WEBVTT

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[SQUEAKING]

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[RUSTLING]

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[CLICKING]

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MATTHEW VANDER HEIDEN:
So last time, we

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discussed the TCA cycle.

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And that allows us to
then, you know, say

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how we can take glucose and
completely oxidize those six

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glucose carbons into CO2.

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And you know, of course,
glycolysis converts glucose

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into two pyruvate.

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Pyruvate has two carbons, and
then pyruvate dehydrogenase

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can release the first
of those carbons as CO2.

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It generates an acetyl CoA.

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That acetyl CoA then
enters the TCA cycle,

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and two other CO2s
are released--

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one of the isocitrate
dehydrogenase

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step, one of the alpha
ketoglutarate dehydrogenase

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step.

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Now, we discussed that
the TCA cycle is useful

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because it allows you
to oxidize anything that

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can be turned into
acetyl CoA into CO2,

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and that includes
fatty acids, which

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we will spend a lot of
time talking about today.

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Now, the TCA cycle, as I
mentioned, just by review,

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is also very useful as a
way to make stuff-- lots

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of useful intermediates.

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But we discussed last time
if we're going to do that--

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that is, because it
functions as a cycle--

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if we remove stuff
from the cycle,

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something has to be added back
in-- so-called anaplerosis--

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in order to have it continue
to function as a cycle.

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Now, you'll note-- we
weren't explicit about this,

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but this is oxidation.

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Remember, carbon oxidation
is generally favorable.

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So delta G of this
will be less than 0.

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However, unlike
glycolysis, where

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we discussed that most of
the harnessing of energy--

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that is, the favorable oxidation
of glucose to pyruvate--

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was captured to directly keep an
ATP/ADP ratio high in the cell,

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you can see that most of the
energy output of the TCA cycle

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isn't actually direct
synthesis of ATP or GTP.

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Instead, what we have is
we have most of that energy

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as being captured and charging
up a ratio of NADH to NAD,

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or FADH2 to FAD.

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And we'll see over the
next several lectures

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how we can harness electron
transfer from those molecules

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to oxygen to make ATP, as
well as do some other work.

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But before we get
to that, I want

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to first focus a
bit on fat, which,

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of course, is the most reduced
carbon biomolecule in the cell.

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And so that's chains of
fully reduced carbon.

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And of course, this is the
most chemically dense way

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to store energy--

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as carbon.

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Intuitively, you know this,
because what's oil and gas?

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It's chains of
reduced hydrocarbons.

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Of course, those
are better fuels

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than wood, which are,
as we saw before,

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based on carbohydrate
alcohol carbons.

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You also know
intuitively that fat

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has more calories than sugar--

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exactly same ideas.

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And so I want to
start by discussing

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what biological fat
is, and then that

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will lead into a
discussion about how

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we can oxidize the fat,
also, as a way to get energy.

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Now, most biological
fat is packaged

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into molecules called lipids.

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And so I want to make
clear that lipids are not

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the same thing as fat.

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More correctly, a lipid contains
fat-- or more precisely,

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something called a fatty acid.

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And so what is a fatty acid?

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Well, it's this fully
saturated hydrocarbon

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with a carboxylic
acid on the end.

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And so we have a
carboxylic acid followed

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by some chain of fully
saturated hydrocarbons.

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So it differs from
oil and gasoline

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in that it has this carboxylic
acid handle, if you will,

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on the end that basically allows
biology to build and break down

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these fatty acids.

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Now, most biological fatty acids
have even numbers of carbons.

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And it turns out that that's
a consequence of the fact

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that it's built and broken
down into these two carbon

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acetyl CoA units.

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And the most common lengths--

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that is, how long
these chains are.

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So in biology, they can vary
anywhere from 4 to 36 carbons

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long.

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But the most common ones
are 12 to 24 carbons,

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with 16 carbons and 18 carbons
being by far the most abundant

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in cells.

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Now, it's worth
mentioning what some

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of the names of these
more common ones are,

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because you'll see them.

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And so the fully saturated
16 carbon fatty acid--

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so 16 carbon total.

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14, 15, 16, including
the carboxylic acid.

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This is referred
to as palmitate.

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Or it's drawn in the
acid form, palmitic acid.

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And the systematic name for
this is hexadecanoic acid.

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The other common one,
the 18 carbon version--

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so same molecule, but
two carbons longer.

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That's referred to as
stearate, or stearic acid,

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if drawn in the acid form.

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Or the systematic name
would be octadecanoic acid.

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Now, oftentimes
things like palmitate

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can also be drawn like this.

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So there's 16 carbons.

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Another way to draw palmitate.

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And you'll note that
palmitate as well as stearate

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here are fully saturated.

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What do I mean by saturated?

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I mean fully saturated
by electrons.

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There's no way to reduce
this molecule further,

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unless, of course, we reduce
the carboxylic acid on the end.

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And so palmitate
would be the most

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saturated 16 carbon fatty acid.

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Stearate is the most saturated
18 carbon fatty acid.

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Now, if I add a double bond
to one of these molecules,

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that's an oxidation.

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So just like when we
added a double bond

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to succinate to make
fumarate in the TCA cycle.

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I showed that last time.

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That's an oxidation reaction.

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And so an unsaturated
fatty acid is

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a fatty acid that is no longer
fully saturated with electrons.

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That means it is
not fully reduced.

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And so, remember, you store
energy as reduced carbon.

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And so an unsaturated fatty
acid stores less energy

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than a saturated fatty
acid because it's

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more oxidized than the
saturated fatty acid.

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And so just as a couple
examples here-- so here's

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the example of a 16-carbon
unsaturated fatty acid.

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So I introduce a double bond.

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I'll draw it in
the acid form here.

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And so here you got 5,
6, 7, 8 plus 7 is 15--

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16 carbons total,
one double bond.

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This is all middle oleic acid,
more systematically named

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hexadecene acid.

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And the 18-carbon version
would be as follows.

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So I added two extra carbons
on this end of the molecule.

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This is oleic acid,
or octadecanoic acid.

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Now, note I put a
double bond in here.

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You'll remember from
organic chemistry

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that double bonds can exist
in a trans or a cis form.

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And so if it's trans,
it would be like this.

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If it's cis, the
double bond would be

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like that in the carbon chain.

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And so just to show
you here on the models

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that this can matter, so here
is a double bonded carbon.

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And so these two red guys
are cis to each other.

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And this purple
is trans to that.

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Now, if I put this onto
a fatty acid chain,

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you can see that there's
a big difference there.

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So if I add the
double bond in here

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and it's continued the
chain here on a trans bond,

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it's a relatively
straight molecule,

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whereas if I go
here in a cis bond,

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I now introduce a kink
into the alkyl chain.

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So biological fatty
acids are always cis.

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And this is
structurally important

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because it actually creates
this kink in fatty acids

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that are not fully saturated.

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Now, obviously, as
you might guess,

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the number of double
bonds and the locations

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of the double bonds will change
the structure and therefore

00:10:47.000 --> 00:10:49.380
the properties of
the fatty acids.

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And so we need a
nomenclature that

00:10:50.960 --> 00:10:55.020
allows us to describe
what's going on here.

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And so the simplest
nomenclature is

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as follows, where we basically
have the number of carbons

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and the fatty acids,
say 18, followed

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by the number of double bonds.

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So an 18:1 fatty acid,
that's oleic acid--

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so 18 carbons long,
one double bond--

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18:0 would be steric acid--

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18 carbons long, zero double
bonds; 16:0, palmitate--

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palmitic acid--

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16 carbons long,
zero double bonds.

