to put glycerol
and the C6 fatty acid,

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00:02:44,570 --> 00:02:49,090
and the C16 fatty acid,
and C15 fatty acid.

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00:02:53,790 --> 00:02:55,210
All right.

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00:02:55,210 --> 00:02:59,140
And each one of these, we're
going to follow the metabolism,

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00:02:59,140 --> 00:03:06,610
and see how much ATP we're going
to need to put in or generate.

54
00:03:06,610 --> 00:03:10,450
Also, the redox cofactors
in ADH or FADH2.

55
00:03:13,270 --> 00:03:14,740
Also, for fatty
acids, we're going

56
00:03:14,740 --> 00:03:18,700
to be dealing with
beta-oxidation.

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00:03:18,700 --> 00:03:22,400
And pretty much every
single molecule,

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00:03:22,400 --> 00:03:24,190
when it's going to
be born completely,

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00:03:24,190 --> 00:03:26,840
it's going to generate
first acetyl-CoA.

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00:03:29,380 --> 00:03:30,150
All right.

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00:03:30,150 --> 00:03:37,300
And here, we're going to tally
up the total amount of ATP

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00:03:37,300 --> 00:03:38,770
for each one of them.

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00:03:38,770 --> 00:03:41,720
And then we're going to tally
up for the entire molecule.

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00:03:41,720 --> 00:03:44,190
So let's start with
the glycerol molecule.

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00:03:44,190 --> 00:03:48,100
Now, if you have watched
the problem set seven,

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00:03:48,100 --> 00:03:51,250
you might recognize
the following pathway.

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00:03:51,250 --> 00:03:53,740
As we just discussed,
triacylglyceride

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00:03:53,740 --> 00:03:56,370
can be hydrolyzed
to form glycerol.

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00:03:56,370 --> 00:04:00,000
And the glycerol, then,
is first phosphorylated

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00:04:00,000 --> 00:04:04,550
by glycerol kinase, and
oxidized by glycerol phosphate

71
00:04:04,550 --> 00:04:08,290
dehydrogenase, to generate
dihydro acetyl phosphate, which

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00:04:08,290 --> 00:04:11,470
can then enter the
glycolysis, and follow

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00:04:11,470 --> 00:04:15,100
glycolysis all the way to
pyruvate, and then acetyl-CoA.

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00:04:15,100 --> 00:04:19,740
From then, acetyl-CoA can
go into the TCA cycle.

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00:04:19,740 --> 00:04:22,230
So let's tally up
how much energy

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00:04:22,230 --> 00:04:25,140
we can get from one
molecule of glycerol.

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00:04:25,140 --> 00:04:27,630
Let's take a look
specifically at the steps

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00:04:27,630 --> 00:04:33,340
where we are generating ATP,
or generating redox cofactors,

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00:04:33,340 --> 00:04:37,240
such as NADH or FADH2.

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00:04:37,240 --> 00:04:39,260
First, we need to put in ATP.

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00:04:39,260 --> 00:04:41,830
Neglect glycerol kinase.

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00:04:41,830 --> 00:04:44,780
But we're going to
get back one ATP

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00:04:44,780 --> 00:04:46,900
in the phosphoglycerate
kinase step,

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00:04:46,900 --> 00:04:50,360
and one ATP in the
pyruvate kinase step.

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00:04:50,360 --> 00:04:53,680
So the net ATP formation is one.

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00:04:53,680 --> 00:04:56,790
Now in the
glycolysis, we're also

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00:04:56,790 --> 00:05:00,300
going to generate one NADH,
in the pyruvate dehydrogenase

88
00:05:00,300 --> 00:05:04,140
another NADH, and the
glycerol-3-phosphate

89
00:05:04,140 --> 00:05:06,600
dehydrogenase will
generate also an NADH.

90
00:05:06,600 --> 00:05:08,730
Now, keep in mind,
this NADH is going

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00:05:08,730 --> 00:05:10,860
to be outside the
mitochondria, so we're

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00:05:10,860 --> 00:05:13,230
going to have to use a
shuttle to bring it in.

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00:05:13,230 --> 00:05:15,450
But we're considering
that we're using

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00:05:15,450 --> 00:05:18,060
an efficient shuttle, that gives
us the full amount of energy

95
00:05:18,060 --> 00:05:19,410
for this NADH.

96
00:05:19,410 --> 00:05:21,270
So, once again, the
total, it's going

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00:05:21,270 --> 00:05:22,630
to be three molecules of NADH.

98
00:05:25,650 --> 00:05:28,890
So, going back to
our table, we said

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00:05:28,890 --> 00:05:33,150
the glycerol is going to give
us a net one molecule of ATP,

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00:05:33,150 --> 00:05:35,720
three molecules of NADH.

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00:05:35,720 --> 00:05:39,570
There's going to be no
FADH2, no beta-oxidation,

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00:05:39,570 --> 00:05:42,480
and we're going to get one
molecule of acetyl-CoA.

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00:05:42,480 --> 00:05:44,820
As you've seen by
this point many times,

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00:05:44,820 --> 00:05:47,580
acetyl-CoA will
enter the TCA cycle,

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00:05:47,580 --> 00:05:50,370
where it's going to be
completely oxidized to two CO2

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00:05:50,370 --> 00:05:53,280
molecules, and in the
process is going to generate

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00:05:53,280 --> 00:05:56,070
the equivalent of 12 ATPs.

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00:05:56,070 --> 00:05:59,800
Let's take a look at where
those are coming from.

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00:05:59,800 --> 00:06:02,350
Here is a schematic
of the TCA cycle.

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00:06:02,350 --> 00:06:05,710
And one acetyl-CoA
molecule comes in,

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00:06:05,710 --> 00:06:10,930
and it's going to generate one,
two, three molecules of NADH,

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00:06:10,930 --> 00:06:15,500
one molecule of FADH2,
and one molecule of GTP.

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00:06:15,500 --> 00:06:19,040
Now, if we keep in mind
that for every FADH2

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00:06:19,040 --> 00:06:22,720
we generate about two
ATPs, and for every NADH

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00:06:22,720 --> 00:06:26,870
we generate three ATPs, that's
a total of, 3 times 3 is 9,

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00:06:26,870 --> 00:06:30,880
plus 2 is 11, plus a GDP
is equivalent to an ATP.

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00:06:30,880 --> 00:06:35,110
That's about 12 molecules of
ATP per molecule of acetyl-CoA

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00:06:35,110 --> 00:06:36,920
that enters the TCA cycle.

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00:06:36,920 --> 00:06:39,040
So now let's tally
up how much energy

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00:06:39,040 --> 00:06:41,570
we can get from one
molecule of glycerol.

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00:06:41,570 --> 00:06:44,590
So we know we get
one ATP, three NADHs,

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00:06:44,590 --> 00:06:48,860
now each NADH is going to give
us three molecules of ATP.

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00:06:48,860 --> 00:06:53,260
Now FADH2, we know these
give two molecules of ATP.

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00:06:53,260 --> 00:06:55,330
We don't have any
beta-oxidation--

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00:06:55,330 --> 00:06:57,730
we're going to be talking
more about fatty acids--

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00:06:57,730 --> 00:07:01,750
and acetyl-CoA we just talked
about, we get 12 molecules

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00:07:01,750 --> 00:07:03,910
of ATP per acetyl-CoA.

128
00:07:03,910 --> 00:07:07,840
So, the total here
is 12 plus 9, plus 1,

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00:07:07,840 --> 00:07:14,090
that's going to be 22 ATPs
from one molecule of glycerol.

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00:07:14,090 --> 00:07:16,100
Now let's talk about
the fatty acids.

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00:07:16,100 --> 00:07:17,870
In order to metabolize
them, first we

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00:07:17,870 --> 00:07:20,720
need to activate
them into thioesters.

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00:07:20,720 --> 00:07:25,100
These are going to be thioesters
formed with coenzyme A, or CoA.

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00:07:25,100 --> 00:07:27,530
Here's an overview of
the activation process

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00:07:27,530 --> 00:07:32,840
by which fatty acids become
fatty acid thioesters.

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00:07:32,840 --> 00:07:35,240
Of course, this is written
for the C6 fatty acid,

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00:07:35,240 --> 00:07:37,790
but would occur for
any other fatty acid,

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00:07:37,790 --> 00:07:41,590
regardless of the chain length.

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00:07:41,590 --> 00:07:45,190
Now this process is catalyzed
by acetyl-CoA synthetase, that

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00:07:45,190 --> 00:07:52,930
uses ATP to first generate
this mixed anhydride, with AMP.

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00:07:52,930 --> 00:07:54,715
This process is
called adenylation.

142
00:07:54,715 --> 00:07:57,910
So this activates
the acid, which

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00:07:57,910 --> 00:08:00,950
then reacts with
coenzyme A shown here,

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00:08:00,950 --> 00:08:05,710
HS-CoA, which will generate the
thioester of the fatty acid.

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00:08:05,710 --> 00:08:08,440
Now, here we are using
one molecule of ATP,

146
00:08:08,440 --> 00:08:10,930
but we're breaking it into
alpha-phosphate to generate

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00:08:10,930 --> 00:08:14,860
pyrophosphate, which is
then broken down into two

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00:08:14,860 --> 00:08:16,420
inorganic phosphates.