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So if we have one double
bond, oftentimes this

00:11:39.110 --> 00:11:52.480
is referred to as a MUFA, or
monounsaturated fatty acid.

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And, of course, if I
have many double bonds--

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more than one-- that's a PUFA,
or a polyunsaturated fatty

00:12:03.370 --> 00:12:04.930
acid--

00:12:04.930 --> 00:12:07.010
probably heard those terms.

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So what's an example of a
polyunsaturated fatty acid?

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Well, a common one is an 18:2
polyunsaturated fatty acids--

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18 carbons, two double bonds.

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The common biological one
is called linoleic acid--

00:12:26.980 --> 00:12:58.100
and CH3-- and so 1, 2 double
bonds, 4, 5, 6, 7, 8, 9, 10,

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17, 18 carbons total, 18:2
fatty acid, linoleic acid--

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formal name is
octadecadiene oleic acid.

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If I make it more unsaturated--

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so 18:3-- that is linolenic
acid, or octadecatrienoic acid.

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And if I painfully draw
out the entire thing--

00:14:10.510 --> 00:14:16.890
so we've got 1, 2, 3, double
bonds, 1, 2, 3, 4, 5, 6, 7, 8,

00:14:16.890 --> 00:14:20.550
9, 10, 17, 18 carbons total--

00:14:20.550 --> 00:14:27.690
18:3 polyunsaturated fatty acid
with three double bonds in it.

00:14:27.690 --> 00:14:30.420
In all of these cases,
all of those double bonds

00:14:30.420 --> 00:14:33.300
are cis double bonds.

00:14:33.300 --> 00:14:39.030
And you'll also notice
that the spacing of them

00:14:39.030 --> 00:14:44.250
is not entirely random
either, at least as I drew it.

00:14:44.250 --> 00:14:46.710
The first of all is
that these are not

00:14:46.710 --> 00:14:48.600
conjugated double
bonds, so you see

00:14:48.600 --> 00:14:53.730
that there's a carbon in all
cases between the double bond.

00:14:53.730 --> 00:14:58.470
And also, you'll notice that
most of the double bonds are

00:14:58.470 --> 00:15:02.160
actually started, if you
count from this end--

00:15:02.160 --> 00:15:04.650
from the acid end--

00:15:04.650 --> 00:15:09.640
this would be carbon 9 and
10-- so 1 plus 7 is 8, 9, 10.

00:15:09.640 --> 00:15:12.240
Each of them-- the first
double bond I put in

00:15:12.240 --> 00:15:16.230
is between carbons 9 and
10 going in this direction.

00:15:16.230 --> 00:15:21.180
And that's a consequence
of the conserved enzymes

00:15:21.180 --> 00:15:24.640
that introduced these double
bonds into the molecule.

00:15:24.640 --> 00:15:29.530
Now, obviously this
spacing matters.

00:15:29.530 --> 00:15:31.560
And so we need a way
in the nomenclature

00:15:31.560 --> 00:15:34.680
in order to denote that.

00:15:34.680 --> 00:15:38.430
That is where exactly the
double bonds are located.

00:15:38.430 --> 00:15:39.910
And there are sort of two ways.

00:15:39.910 --> 00:15:41.550
We can count we can
count from one end.

00:15:41.550 --> 00:15:43.480
Or, we can count
from the other end.

00:15:43.480 --> 00:15:47.280
Now, the most systematic way--

00:15:47.280 --> 00:15:52.530
correct way now is to count
from the carboxylic acid end.

00:15:52.530 --> 00:15:56.670
So very similar to sugars,
we counted carbon 1 of sugars

00:15:56.670 --> 00:16:00.000
to be the one that was closest
to the end of the molecule

00:16:00.000 --> 00:16:02.280
where the carbonyl was located.

00:16:02.280 --> 00:16:04.260
So same thing in
fatty acid, so this

00:16:04.260 --> 00:16:07.360
would be carbon 1 count
in that direction.

00:16:07.360 --> 00:16:14.700
And so the nomenclature would
be then to put it in a delta 9,

00:16:14.700 --> 00:16:19.170
would be a double bond between
the 9th and 10th carbon

00:16:19.170 --> 00:16:22.150
counting from the
carboxylic acid.

00:16:22.150 --> 00:16:28.830
And so the 18:2 fatty acid
I drew here, linoleic acid,

00:16:28.830 --> 00:16:34.830
would more precisely be
18:2, delta 9, delta 12.

00:16:34.830 --> 00:16:39.630
That's because it's carbon
9, 10, 11, 12-- so carbon 9

00:16:39.630 --> 00:16:44.010
and 10 and 12 and 13.

00:16:44.010 --> 00:16:51.510
Linolenic acid--
18:3, delta 9 12, 15--

00:16:51.510 --> 00:16:57.360
so 9, 10, 11, 12,
13, 14, 15 to say

00:16:57.360 --> 00:17:01.800
where the double bonds are
in the polyunsaturated fatty

00:17:01.800 --> 00:17:02.610
acids.

00:17:02.610 --> 00:17:05.220
As you can see, most
polyunsaturated fatty acids

00:17:05.220 --> 00:17:09.200
is a consequence that
they're not conjugated.

00:17:09.200 --> 00:17:14.119
You'll see that the double bonds
are placed every three carbons.

00:17:14.119 --> 00:17:21.109
Now, this three carbon spacing
is maintained even in the--

00:17:21.109 --> 00:17:25.520
often in biology, even in the
exceptions, where the first one

00:17:25.520 --> 00:17:28.250
is not between carbon 9 and 10.

00:17:28.250 --> 00:17:31.160
And so a classic
example of that is

00:17:31.160 --> 00:17:36.450
the polyunsaturated fatty
acid arachidonic acid,

00:17:36.450 --> 00:17:45.620
which is a 20 carbine fatty
acid with four double bonds

00:17:45.620 --> 00:17:48.980
at carbons 5, 8, 11, and 14.

00:17:48.980 --> 00:17:53.570
So arachidonic acid, you
may have heard in the past,

00:17:53.570 --> 00:17:56.390
is a key signaling fatty acid.

00:17:56.390 --> 00:17:59.750
It's mobilized and
used to generate

00:17:59.750 --> 00:18:01.490
some inflammatory mediators.

00:18:01.490 --> 00:18:04.430
It's the enzyme that
acts on this to generate

00:18:04.430 --> 00:18:07.850
the inflammatory mediators--
is the target of very common

00:18:07.850 --> 00:18:12.350
drugs, like aspirin or other
nonsteroidal anti-inflammatory

00:18:12.350 --> 00:18:13.190
drugs--

00:18:13.190 --> 00:18:15.210
ibuprofen, et cetera.

00:18:15.210 --> 00:18:18.230
And this molecule,
drawing it like this,

00:18:18.230 --> 00:18:24.740
should fully describe to
you what it would look like.

00:18:24.740 --> 00:18:27.710
Now, there's also an
older nomenclature

00:18:27.710 --> 00:18:30.980
that numbers fatty
acids to name them

00:18:30.980 --> 00:18:32.840
and where the double
bonds are located--

00:18:32.840 --> 00:18:36.830
not from the carbonyl side,
but from the other end

00:18:36.830 --> 00:18:38.060
of the molecule.

00:18:38.060 --> 00:18:39.740
And I mentioned
this nomenclature

00:18:39.740 --> 00:18:44.270
because it's still used quite
often in popular culture.

00:18:44.270 --> 00:18:47.060
And so to do this,
it's basically--

00:18:47.060 --> 00:18:51.030
refers to this, I guess,
as the alpha carbon.