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00:08:16,420 --> 00:08:18,430
And the energy in this
reaction, catalyzed

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00:08:18,430 --> 00:08:22,450
by inorganic
pyrophosphatase, drives

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00:08:22,450 --> 00:08:25,330
the reaction towards the right.

152
00:08:25,330 --> 00:08:29,020
Now, since we're generating
AMP in the second step,

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00:08:29,020 --> 00:08:32,799
we need a second molecule of
ATP to convert this AMP back

154
00:08:32,799 --> 00:08:34,909
to ADP.

155
00:08:34,909 --> 00:08:38,900
So, overall, this process
requires two molecules of ATP

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00:08:38,900 --> 00:08:43,039
to generate one molecule of
the fatty acid thioester.

157
00:08:43,039 --> 00:08:46,160
Once a fatty acid is
activated into a thioester

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00:08:46,160 --> 00:08:50,580
with coenzyme A, it can
now undergo beta-oxidation.

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00:08:50,580 --> 00:08:53,750
This is a set of reactions in
which the fatty acid is broken

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00:08:53,750 --> 00:08:58,580
down into a shorter fatty acid
and one molecule of acetyl-CoA.

161
00:08:58,580 --> 00:09:01,010
The process then can
repeat over and over,

162
00:09:01,010 --> 00:09:03,560
until the entire fatty
acid is broken down

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00:09:03,560 --> 00:09:05,910
into acetyl-CoA molecules.

164
00:09:05,910 --> 00:09:08,660
So let's take a look at
how beta-oxidation works.

165
00:09:08,660 --> 00:09:11,630
Here is an overview of
beta-oxidation pathway.

166
00:09:11,630 --> 00:09:16,240
We're starting with a fatty
acyl-CoA thioester that

167
00:09:16,240 --> 00:09:20,370
has "n" carbons, and by
the end of the process,

168
00:09:20,370 --> 00:09:24,290
we're going to get a thioester
that has "n" minus 2 carbons,

169
00:09:24,290 --> 00:09:26,540
and the remaining
two carbons are

170
00:09:26,540 --> 00:09:29,690
going to be in the
form of acetyl-CoA.

171
00:09:29,690 --> 00:09:31,930
Now, this beta-oxidation
involves four steps.

172
00:09:31,930 --> 00:09:35,750
In the first step, we're
going to use a dehydrogenase

173
00:09:35,750 --> 00:09:40,050
to oxidize this single
bond between the alpha

174
00:09:40,050 --> 00:09:44,720
and beta carbons, and
make a trans double bond.

175
00:09:44,720 --> 00:09:48,410
So this is the alpha carbon,
this is the beta carbon.

176
00:09:48,410 --> 00:09:53,690
So these fatty acyl-CoA
dehydrogenases,

177
00:09:53,690 --> 00:09:55,180
there are actually
several of them,

178
00:09:55,180 --> 00:09:56,721
and they have
different specificities

179
00:09:56,721 --> 00:09:58,730
for short, medium,
long, and very

180
00:09:58,730 --> 00:10:01,730
long chain fatty acyl-CoAs.

181
00:10:01,730 --> 00:10:05,420
But regardless, there
will be some dehydrogenase

182
00:10:05,420 --> 00:10:09,590
to act on any length
fatty acyl-CoA,

183
00:10:09,590 --> 00:10:13,060
and introduce this
trans double bond.

184
00:10:13,060 --> 00:10:16,040
In the next step, we
add one water molecule

185
00:10:16,040 --> 00:10:19,670
to generate a
beta-hydroxyacyl-CoA, which

186
00:10:19,670 --> 00:10:24,630
is subsequently oxidized to
generate a beta-ketoacyl-CoA.

187
00:10:24,630 --> 00:10:27,020
In this oxidation,
we're going to use NAD,

188
00:10:27,020 --> 00:10:29,030
generating one molecule NADH.

189
00:10:29,030 --> 00:10:35,090
Finally, the thiolase, or
beta-ketoacyl thiolase,

190
00:10:35,090 --> 00:10:38,630
is going to break down this
bond between the alpha and beta

191
00:10:38,630 --> 00:10:42,500
carbons, in a reverse
Claisen reaction,

192
00:10:42,500 --> 00:10:44,570
to generate one
molecule of acetyl-CoA.

193
00:10:44,570 --> 00:10:50,260
And the remainder of the fatty
acid is another thioester.

194
00:10:50,260 --> 00:10:52,930
So one round of
beta-oxidation is

195
00:10:52,930 --> 00:10:55,520
going to generate one
molecule of FADH2,

196
00:10:55,520 --> 00:10:58,120
and one molecule
of NADH, as well

197
00:10:58,120 --> 00:11:01,210
as one molecule of acetyl-CoA.

198
00:11:01,210 --> 00:11:05,260
Now let's update our table
with the information we just

199
00:11:05,260 --> 00:11:05,980
learned.