00:18:51.030 --> 00:18:53.930
So counting in Greek,
going this direction,

00:18:53.930 --> 00:18:57.980
the final carbon in
the fatty acid, omega--

00:18:57.980 --> 00:19:00.390
the last letter
the Greek alphabet.

00:19:00.390 --> 00:19:02.210
And so if you count
from the other end,

00:19:02.210 --> 00:19:08.970
we could also give this
different nomenclature.

00:19:08.970 --> 00:19:15.860
And so in this case, our
18:3 linolenic acid, 18:3,

00:19:15.860 --> 00:19:28.590
delta 9, 12, 15, we could also
say is 18:3, omega 3, 6, 9.

00:19:28.590 --> 00:19:30.690
So now we're counting
from this end--

00:19:30.690 --> 00:19:35.700
1, 2, 3, first double
the bond, 4, 5, 6,

00:19:35.700 --> 00:19:39.030
next double bond, 7,
8, 9, next double bond.

00:19:39.030 --> 00:19:44.890
And so thus, 18:1, by
this nomenclature--

00:19:44.890 --> 00:19:52.140
18:1, delta 9, would
be the same as 18:1,

00:19:52.140 --> 00:19:57.450
omega 9 because it's obviously
meeting in the middle.

00:19:57.450 --> 00:20:04.460
But if we did 18:1, delta 12,
that would be 18:1, omega 6.

00:20:04.460 --> 00:20:09.680
18:1, delta 15 would
be 18:1, omega 3.

00:20:09.680 --> 00:20:11.570
And so I mention
this because you'll

00:20:11.570 --> 00:20:14.900
hear about so-called
omega 3 fatty acids.

00:20:14.900 --> 00:20:18.680
The major omega 3 fatty acid
that they're talking about

00:20:18.680 --> 00:20:20.600
is linolenic acid.

00:20:20.600 --> 00:20:23.900
And it's an omega 3 fatty acid
using the nomenclature counting

00:20:23.900 --> 00:20:25.130
from the other side.

00:20:25.130 --> 00:20:30.200
Or, you could also say
it's 18:3, delta 9, 12, 15.

00:20:30.200 --> 00:20:32.930
Now, I want to mention one
of the reasons you hear about

00:20:32.930 --> 00:20:36.410
omega 3 fatty acids
is that, in general,

00:20:36.410 --> 00:20:42.320
there are fatty acids such as
those that humans cannot make.

00:20:42.320 --> 00:20:44.510
And so we have to get
those from the diet.

00:20:44.510 --> 00:20:48.890
And so this is the concept
called essential fatty acids.

00:20:48.890 --> 00:20:51.350
And so somewhat like
vitamins, there's

00:20:51.350 --> 00:20:53.390
things out there
that our physiology

00:20:53.390 --> 00:20:57.620
uses that we have to get
from other organisms making.

00:20:57.620 --> 00:21:00.000
And therefore, we
have to eat them.

00:21:00.000 --> 00:21:03.110
And so if you hear this
term essential fatty acid,

00:21:03.110 --> 00:21:05.840
it's basically referring
to specific fatty acids

00:21:05.840 --> 00:21:11.390
where we lack the enzymes to
place all the double bonds

00:21:11.390 --> 00:21:15.530
to be in the place where
it's useful for some aspect

00:21:15.530 --> 00:21:19.230
of our biology.

00:21:19.230 --> 00:21:22.260
Now, lots of nomenclature here--

00:21:25.120 --> 00:21:29.500
the reason I discuss this is
because this diversity of chain

00:21:29.500 --> 00:21:33.700
length and double bonds creates
different properties and nature

00:21:33.700 --> 00:21:38.110
uses these diverse chemical
properties of the fatty acids--

00:21:38.110 --> 00:21:40.360
that is, different links
and different degrees

00:21:40.360 --> 00:21:44.830
of unsaturation or saturation
positions of the double bonds--

00:21:44.830 --> 00:21:47.740
to take advantage
of those properties

00:21:47.740 --> 00:21:51.350
to do different
things in biology.

00:21:51.350 --> 00:21:54.700
And so a lot of this has to do--
a lot of why fatty acids are

00:21:54.700 --> 00:21:58.390
useful is that they are
not soluble in water

00:21:58.390 --> 00:22:00.310
or poorly soluble in water.

00:22:00.310 --> 00:22:02.920
You know this just from
the common experience

00:22:02.920 --> 00:22:04.660
of making salad dressing.

00:22:04.660 --> 00:22:07.600
And so you mix the oil in the
vinegar in the salad dressing,

00:22:07.600 --> 00:22:12.340
and so the oil is largely
made out of fatty acids,

00:22:12.340 --> 00:22:13.660
made out of lipids.

00:22:13.660 --> 00:22:19.480
And those fatty acids are not
soluble in the vinegar part,

00:22:19.480 --> 00:22:22.630
the water part of the molecule.

00:22:22.630 --> 00:22:28.300
Now, the fatty acid themselves--

00:22:28.300 --> 00:22:31.270
the chain length and the
number of double bonds

00:22:31.270 --> 00:22:34.090
will affect other
properties, such as

00:22:34.090 --> 00:22:35.810
the melting temperature.

00:22:35.810 --> 00:22:43.510
So in general, the melting
temperature of a fatty acid

00:22:43.510 --> 00:22:55.290
will decrease with
shorter chain length

00:22:55.290 --> 00:23:04.650
and decrease with more
unsaturation-- so more double

00:23:04.650 --> 00:23:05.560
bonds.

00:23:05.560 --> 00:23:07.050
So the more double
bonds I put in

00:23:07.050 --> 00:23:11.790
and the shorter it is, the
lower the melting temperature.

00:23:11.790 --> 00:23:16.860
And so you guys know this,
from just cooking experience,

00:23:16.860 --> 00:23:17.980
to be the case.

00:23:17.980 --> 00:23:27.890
And so animal fatty acids
tend to be more saturated.

00:23:31.400 --> 00:23:33.530
And because they're
more saturated,

00:23:33.530 --> 00:23:36.830
they have a higher
melting temperature.

00:23:36.830 --> 00:23:39.750
And so they're solids
at room temperature.

00:23:39.750 --> 00:23:43.280
So think about it--
animal fat, butter, lard--

00:23:43.280 --> 00:23:47.280
these things are solid
at room temperature.

00:23:47.280 --> 00:23:49.535
So plant fatty acids--

00:23:52.170 --> 00:24:01.440
they tend to be more
unsaturated fatty acids.

00:24:01.440 --> 00:24:04.080
And they're liquids
at room temperature.

00:24:04.080 --> 00:24:07.200
And you know this because
cooking oil made from plants

00:24:07.200 --> 00:24:10.630
is typically a liquid
at room temperature.

00:24:10.630 --> 00:24:16.260
Now, you might be
aware that olive oil

00:24:16.260 --> 00:24:19.770
has a lot of monounsaturated
fatty acids, a lot of MUFAs.

00:24:19.770 --> 00:24:22.780
Olive oil, unlike
other plant oils,

00:24:22.780 --> 00:24:24.750
which are more
polyunsaturated fatty acids--

00:24:24.750 --> 00:24:26.640
if you put those in
the refrigerator,

00:24:26.640 --> 00:24:29.670
the olive oil will
tend to form a solid,

00:24:29.670 --> 00:24:32.560
whereas your canola
oil will not.

00:24:32.560 --> 00:24:34.200
And that's a
consequence of the fact

00:24:34.200 --> 00:24:37.260
that the more unsaturated
fatty acids are,

00:24:37.260 --> 00:24:40.990
the lower the
melting temperature.

00:24:40.990 --> 00:24:43.200
And so the more
likely it is to be

00:24:43.200 --> 00:24:46.320
a liquid or a solid in
the fridge or at room

00:24:46.320 --> 00:24:49.860
temperature across these
different fatty acids.

00:24:49.860 --> 00:24:51.840
To show here on
the slide, here's

00:24:51.840 --> 00:24:54.480
just something I stole
from the textbook.

00:24:54.480 --> 00:24:57.420
It basically gives
the composition

00:24:57.420 --> 00:25:00.270
of some things you might
be aware of-- so olive oil,

00:25:00.270 --> 00:25:01.860
butter, and beef fat.

00:25:01.860 --> 00:25:04.380
So you can see as we go
down the spectrum here,

00:25:04.380 --> 00:25:09.330
you have longer chain
lengths and a reduction

00:25:09.330 --> 00:25:10.950
in the number of double bonds.

00:25:10.950 --> 00:25:13.920
And, of course, beef fat,
if you've ever handled it,

00:25:13.920 --> 00:25:18.060
is a much firmer solid
at room temperature

00:25:18.060 --> 00:25:23.740
than butter, which is of course
solid at room temperature,

00:25:23.740 --> 00:25:26.190
whereas olive oil is not.

00:25:26.190 --> 00:25:30.030
And that follows this
with the chain length

00:25:30.030 --> 00:25:32.190
and the double bonds
really affecting

00:25:32.190 --> 00:25:36.030
the melting temperature
of these different fats.

00:25:36.030 --> 00:25:37.860
Just a couple of sides
so you can better

00:25:37.860 --> 00:25:39.780
understand your food--

00:25:39.780 --> 00:25:43.020
and so you may have
heard about or seen

00:25:43.020 --> 00:25:50.670
on the side of your food
packaging hydrogenated oils.

00:25:50.670 --> 00:25:53.940
So what's a hydrogenated oil?

00:25:53.940 --> 00:25:55.860
Well, that's basically
taking a plant

00:25:55.860 --> 00:26:03.090
oil, which has unsaturated fatty
acids and hydrogenating it.

00:26:03.090 --> 00:26:05.038
That is adding hydrogen.

00:26:05.038 --> 00:26:05.830
Well, what is that?

00:26:05.830 --> 00:26:07.830
It's not really the
hydrogen that's being added.

00:26:07.830 --> 00:26:09.660
It's adding electrons
so it's taking it

00:26:09.660 --> 00:26:14.310
from being a unsaturated fatty
acid to chemically making

00:26:14.310 --> 00:26:16.230
it a saturated fatty acid.

00:26:16.230 --> 00:26:17.970
And it's a way to
take plant oils

00:26:17.970 --> 00:26:20.880
and make it such that it's
solid at room temperature.

00:26:20.880 --> 00:26:24.870
An example of a hydrogenated
oil would be margarine--

00:26:24.870 --> 00:26:30.990
plant oil that would be liquid,
reduce it chemically such

00:26:30.990 --> 00:26:35.010
that it's fully saturated,
and now it's a solid at room

00:26:35.010 --> 00:26:37.000
temperature.

00:26:37.000 --> 00:26:42.130
Sure you've also heard
of so-called trans fats.

00:26:42.130 --> 00:26:45.520
So what's a trans fat
other than something

00:26:45.520 --> 00:26:47.530
cooked up in the
devil's kitchen?

00:26:47.530 --> 00:26:51.220
So trans fats are
basically taking animal

00:26:51.220 --> 00:26:55.690
fat and introducing chemically
double bonds into them such

00:26:55.690 --> 00:26:58.930
that you have this solid
that is now a liquid at room

00:26:58.930 --> 00:27:00.230
temperature.

00:27:00.230 --> 00:27:04.290
Now, this is done chemically to
introduce those double bonds.

00:27:04.290 --> 00:27:07.240
And so if you're introducing
a double bond chemically

00:27:07.240 --> 00:27:10.150
by oxidizing the
fatty acid, you'll

00:27:10.150 --> 00:27:12.550
get some cis and some trans.

00:27:12.550 --> 00:27:15.310
Cis is what biology does
because it introduces them

00:27:15.310 --> 00:27:16.390
with an enzyme.

00:27:16.390 --> 00:27:18.730
Trans versus cis
is not controlled

00:27:18.730 --> 00:27:20.230
when it's done chemically.

00:27:20.230 --> 00:27:23.800
And so this leads
to these unnatural

00:27:23.800 --> 00:27:28.570
trans fatty acids, which
lead to health issues

00:27:28.570 --> 00:27:30.530
and are now banned
in many cities,

00:27:30.530 --> 00:27:34.750
including here in
Cambridge, Massachusetts.

00:27:34.750 --> 00:27:38.020
Last aside is-- as all of
us have probably experienced

00:27:38.020 --> 00:27:41.590
our oils or fats going rancid--

00:27:41.590 --> 00:27:42.370
so what is that?

00:27:42.370 --> 00:27:47.855
So that's oxygen
oxidizing the fatty acid.

00:27:47.855 --> 00:27:50.230
And so if you want to protect
your oil from going rancid,

00:27:50.230 --> 00:27:52.540
the thing to do is just
keep it sealed, right?

00:27:52.540 --> 00:27:54.820
Keep oxygen away
from it and your oil

00:27:54.820 --> 00:27:58.490
will last a lot longer.

00:27:58.490 --> 00:28:01.340
So that's fatty acids.

00:28:01.340 --> 00:28:04.490
In biology, most fatty
acids aren't sitting around

00:28:04.490 --> 00:28:05.690
by themselves.

00:28:05.690 --> 00:28:08.090
They're esterified
to an alcohol.

00:28:08.090 --> 00:28:11.540
And as we mentioned
in an earlier lecture,

00:28:11.540 --> 00:28:17.720
a lipid equals a
fatty acid that's

00:28:17.720 --> 00:28:23.915
esterified to an alcohol.

00:28:28.010 --> 00:28:31.190
So we spent some time in
the prior lecture talking

00:28:31.190 --> 00:28:35.540
about doing this to
make phospholipids.

00:28:35.540 --> 00:28:39.890
And that's an example of a
lipid-- fatty acids esterified

00:28:39.890 --> 00:28:44.210
to make this phospholipid,
which gave us

00:28:44.210 --> 00:28:46.910
both a polar and a
nonpolar end and allowed

00:28:46.910 --> 00:28:48.450
us to create membranes.

00:28:48.450 --> 00:28:51.830
And so lipids have lots of
important functions in cells.

00:28:51.830 --> 00:28:55.850
And so there's the
barrier function, which

00:28:55.850 --> 00:28:59.180
is basically membranes,
things like phospholipids

00:28:59.180 --> 00:29:01.430
we talked about last time.

00:29:01.430 --> 00:29:05.520
There's also signaling
functions of lipids.

00:29:05.520 --> 00:29:10.430
So I mentioned
arachidonic acid earlier.

00:29:10.430 --> 00:29:12.530
You'll certainly encounter
signaling functions

00:29:12.530 --> 00:29:16.370
of lipids in other courses.

00:29:16.370 --> 00:29:19.700
And then the last
one, which is really

00:29:19.700 --> 00:29:21.890
the reason why we
talk about it now,

00:29:21.890 --> 00:29:26.720
is lipids are great
for energy storage

00:29:26.720 --> 00:29:31.310
because it's the most
reduced carbons, so the most

00:29:31.310 --> 00:29:36.830
dense way to store
energy as reduced carbon.