200
00:11:05,980 --> 00:11:09,010
So, as we just said,
for every fatty acid

201
00:11:09,010 --> 00:11:11,710
we need to expend
two molecules of ATP,

202
00:11:11,710 --> 00:11:14,410
to transform them
into the thioesters.

203
00:11:14,410 --> 00:11:17,590
That's why I put here minus
2 for each one of the three

204
00:11:17,590 --> 00:11:19,000
fatty acids.

205
00:11:19,000 --> 00:11:21,160
We also learned that
in beta-oxidation, we

206
00:11:21,160 --> 00:11:26,720
generate one molecule of FADH2,
and one molecule of NADH.

207
00:11:26,720 --> 00:11:29,650
So, for every beta-oxidation,
we generate the equivalent

208
00:11:29,650 --> 00:11:31,120
of five ATP.

209
00:11:34,720 --> 00:11:36,940
Now we're ready to
calculate how much energy we

210
00:11:36,940 --> 00:11:41,410
can get from each of the three
fatty acids in our problem.

211
00:11:41,410 --> 00:11:50,520
Now, for the C6 fatty acid
that's what's represented here,

212
00:11:50,520 --> 00:11:53,370
we discussed, we're
going to activate it,

213
00:11:53,370 --> 00:11:57,100
we're going to need to
use two ATP molecules

214
00:11:57,100 --> 00:12:03,580
and coenzyme A. We're going
to form the thioester.

215
00:12:06,250 --> 00:12:09,841
And then we're going
to do beta-oxidation

216
00:12:09,841 --> 00:12:13,650
Now, for a fatty acid
that has six carbons,

217
00:12:13,650 --> 00:12:15,530
we're going to do
the beta-oxidation,

218
00:12:15,530 --> 00:12:17,520
and the molecule is
going to cleave there,

219
00:12:17,520 --> 00:12:19,440
and we're going to
do it one more time,

220
00:12:19,440 --> 00:12:21,840
the molecule is going
to be cleaved there.

221
00:12:21,840 --> 00:12:25,890
So we're going to do two
rounds of beta-oxidation.

222
00:12:29,330 --> 00:12:31,955
And each one of
these two carbons

223
00:12:31,955 --> 00:12:33,330
is going to become
an acetyl-CoA.

224
00:12:33,330 --> 00:12:36,200
So we're going to generate
three acetyl-CoAs.

225
00:12:39,220 --> 00:12:44,290
Now, similarly, for
the C16 fatty acid--

226
00:12:44,290 --> 00:12:50,020
two, four, six,
eight, 10, 12, 14, 16.

227
00:12:53,030 --> 00:12:58,930
All right, it's going to first
activate two molecules of ATP

228
00:12:58,930 --> 00:13:14,020
and coenzyme A to form the
thioester, with 16 carbons.

229
00:13:14,020 --> 00:13:18,690
And this will undergo
beta-oxidation.

230
00:13:18,690 --> 00:13:22,420
And we're going to do it one,
two, three, four, five, six,

231
00:13:22,420 --> 00:13:25,040
seven times.

232
00:13:25,040 --> 00:13:34,740
OK, so seven rounds
of beta-oxidation

233
00:13:34,740 --> 00:13:39,630
is going to generate eight
molecules of acetyl-CoA.

234
00:13:39,630 --> 00:13:41,940
Now let's go back and put
in all this information

235
00:13:41,940 --> 00:13:43,080
into our table.

236
00:13:43,080 --> 00:13:47,040
So for the C6 fatty acid, we
expended two molecules of ATP

237
00:13:47,040 --> 00:13:53,320
to activate it, and then we did
two rounds of beta-oxidation,

238
00:13:53,320 --> 00:13:57,650
and we generated three
molecules of acetyl-CoA.

239
00:13:57,650 --> 00:14:00,020
For the C16 fatty
acid, again, we

240
00:14:00,020 --> 00:14:04,670
activated then we did seven
rounds beta-oxidation,

241
00:14:04,670 --> 00:14:09,290
and we generated eight
molecules of acetyl-CoA.

242
00:14:09,290 --> 00:14:12,740
So for the C6 fatty acid,
we have a grand total of,

243
00:14:12,740 --> 00:14:17,740
3 times 12 is 36, plus 2
times 5, 10, is 46, minus 2,

244
00:14:17,740 --> 00:14:21,600
is 44 molecules of ATP.

245
00:14:21,600 --> 00:14:25,740
For the C16 fatty
acid, well, 8 times 12

246
00:14:25,740 --> 00:14:36,590
is 96, plus 35, minus 2,
that's 129 molecules of ATP.

247
00:14:36,590 --> 00:14:38,930
Now the C15 fatty acid is
going to be a little bit more

248
00:14:38,930 --> 00:14:42,600
complicated, because on one
hand, it has a double bond,

249
00:14:42,600 --> 00:14:44,930
so we need to figure out
how to deal with that.

250
00:14:44,930 --> 00:14:48,350
On the other hand, it's
an odd chain fatty acid,

251
00:14:48,350 --> 00:14:50,420
and as you imagine, the
beta-oxidation breaks off

252
00:14:50,420 --> 00:14:52,310
two carbons at a time.

253
00:14:52,310 --> 00:14:54,980
So the last time we
do beta-oxidation,

254
00:14:54,980 --> 00:14:57,350
we're going to be left
with three carbons.

255
00:14:57,350 --> 00:14:59,120
That's called
propionyl-CoA, and we'll

256
00:14:59,120 --> 00:15:01,202
have to figure out
what to do with that.

257
00:15:01,202 --> 00:15:02,660
Just as with the
other fatty acids,

258
00:15:02,660 --> 00:15:04,490
the C15 fatty acid
is going to need

259
00:15:04,490 --> 00:15:07,640
to be activated into
a thioester with CoA.

260
00:15:07,640 --> 00:15:12,600
So this is going to cost two
ATP molecules, and, of course,

261
00:15:12,600 --> 00:15:15,600
we need to add the CoA.

262
00:15:15,600 --> 00:15:20,930
And now, this is the thioester
of our C15 fatty acid.

263
00:15:20,930 --> 00:15:24,810
Now, since the double
bond is pretty far away

264
00:15:24,810 --> 00:15:26,550
from the business-end
of the molecule,

265
00:15:26,550 --> 00:15:30,730
we can do a number of
rounds of beta-oxidation.

266
00:15:30,730 --> 00:15:36,230
In fact, we can do
beta-oxidation once, twice.

267
00:15:36,230 --> 00:15:39,480
So two rounds of
beta-oxidation is

268
00:15:39,480 --> 00:15:44,790
going to give us this molecule.

269
00:15:44,790 --> 00:15:50,710
Two rounds beta-oxidation.

270
00:15:50,710 --> 00:15:52,510
In each one of
these rounds we're

271
00:15:52,510 --> 00:15:55,360
going to generate one
molecule of acetyl-CoA,

272
00:15:55,360 --> 00:15:57,010
so two acetyl-CoA.

273
00:16:02,670 --> 00:16:07,410
So we get this fatty
acid taiyo thioester,

274
00:16:07,410 --> 00:16:10,860
which contains a
beta-gamma double bond.

275
00:16:10,860 --> 00:16:12,720
Now, it turns out
there is an enzyme that

276
00:16:12,720 --> 00:16:17,130
can isomerize this double bond
into an alpha-beta double bond.

277
00:16:17,130 --> 00:16:19,440
So this is what is
going to happen next.

278
00:16:19,440 --> 00:16:22,830
The double bond moves from the
beta-gamma to the alpha-beta.

279
00:16:22,830 --> 00:16:26,160
Now, this looks a lot
like an intermediate

280
00:16:26,160 --> 00:16:28,290
in the beta-oxidation.

281
00:16:28,290 --> 00:16:31,650
Once again, this reaction is
catalyzed by am isomerase.

282
00:16:35,490 --> 00:16:38,970
And this alpha-beta
unsaturated thioester

283
00:16:38,970 --> 00:16:44,650
can continue in a manner
similar to beta-oxidation.

284
00:16:44,650 --> 00:16:50,860
So, first it's going to add
water to form a hydroxyl here

285
00:16:50,860 --> 00:16:51,860
at the beta position.

286
00:16:51,860 --> 00:16:55,550
Then that hydroxyl is getting
oxidized to form a keto group.

287
00:16:55,550 --> 00:16:58,670
And the thiolase is going
to generate acetyl-CoA,

288
00:16:58,670 --> 00:17:00,960
and another
thioester shown here.

289
00:17:00,960 --> 00:17:06,550
So, from here, we're going to
generate one molecule of NADH,

290
00:17:06,550 --> 00:17:09,140
and one molecule of acetyl-CoA.

291
00:17:13,569 --> 00:17:17,710
All right, now
this is a thioester

292
00:17:17,710 --> 00:17:20,800
of a completely
saturated fatty acid.

293
00:17:20,800 --> 00:17:22,900
Now of course, it's
still odd chained,

294
00:17:22,900 --> 00:17:26,380
so we have one, six,
seven, eight, nine carbons.

295
00:17:26,380 --> 00:17:30,380
So we can do beta-oxidation
actually three times.

296
00:17:32,970 --> 00:17:34,930
So, three rounds
of beta-oxidation.

297
00:17:37,900 --> 00:17:42,960
And it's going to take us to
three molecules of acetyl-CoA.