00:29:36.830 --> 00:29:41.830
So the simplest
lipid and the one

00:29:41.830 --> 00:29:44.380
used for energy
storage is referred

00:29:44.380 --> 00:29:58.352
to as a triacylglyceride,
often abbreviated as a TAG--

00:29:58.352 --> 00:29:59.060
triacylglyceride.

00:29:59.060 --> 00:30:03.830
And we can see now how we
can make a triacylglyceride

00:30:03.830 --> 00:30:07.910
as well as how it relates to
other pathways in metabolism

00:30:07.910 --> 00:30:09.330
that we've encountered.

00:30:09.330 --> 00:30:13.610
And so here's our old
friend from glycolysis.

00:30:18.840 --> 00:30:21.270
Hopefully you
recognize this molecule

00:30:21.270 --> 00:30:28.170
as the phosphorylated
triose dihydroxyacetone

00:30:28.170 --> 00:30:32.010
phosphate, also an
intermediate in glycolysis.

00:30:32.010 --> 00:30:40.695
And so if we reduce this
ketone to the alcohol--

00:30:44.090 --> 00:30:50.140
so two electrons from NADH.

00:30:50.140 --> 00:30:54.950
Reduce that ketone, that will
oxidize the NADH to NAD+.

00:30:54.950 --> 00:30:59.680
If we also remove the
phosphate, now what do we have?

00:30:59.680 --> 00:31:02.350
Now we have the alcohol.

00:31:05.240 --> 00:31:10.750
And this molecule is glycerol.

00:31:10.750 --> 00:31:14.440
And so now this glycerol,
as we talked about before,

00:31:14.440 --> 00:31:18.880
we can take three fatty
acids, esterify them

00:31:18.880 --> 00:31:20.605
to each of those alcohols.

00:31:39.590 --> 00:31:44.270
And now we have a
glycerol molecule

00:31:44.270 --> 00:31:49.280
with three fatty acids
esterified to the alcohols

00:31:49.280 --> 00:31:50.820
on the glycerol.

00:31:50.820 --> 00:31:53.660
This is a triacylglyceride.

00:31:53.660 --> 00:31:58.410
Now, of course triacylglycerides
are not soluble in water.

00:31:58.410 --> 00:32:03.740
And so when we make these
in cells for energy storage,

00:32:03.740 --> 00:32:08.820
they're stored as
so-called lipid droplets.

00:32:08.820 --> 00:32:11.960
And so if you look here at
the slide, here's an example.

00:32:11.960 --> 00:32:15.650
This up here is an
adipocyte from an animal.

00:32:15.650 --> 00:32:19.290
This down here, I
think, is a plant cell.

00:32:19.290 --> 00:32:25.970
And so in both cases, you
have these large droplets

00:32:25.970 --> 00:32:30.380
that would be basically
droplets of triacylglycerides

00:32:30.380 --> 00:32:34.770
that basically form as a way
for long-term energy storage.

00:32:34.770 --> 00:32:38.720
And so while we think
of, at least as people,

00:32:38.720 --> 00:32:43.700
our adipocytes, our fat cells,
as storing our fat, they do.

00:32:43.700 --> 00:32:45.770
But they're really
specialized cell types

00:32:45.770 --> 00:32:48.380
that have these
giant lipid droplets,

00:32:48.380 --> 00:32:51.440
whereas many cells actually
have much smaller lipid

00:32:51.440 --> 00:32:57.110
droplets as a way to
store triacylglycerides

00:32:57.110 --> 00:33:01.505
as a way to store energy
as reduced carbon.

00:33:04.870 --> 00:33:06.670
I also want to say
that if you look

00:33:06.670 --> 00:33:09.460
at this, unlike the
phospholipids that we described

00:33:09.460 --> 00:33:12.340
earlier as ways to
build membranes,

00:33:12.340 --> 00:33:14.440
these don't have
a charge on them.

00:33:14.440 --> 00:33:16.240
And so they're
sometimes referred to

00:33:16.240 --> 00:33:20.380
as so-called neutral lipids.

00:33:20.380 --> 00:33:22.270
And it's really
this neutral lipids

00:33:22.270 --> 00:33:27.370
that allow them to clump
together in these oil

00:33:27.370 --> 00:33:30.850
particles, if you will-- these
lipid droplets in cells that

00:33:30.850 --> 00:33:34.310
are good for energy storage.

00:33:34.310 --> 00:33:36.910
Now, why specifically
are neutral

00:33:36.910 --> 00:33:38.470
lipids good for energy storage?

00:33:38.470 --> 00:33:41.170
Well, really
chemically dense way

00:33:41.170 --> 00:33:43.720
to store energy, the
most reduced carbon.

00:33:43.720 --> 00:33:49.150
And by forming these
droplets, not unlike the oil

00:33:49.150 --> 00:33:53.050
in your salad dressing, another
neutral lipid forming droplets

00:33:53.050 --> 00:33:56.080
within the vinegar,
this is a way

00:33:56.080 --> 00:33:58.810
that you store reduced
carbon without having

00:33:58.810 --> 00:34:00.950
to carry around water.

00:34:00.950 --> 00:34:04.870
And so if we store energy
as carbohydrates, starch

00:34:04.870 --> 00:34:08.989
or glycogen, these molecules
have to exist in water.

00:34:08.989 --> 00:34:11.500
So you're carrying around
the starch and glycogen.

00:34:11.500 --> 00:34:14.620
But as an animal, we're also
carrying around the water.

00:34:14.620 --> 00:34:18.699
If we're carrying around
reduced carbon as lipids,

00:34:18.699 --> 00:34:21.100
we can now exclude
the water from it.

00:34:21.100 --> 00:34:22.600
And so it's much more dense.

00:34:22.600 --> 00:34:24.580
And we can, in a
more efficient way,

00:34:24.580 --> 00:34:29.350
carry around this
material without having

00:34:29.350 --> 00:34:30.230
to carry the water.

00:34:30.230 --> 00:34:34.420
And so gram for gram, fat
is a much more efficient way

00:34:34.420 --> 00:34:39.429
to pack on calories that we
can burn later than storing

00:34:39.429 --> 00:34:41.710
it as carbohydrate.

00:34:41.710 --> 00:34:45.310
Fat's also nice because
it forms a nice insulator.

00:34:45.310 --> 00:34:46.330
And so it makes sense.

00:34:46.330 --> 00:34:48.699
As animals, we need to
survive the winter--

00:34:48.699 --> 00:34:50.980
pack on all kinds
of calories as fat,

00:34:50.980 --> 00:34:53.469
don't have to carry
around as water.

00:34:53.469 --> 00:34:56.170
Just have the energy
there as reduced carbon,

00:34:56.170 --> 00:34:57.970
and then we can
slowly release it

00:34:57.970 --> 00:35:01.000
over the course of
the winter, as well as

00:35:01.000 --> 00:35:05.620
use it to keep us warm, and
then build up those stores again

00:35:05.620 --> 00:35:10.060
during the summer months when
there's more food available.

00:35:10.060 --> 00:35:14.650
Fat, of course, has months
worth of energy packed into it,

00:35:14.650 --> 00:35:18.790
whereas carbohydrates that we
carry around-- our glycogen--

00:35:18.790 --> 00:35:20.960
has less than a day's
worth of energy.

00:35:20.960 --> 00:35:24.970
So we could live off of
our fat for the winter.

00:35:24.970 --> 00:35:28.640
We can't live off of our
glycogen for the winter.

00:35:28.640 --> 00:35:30.340
Now, the big trade-off
here is that it's

00:35:30.340 --> 00:35:32.290
much slower to mobilize fat.

00:35:32.290 --> 00:35:35.200
We have to get into
these lipid droplets

00:35:35.200 --> 00:35:37.240
and break off
little pieces of it,

00:35:37.240 --> 00:35:40.450
get them into aqueous
water soluble pieces

00:35:40.450 --> 00:35:42.550
to break it down.

00:35:42.550 --> 00:35:44.650
Glycogen, of course,
is already in water,

00:35:44.650 --> 00:35:46.670
can break it down much faster.

00:35:46.670 --> 00:35:49.360
And so it's much slower
to mobilize the fat.

00:35:49.360 --> 00:35:52.390
But it can be much
more efficient

00:35:52.390 --> 00:35:56.230
in terms of what's
stored, whereas glycogen

00:35:56.230 --> 00:35:58.240
can be mobilized a lot faster.

00:35:58.240 --> 00:36:00.040
And that's really part
of our physiology.

00:36:00.040 --> 00:36:02.080
You will burn your
glycogen first

00:36:02.080 --> 00:36:07.510
when you exercise before you
start burning a lot of fat.

00:36:07.510 --> 00:36:09.880
And I think many
have heard about that

00:36:09.880 --> 00:36:14.110
from just reading and thinking
about what you know about

00:36:14.110 --> 00:36:18.260
exercise physiology.

00:36:18.260 --> 00:36:21.850
Now again, I want
to make the point

00:36:21.850 --> 00:36:26.710
that we all know that fat
has more calories than sugar.

00:36:26.710 --> 00:36:29.030
And the reason for
that is, to be clear,

00:36:29.030 --> 00:36:31.600
is because it's more reduced.

00:36:31.600 --> 00:36:34.330
And so the energy that's
released from burning fat,

00:36:34.330 --> 00:36:37.540
just like the energy that's
released from burning sugar,

00:36:37.540 --> 00:36:41.530
comes because the
transfer of electrons

00:36:41.530 --> 00:36:46.100
from the reduced hydrocarbon
to oxygen is favorable.

00:36:46.100 --> 00:36:49.160
And that is how
energy is released.

00:36:49.160 --> 00:36:52.030
And so fat is more
reduced than sugar,

00:36:52.030 --> 00:36:56.590
and so more electrons
to transfer, and so more

00:36:56.590 --> 00:37:00.400
energy released
than burning sugar.

00:37:00.400 --> 00:37:05.020
So now let's go through, in a
pathway sense, how does nature,

00:37:05.020 --> 00:37:07.750
rather than taking gasoline
and just igniting and releasing

00:37:07.750 --> 00:37:11.650
a lot of energy, how
does nature stepwise

00:37:11.650 --> 00:37:15.580
break down fatty acids in a
way that energy release can

00:37:15.580 --> 00:37:18.280
be controlled in the
same way we described it

00:37:18.280 --> 00:37:22.960
for carbohydrates-- glycolysis
in the TSA cycle, controlled

00:37:22.960 --> 00:37:25.270
stepwise energy release
that can be captured

00:37:25.270 --> 00:37:27.240
to do things like make ATP.

00:37:30.320 --> 00:37:36.160
How does the same thing work
for oxidation of fatty acids?

00:37:36.160 --> 00:37:40.420
Well, if as organisms
we store fatty acids

00:37:40.420 --> 00:37:44.620
in these triacylglycerides
or other neutral lipids,

00:37:44.620 --> 00:37:50.260
the first step is we have to get
them out of the neutral lipids.

00:37:50.260 --> 00:37:55.000
And so if we start with
a triacylglyceride,

00:37:55.000 --> 00:37:59.570
the first step is to
use a lipase molecule.

00:37:59.570 --> 00:38:03.040
So a lipase just
breaks that ester bond.

00:38:03.040 --> 00:38:16.280
And so you basically
now have glycerol

00:38:16.280 --> 00:38:20.340
plus the three fatty acids.

00:38:20.340 --> 00:38:26.870
We're going to spend
most of our time

00:38:26.870 --> 00:38:29.500
today discussing how you
break down the fatty acids.

00:38:29.500 --> 00:38:31.880
However, I want to
mention, it should be clear

00:38:31.880 --> 00:38:34.760
how you're also going to
metabolize the glycerol.

00:38:34.760 --> 00:38:39.755
So glycerol-- we can
oxidize the glycerol.

00:38:43.550 --> 00:38:47.750
So now if we oxidize
that alcohol,

00:38:47.750 --> 00:38:49.260
what are we going to get?

00:38:49.260 --> 00:38:59.470
We're going to get
dihydroxyacetone.

00:38:59.470 --> 00:39:07.510
And then if we phosphorylate one
of the ends of that with ATP,

00:39:07.510 --> 00:39:11.380
now we get
dihydroxyacetone phosphate.

00:39:11.380 --> 00:39:20.590
And that, of course,
can go into glycolysis,

00:39:20.590 --> 00:39:23.260
generate pyruvate,
generate acetyl-CoA,

00:39:23.260 --> 00:39:26.650
oxidize that acetyl-CoA
in the TCA cycle,

00:39:26.650 --> 00:39:30.250
get energy from the
glycerol part of the lipid.

00:39:33.080 --> 00:39:35.780
So what about oxidizing
the fatty acids?

00:39:35.780 --> 00:39:38.840
Well, the first thing
we have to talk about

00:39:38.840 --> 00:39:42.230
to oxidize the fatty
acids is, where is this

00:39:42.230 --> 00:39:44.460
going to occur in the cell?

00:39:44.460 --> 00:39:48.780
And so lipid droplets are
floating out there in the cell.

00:39:48.780 --> 00:39:54.230
And so you mobilize these
pieces with the lipase.

00:39:54.230 --> 00:39:57.560
Well, the glycerol now is
sitting there in the cytosol.

00:39:57.560 --> 00:40:01.250
That can form the hydroxy
dihydroxyacetone phosphate

00:40:01.250 --> 00:40:05.450
and be burned in glycolysis,
which is in the cytosol.

00:40:05.450 --> 00:40:07.700
But once we generate
that pyruvate-- remember

00:40:07.700 --> 00:40:10.580
that pyruvate had to get
into the mitochondria

00:40:10.580 --> 00:40:12.560
where we turned it
into acetyl-CoA.

00:40:12.560 --> 00:40:17.240
So acetyl-CoA was present
in the mitochondrial matrix.

00:40:17.240 --> 00:40:26.830
So that is here in the
matrix of the mitochondria

00:40:26.830 --> 00:40:29.050
where the TCA cycle
happens-- remember,

00:40:29.050 --> 00:40:32.660
glycolysis in the cytosol,
TCA cycle in the matrix.

00:40:32.660 --> 00:40:35.690
And so that pyruvate eight
needed to get into the matrix.

00:40:35.690 --> 00:40:38.050
So we could turn
it into acetyl-CoA.

00:40:38.050 --> 00:40:40.630
And then that acetyl-CoA
was in the right place

00:40:40.630 --> 00:40:47.770
to be entered into the TCA
cycle and turned into CO2.

00:40:47.770 --> 00:40:51.380
Well, fatty acid oxidation
has the same thing.

00:40:51.380 --> 00:40:53.830
And so if those fatty acids
are generated out here

00:40:53.830 --> 00:40:56.770
in the cytosol when
they're lipases remove them

00:40:56.770 --> 00:40:59.110
from the lipid
droplet, it turns out

00:40:59.110 --> 00:41:01.600
we're going to burn
the acetyl-CoA we

00:41:01.600 --> 00:41:04.120
get from the breakdown
of the fatty acids.