298
00:17:42,960 --> 00:17:44,910
And the last portion
of the molecule

299
00:17:44,910 --> 00:17:49,340
is going to be this molecule,
which we call propionyl-CoA,

300
00:17:49,340 --> 00:17:51,630
is a three carbon thioester.

301
00:17:55,960 --> 00:18:02,290
So far we have generated
two, three, and another three

302
00:18:02,290 --> 00:18:05,370
here, six molecule
of acetyl-CoA.

303
00:18:05,370 --> 00:18:07,950
And we've done,
two, another three,

304
00:18:07,950 --> 00:18:10,480
five rounds of beta-oxidation.

305
00:18:10,480 --> 00:18:14,850
And we also generated an
additional NADH molecule.

306
00:18:14,850 --> 00:18:17,134
So now let's update our
table with this information,

307
00:18:17,134 --> 00:18:18,550
and then we're
going to figure out

308
00:18:18,550 --> 00:18:20,590
what happens to propionyl-CoA.

309
00:18:20,590 --> 00:18:23,720
As we just discussed,
the C15 fatty acid

310
00:18:23,720 --> 00:18:26,900
is going to get activated,
so we need to ATPs there.

311
00:18:26,900 --> 00:18:32,420
Then it's going to undergo
five rounds of beta-oxidation.

312
00:18:32,420 --> 00:18:36,980
And we generated a total of
six molecules of acetyl-CoA,

313
00:18:36,980 --> 00:18:40,440
and one additional
molecule of NADH.

314
00:18:40,440 --> 00:18:42,830
Let's now take a look
at propionyl-CoA,

315
00:18:42,830 --> 00:18:45,170
and see how we metabolize
it, and how much energy

316
00:18:45,170 --> 00:18:46,370
we can generate from it.

317
00:18:46,370 --> 00:18:49,760
It turns out the first step is
to expand from a three carbon

318
00:18:49,760 --> 00:18:52,530
molecule to a four
carbon molecule.

319
00:18:52,530 --> 00:18:58,460
This happens by adding one CO2.

320
00:18:58,460 --> 00:19:00,050
Of course, this
process will require

321
00:19:00,050 --> 00:19:02,510
the expense of an ATP molecule.

322
00:19:02,510 --> 00:19:05,240
We generate this
methylmalonyl-CoA,

323
00:19:05,240 --> 00:19:08,690
which is a branched four
carbon chain molecule.

324
00:19:08,690 --> 00:19:12,100
And another enzyme,
racemase, is going

325
00:19:12,100 --> 00:19:14,170
to interconvert
this stereocenter

326
00:19:14,170 --> 00:19:17,110
from the S-configuaration
to the R-configuration.

327
00:19:17,110 --> 00:19:20,890
Finally, this
methylmalonyl-CoA is

328
00:19:20,890 --> 00:19:23,980
going to undergo a
rearrangement of the groups

329
00:19:23,980 --> 00:19:27,070
to generate a linear
molecule, succinyl-CoA.

330
00:19:27,070 --> 00:19:30,220
Now, this is one of the most
fascinating transformations

331
00:19:30,220 --> 00:19:33,070
in the whole
biochemistry, and involves

332
00:19:33,070 --> 00:19:36,460
an enzyme called
methylmalonyl-CoA mutase, which

333
00:19:36,460 --> 00:19:40,890
requires cobalamin, or
the coenzyme derived

334
00:19:40,890 --> 00:19:41,860
from vitamin B12.

335
00:19:46,240 --> 00:19:48,010
This unusual
transformation catalyzed

336
00:19:48,010 --> 00:19:50,560
by the methylmalonyl-CoA
mutase, the enzyme that

337
00:19:50,560 --> 00:19:54,490
requires vitamin
B12 cofactor, it's

338
00:19:54,490 --> 00:19:59,680
fascinating because it
involves a carbon skeletal

339
00:19:59,680 --> 00:20:02,000
rearrangement of the molecule.

340
00:20:02,000 --> 00:20:05,782
And this reaction occurs
via a radical mechanism.

341
00:20:05,782 --> 00:20:10,850
The radical is obtained by
breaking a carbon metal bond.

342
00:20:10,850 --> 00:20:13,730
In this case, it's a
carbon-cobalt bond.

343
00:20:13,730 --> 00:20:16,400
Now succinyl-CoA is
a familiar molecule,

344
00:20:16,400 --> 00:20:18,840
you've encountered
it in the TCA cycle.

345
00:20:18,840 --> 00:20:23,720
However, we cannot use the TCA
cycle directly to completely

346
00:20:23,720 --> 00:20:26,870
metabolize succinyl-CoA, as all
the intermediates in the TCA

347
00:20:26,870 --> 00:20:30,080
cycle are in fact in
catalytic amounts.