00:41:04.120 --> 00:41:06.600
That acetyl-CoA needs
to be in the matrix

00:41:06.600 --> 00:41:09.410
so it has access
to the TCA cycle.

00:41:09.410 --> 00:41:13.630
And so we need to get the
fatty acid from the cytosol

00:41:13.630 --> 00:41:16.360
inside the mitochondria.

00:41:16.360 --> 00:41:18.820
Now, part of this--
remember, our CoA

00:41:18.820 --> 00:41:22.370
group that I drew last time
is this giant molecule.

00:41:22.370 --> 00:41:25.360
And so acetyl-CoA is not
this little two carbon unit.

00:41:25.360 --> 00:41:27.410
It's this big, giant molecule.

00:41:27.410 --> 00:41:30.850
And so by generating the
acetyl-CoA in the mitochondria,

00:41:30.850 --> 00:41:33.310
we obviate the need
to get this giant CoA

00:41:33.310 --> 00:41:36.610
group across the
mitochondrial membranes.

00:41:36.610 --> 00:41:38.080
But, of course,
we do need to get

00:41:38.080 --> 00:41:43.070
the fatty acid into the
right location as well.

00:41:43.070 --> 00:41:46.120
And so the way that
that fatty acid

00:41:46.120 --> 00:41:49.390
is transported there is
actually via a system

00:41:49.390 --> 00:41:52.510
called the carnitine shuttle.

00:41:52.510 --> 00:41:56.200
But there's sort of a little bit
of a roundabout way to do it.

00:41:56.200 --> 00:41:57.940
And that is, we
are going to need

00:41:57.940 --> 00:42:02.020
to do two things-- get the fatty
acid inside the mitochondria

00:42:02.020 --> 00:42:09.350
as well as activate it
with this coenzyme A group.

00:42:09.350 --> 00:42:15.340
And it turns out that
the fatty acid is first

00:42:15.340 --> 00:42:20.470
activated in the cytosol
by adding the coenzyme A

00:42:20.470 --> 00:42:25.630
group to the acid on the end,
very much like acetyl-CoA.

00:42:25.630 --> 00:42:40.190
And so here is some generic
chain length fatty acid.

00:42:40.190 --> 00:42:44.980
And it turns out that
there's an enzyme called

00:42:44.980 --> 00:42:57.940
acyl-CoA synthetase
that is going

00:42:57.940 --> 00:43:10.460
to take ATP and adenylate this
acid group on the fatty acid.

00:43:26.030 --> 00:43:31.820
And so this is
basically an AMP that's

00:43:31.820 --> 00:43:37.030
been used to adenylate
the fatty acid itself.

00:43:37.030 --> 00:43:38.720
Now, you'll notice
by doing this,

00:43:38.720 --> 00:43:41.030
we generate a pyrophosphate.

00:43:41.030 --> 00:43:43.700
And that pyrophosphate
can be turned

00:43:43.700 --> 00:43:46.040
into two inorganic phosphates--

00:43:46.040 --> 00:43:47.690
same trick we've
seen before that

00:43:47.690 --> 00:43:51.140
basically can pull a
reaction that otherwise

00:43:51.140 --> 00:43:52.580
would be unfavorable forward.

00:43:52.580 --> 00:43:58.860
In this case, it's adding the
CoA group to this fatty acid.

00:43:58.860 --> 00:44:11.880
And what happens next is that
CoA comes in and replaces

00:44:11.880 --> 00:44:30.870
the AMP such that you generate
this fatty acyl-CoA molecule,

00:44:30.870 --> 00:44:36.010
which is basically acetyl-CoA
but with some arbitrary longer

00:44:36.010 --> 00:44:40.560
a number of reduced hydrocarbons
in the chain-- so not

00:44:40.560 --> 00:44:44.010
a 2-carbon unit, but a fatty
acid-- a many carbon unit

00:44:44.010 --> 00:44:47.580
fatty acid with whatever
other properties happen

00:44:47.580 --> 00:44:50.010
to be on fatty
acid, where now you

00:44:50.010 --> 00:44:54.600
have this fatty acyl-CoA
instead of the fatty acid.

00:44:54.600 --> 00:44:57.110
So it turns out this
fatty acyl-CoA then

00:44:57.110 --> 00:45:02.060
is subjected to a shuttle
called the carnitine shuttle

00:45:02.060 --> 00:45:06.200
to actually get it
into the mitochondria.

00:45:06.200 --> 00:45:10.040
And so what is carnitine?

00:45:10.040 --> 00:45:15.770
So carnitine is a
small molecule--

00:45:15.770 --> 00:45:16.505
looks like this.

00:45:38.290 --> 00:45:41.280
So this here is carnitine.

00:45:41.280 --> 00:45:48.890
And it turns out that this
hydroxyl group, basically,

00:45:48.890 --> 00:45:55.550
is swapped for the CoA
on the fatty acyl-CoA.

00:45:55.550 --> 00:46:37.580
And so if this here is
some generic fatty CoA,

00:46:37.580 --> 00:46:40.730
you end up with this
molecule, which is

00:46:40.730 --> 00:46:50.320
called a fatty acyl carnitine.

00:46:50.320 --> 00:46:55.390
So all I've done is take the
CoA off and move the fatty acid

00:46:55.390 --> 00:47:00.850
to make this ester here with
the alcohol on the carnitine.

00:47:00.850 --> 00:47:05.800
And this fatty acyl
carnitine can now

00:47:05.800 --> 00:47:11.740
be transported across the
mitochondrial membrane-- so

00:47:11.740 --> 00:47:14.470
from the cytosol to
the mitochondria.

00:47:14.470 --> 00:47:19.390
Here we have our
fatty acyl carnitine.

00:47:19.390 --> 00:47:23.560
And then that fatty
acyl carnitine

00:47:23.560 --> 00:47:30.890
can exchange a CoA
for the carnitine

00:47:30.890 --> 00:47:36.120
and regenerate
the fatty acyl-CoA

00:47:36.120 --> 00:47:38.550
in the mitochondrial matrix.

00:47:38.550 --> 00:47:43.890
This whole process is referred
to as the carnitine shuttle

00:47:43.890 --> 00:47:50.910
and is effectively a complex
way to move fatty acyl-CoAs

00:47:50.910 --> 00:47:53.430
from the cytosol into
the mitochondria, where

00:47:53.430 --> 00:47:54.990
they can be oxidized.

00:47:54.990 --> 00:47:57.930
Here's another picture
of it that is maybe

00:47:57.930 --> 00:48:00.210
drawn in a different
way because it's

00:48:00.210 --> 00:48:02.700
a little bit confusing
as something to describe,

00:48:02.700 --> 00:48:11.190
but basically you generate this
fatty acyl-CoA in the cytosol.

00:48:11.190 --> 00:48:15.150
And then the fatty
acyl-CoA is exchanged

00:48:15.150 --> 00:48:16.800
for a fatty acyl carnitine.

00:48:16.800 --> 00:48:19.080
Fatty acyl carnitine
goes into the matrix

00:48:19.080 --> 00:48:22.920
and is used to regenerate
the fatty acyl-CoA.

00:48:22.920 --> 00:48:24.630
The enzymes that do
this is something

00:48:24.630 --> 00:48:27.900
called CPT, or carnitine
palmitoyltransferase.

00:48:32.940 --> 00:48:47.630
Write that down-- carnitine,
which is obviously refers

00:48:47.630 --> 00:48:51.260
to palmitate as the
common fatty acid,

00:48:51.260 --> 00:48:55.250
although CPT will catalyze
many fatty acyl carnitine,

00:48:55.250 --> 00:48:57.620
fatty acyl-CoA interconversions.