348
00:20:30,080 --> 00:20:32,720
So, we're going to use
just part of the TCA cycle,

349
00:20:32,720 --> 00:20:36,230
to generate a molecule,
malate, which then

350
00:20:36,230 --> 00:20:38,200
can be converted into pyruvate.

351
00:20:38,200 --> 00:20:40,730
And pyruvate can then
generate acetyl-CoA

352
00:20:40,730 --> 00:20:45,410
to re-enter the TCA cycle and
be completely metabolized.

353
00:20:45,410 --> 00:20:49,160
Here is the TCA cycle,
to refresh your memory.

354
00:20:49,160 --> 00:20:51,440
And this is
succinyl-CoA that we can

355
00:20:51,440 --> 00:20:55,220
generate from the
methylmalonyl-CoA mutase.

356
00:20:55,220 --> 00:20:57,680
Now, as we said,
succinyl-CoA is going

357
00:20:57,680 --> 00:20:59,720
to be converted to malate.

358
00:20:59,720 --> 00:21:02,660
Malate can then escape
the mitochondria

359
00:21:02,660 --> 00:21:05,570
and continue its transformation
towards pyruvate.

360
00:21:05,570 --> 00:21:07,150
So, in this process,
succinyl-CoA

361
00:21:07,150 --> 00:21:10,070
is going to generate
one molecule of GTP

362
00:21:10,070 --> 00:21:10,950
to form succinate.

363
00:21:10,950 --> 00:21:13,490
And succinate to fumartate
is going to give us

364
00:21:13,490 --> 00:21:16,770
one more molecule of FADH2.

365
00:21:16,770 --> 00:21:20,990
Then malate will escape
the mitochondria.

366
00:21:20,990 --> 00:21:27,570
So to summarize what
happens in the TCA cycle,

367
00:21:27,570 --> 00:21:31,580
succinyl-CoA is going to
give us a molecule of GTP,

368
00:21:31,580 --> 00:21:35,270
and then one more
molecule of FADH2.

369
00:21:35,270 --> 00:21:37,130
And it's going to
make it to malate,

370
00:21:37,130 --> 00:21:40,670
and then malate is going
to be converted to pyruvate

371
00:21:40,670 --> 00:21:42,590
using the malic enzyme.

372
00:21:42,590 --> 00:21:46,040
Now, this is an oxidation
and decarboxylation

373
00:21:46,040 --> 00:21:47,960
that happens in one step.

374
00:21:47,960 --> 00:21:49,550
For the oxidation,
we're going to need

375
00:21:49,550 --> 00:21:53,420
NADP, instead of the usual NAD.

376
00:21:53,420 --> 00:21:57,381
So we're going to generate
one molecule of NADPH.

377
00:21:57,381 --> 00:21:58,880
Now for the purpose
of this problem,

378
00:21:58,880 --> 00:22:03,120
we're going to treat NADPH
as equivalent to NADH.

379
00:22:03,120 --> 00:22:07,290
So malate, via the malic enzyme,
is going to form pyruvate.

380
00:22:07,290 --> 00:22:10,035
And then pyruvate, in the
pyruvate dehydrogenase,

381
00:22:10,035 --> 00:22:14,620
is going to lose one
CO2 and form acetyl-CoA.

382
00:22:14,620 --> 00:22:17,890
In the process we'll also
generate one more NADH,

383
00:22:17,890 --> 00:22:22,330
and now acetyl-CoA can
re-enter the TCA cycle

384
00:22:22,330 --> 00:22:26,470
and be completely
metabolized, generating

385
00:22:26,470 --> 00:22:31,080
in the process about
12 ATP equivalents.

386
00:22:31,080 --> 00:22:33,519
So now let's go back,
and update our table

387
00:22:33,519 --> 00:22:35,310
with all this information
that we found out

388
00:22:35,310 --> 00:22:36,720
about propionyl-CoA.

389
00:22:36,720 --> 00:22:42,070
So as we said, propionyl-CoA
required first the loss

390
00:22:42,070 --> 00:22:46,780
of another ATP to activate it,
to form the methylmalonyl-CoA.

391
00:22:46,780 --> 00:22:51,180
But then methylmalonyl-CoA
converted to succinyl-CoA.

392
00:22:51,180 --> 00:22:54,850
Succinyl-CoA generated
one molecule of GTP,

393
00:22:54,850 --> 00:22:58,290
so we're going to
put plus 1 back here.

394
00:22:58,290 --> 00:23:01,480
Then we're going to get
one molecule of FADH2

395
00:23:01,480 --> 00:23:04,240
the generating
succinate, from going

396
00:23:04,240 --> 00:23:06,460
from succinate to fumarate.

397
00:23:06,460 --> 00:23:07,960
And then, we're
going to generate

398
00:23:07,960 --> 00:23:11,890
two more molecules of NADH,
one at the malate enzyme step,

399
00:23:11,890 --> 00:23:14,020
and one at the pyruvate
dehydrogenase step,

400
00:23:14,020 --> 00:23:16,120
so we have plus 2 here.

401
00:23:16,120 --> 00:23:19,400
And, of course, in the end,
we get one more molecule

402
00:23:19,400 --> 00:23:22,400
of acetyl-CoA as well.

403
00:23:22,400 --> 00:23:28,740
So now we have a total of
seven molecules of acetyl-CoA,

404
00:23:28,740 --> 00:23:32,770
five rounds of beta-oxidation,
one FADH2, three NADHs,

405
00:23:32,770 --> 00:23:37,250
and at a loss of two ATPs.

406
00:23:37,250 --> 00:23:44,580
So this totals up to 118
ATPs for the C15 fatty acid.

407
00:23:44,580 --> 00:23:51,810
Now we can tally the entire
ATP yield of a molecule of fat,

408
00:23:51,810 --> 00:23:54,420
of this triacylglyceride,
and that's

409
00:23:54,420 --> 00:24:01,180
going to be 313
molecules of ATP.

410
00:24:01,180 --> 00:24:04,696
Now that's a lot of energy from
one single molecule of fat.

411
00:24:08,100 --> 00:24:10,570
Now, this problem has
an additional question,

412
00:24:10,570 --> 00:24:14,160
and it asked us to contrast how
much energy we get from a six

413
00:24:14,160 --> 00:24:17,870
carbon fatty acid
and compare that

414
00:24:17,870 --> 00:24:20,610
to how much energy would get
from one molecule of glucose,

415
00:24:20,610 --> 00:24:22,581
which also has six carbons.

416
00:24:22,581 --> 00:24:24,080
Let's take a look
at our table here.

417
00:24:24,080 --> 00:24:29,240
The six carbon fatty acid
generates about 44 molecules

418
00:24:29,240 --> 00:24:31,940
of ATP when completely oxidized.

419
00:24:31,940 --> 00:24:35,240
By contrast, one
molecule of glucose

420
00:24:35,240 --> 00:24:41,340
would generate only about
34 to 36 molecules of ATP.

421
00:24:41,340 --> 00:24:48,450
If you want to follow the same
analysis that we did here--

422
00:24:48,450 --> 00:24:54,450
remember glucose, well, we need
to spend two molecules of ATP

423
00:24:54,450 --> 00:24:56,130
to activate it, but
then we're going

424
00:24:56,130 --> 00:25:00,460
to generate four molecules
of ATP going to pyruvate.

425
00:25:00,460 --> 00:25:05,910
And then there's going to be
two molecules of NADH generated,

426
00:25:05,910 --> 00:25:08,540
one at the GAPDH step, one
at the pyruvate dehydrogenase

427
00:25:08,540 --> 00:25:11,550
step, and finally,
we're going to generate

428
00:25:11,550 --> 00:25:14,280
two molecules of acetyl-CoA.

429
00:25:14,280 --> 00:25:19,370
So the total is going to be, 2
times 12 is 24, plus 4 times 3

430
00:25:19,370 --> 00:25:23,200
is 12, is 36, plus 2, is 38.

431
00:25:27,120 --> 00:25:30,980
So as you guys can
see, the C6 fatty acid

432
00:25:30,980 --> 00:25:35,090
generates actually more ATP
than one molecule of glucose.

433
00:25:35,090 --> 00:25:39,440
And that's probably reasonable,
because the C6 fatty acids

434
00:25:39,440 --> 00:25:42,030
have a lot more C-H bonds.

435
00:25:42,030 --> 00:25:45,260
In other words, the
carbons are more reduced.

436
00:25:45,260 --> 00:25:47,240
In glucose, we have
a lot of hydroxyls,

437
00:25:47,240 --> 00:25:50,790
so the carbons are in a
slightly higher oxidation state.

438
00:25:50,790 --> 00:25:54,770
Therefore, there's less
energy generated total.

439
00:25:54,770 --> 00:25:57,440
Of course, one
molecule of glucose

440
00:25:57,440 --> 00:26:00,080
pales in comparison
with one molecule

441
00:26:00,080 --> 00:26:04,370
of fat, which has
hundreds of ATP generated,

442
00:26:04,370 --> 00:26:06,590
as we thought in part
A of this problem.

443
00:26:06,590 --> 00:26:08,510
Well, that sums up this problem.

444
00:26:08,510 --> 00:26:13,850
I hope it helped you realize why
fats, or triacylglycerides, are

445
00:26:13,850 --> 00:26:17,600
so much more energy dense than
other nutrients, such as sugars

446
00:26:17,600 --> 00:26:19,384
or amino acids.