00:48:57.620 --> 00:48:59.390
And so by doing
that interconversion

00:48:59.390 --> 00:49:02.210
on the cytosolic side and
the mitochondrial side,

00:49:02.210 --> 00:49:05.030
you can use
carnitine as a handle

00:49:05.030 --> 00:49:10.145
to transfer fatty acyl-CoAs
from one compartment to another.

00:49:13.800 --> 00:49:17.760
Now, once that fatty acyl-CoA
is in the mitochondria,

00:49:17.760 --> 00:49:23.670
it can now be oxidized
to acetyl-CoA.

00:49:27.440 --> 00:49:30.860
So now, let's discuss
the series of steps

00:49:30.860 --> 00:49:34.430
that is referred to as
fatty acid oxidation,

00:49:34.430 --> 00:49:36.680
and abbreviated FAO.

00:49:36.680 --> 00:49:48.080
And so, of course, we start here
with our generic fatty acyl-CoA

00:49:48.080 --> 00:49:54.920
in the matrix of the
mitochondria of some arbitrary

00:49:54.920 --> 00:49:57.470
chain length.

00:49:57.470 --> 00:50:00.890
And so the first thing
that we're going to do

00:50:00.890 --> 00:50:04.730
is oxidize this
carbon-carbon bond--

00:50:04.730 --> 00:50:08.810
that is, introduce
a double bond here.

00:50:08.810 --> 00:50:10.460
That's an oxidation reaction.

00:50:10.460 --> 00:50:12.920
It's exactly the
same reaction that we

00:50:12.920 --> 00:50:18.560
saw convert succinate to
fumerate in the TCA cycle.

00:50:18.560 --> 00:50:26.100
That reaction used FAD
as an electron acceptor.

00:50:26.100 --> 00:50:29.570
So we oxidize that
carbon-carbon bond, FAD

00:50:29.570 --> 00:50:32.310
gets reduced to FADH2.

00:50:38.150 --> 00:51:06.970
This is carried out by an enzyme
called acyl-CoA dehydrogenase

00:51:06.970 --> 00:51:10.270
and generates that intermediate.

00:51:10.270 --> 00:51:13.030
Again, now just like
we did in the TCA cycle

00:51:13.030 --> 00:51:15.730
when we converted
fumerate into malate,

00:51:15.730 --> 00:51:20.500
we added water across
this double bond.

00:51:20.500 --> 00:51:22.930
Do exactly the same thing here.

00:51:39.570 --> 00:51:42.030
That generates
this intermediate.

00:51:42.030 --> 00:51:48.210
Now we can oxidize this
carbon here, this alcohol--

00:51:48.210 --> 00:51:51.210
oxidize it to the ketone.

00:51:51.210 --> 00:51:54.240
Of course, you know
how to do this.

00:51:54.240 --> 00:51:57.630
We've now seen it
a million times.

00:51:57.630 --> 00:52:02.500
So that generates
this hydride ion,

00:52:02.500 --> 00:52:19.496
which can be transferred to
NAD+, reducing it to NADH.

00:52:34.170 --> 00:52:46.100
And now what happens next
is CoA basically breaks

00:52:46.100 --> 00:52:48.050
that carbon-carbon bond.

00:52:48.050 --> 00:52:49.260
And what are we left with?

00:52:49.260 --> 00:52:57.710
We're left with over here
release of a acetyl-CoA group,

00:52:57.710 --> 00:53:02.810
which can then go down and be
further oxidized in the TCA

00:53:02.810 --> 00:53:14.920
cycle as well as this
fatty acyl-CoA that

00:53:14.920 --> 00:53:22.090
is two carbons shorter than
the one we started with.

00:53:22.090 --> 00:53:27.370
That can then go back up,
repeat the cycle again

00:53:27.370 --> 00:53:31.150
until, if you start with
an even number of carbons,

00:53:31.150 --> 00:53:36.280
the last one leaves you with
two acetyl-CoA molecules.

00:53:36.280 --> 00:53:39.610
And so per two
carbon units that we

00:53:39.610 --> 00:53:44.740
run through this cycle of
fatty acid oxidation, what

00:53:44.740 --> 00:53:50.250
we get is we get an
acetyl-CoA that comes out,

00:53:50.250 --> 00:53:57.420
we get an FADH2,
and we get an NADH.

00:53:57.420 --> 00:54:00.720
Now, of course, if we start
with an unsaturated fatty acid,

00:54:00.720 --> 00:54:03.150
we don't have to introduce
a double bond into it,

00:54:03.150 --> 00:54:07.560
we don't get the FADH2,
we get less energy

00:54:07.560 --> 00:54:11.570
produced from that molecule.

00:54:11.570 --> 00:54:16.990
And so if this acetyl-CoA goes
on and enters the TCA cycle

00:54:16.990 --> 00:54:21.460
and we fully oxidize it to
CO2, we get three more NADH,

00:54:21.460 --> 00:54:26.900
we get another FADH2,
and we get a GTP.

00:54:26.900 --> 00:54:28.950
It's written up
there as a reminder.

00:54:28.950 --> 00:54:34.340
And so with a fully saturated
per two carbons out,

00:54:34.340 --> 00:54:40.460
we basically get four NADHs,
two FADH2s, and a GTP.

00:54:40.460 --> 00:54:44.330
And that's a fair amount
of energy, if you will,

00:54:44.330 --> 00:54:47.600
released from the oxidation
of this fatty acid

00:54:47.600 --> 00:54:50.962
all the way to CO2.

00:54:50.962 --> 00:54:52.920
We'll come back to that
accounting in a second.

00:54:52.920 --> 00:54:54.510
But first I want to
say, what happens

00:54:54.510 --> 00:54:57.940
if you happen to start with
an odd number of carbons.

00:54:57.940 --> 00:55:00.180
So I mentioned that most
biological fatty acids

00:55:00.180 --> 00:55:01.860
have even numbers of carbons.

00:55:01.860 --> 00:55:08.280
But there are odd chain
carbon lengths of fatty acids.

00:55:08.280 --> 00:55:09.480
Some bacteria make these.

00:55:09.480 --> 00:55:11.130
Sometimes it just happens.

00:55:11.130 --> 00:55:13.140
Obviously, if you
do that, you'll

00:55:13.140 --> 00:55:17.790
end up at the end with
this molecule, which

00:55:17.790 --> 00:55:22.900
is a 3-carbon acetyl-CoA
called propionyl-CoA.

00:55:27.260 --> 00:55:30.410
And so cells need
a way to deal with

00:55:30.410 --> 00:55:33.800
this 3-carbon propionyl-CoA.

00:55:33.800 --> 00:55:37.550
Well, the way they deal with
it is they carboxylic it.

00:55:37.550 --> 00:55:40.340
So if we're going to
add a CO2 to a molecule,

00:55:40.340 --> 00:55:41.460
how do we do that?

00:55:41.460 --> 00:55:42.680
Well, we need a co-factor.

00:55:42.680 --> 00:55:47.720
Remember, we did this with the
pyruvate carboxylase reaction.

00:55:47.720 --> 00:55:49.940
This was the reaction of biotin.

00:55:49.940 --> 00:55:52.970
So we started with bicarbonate.

00:55:52.970 --> 00:55:56.300
We phosphorylated
the bicarbonate.

00:56:03.430 --> 00:56:07.390
And then that
phosphorylated bicarbonate,

00:56:07.390 --> 00:56:11.620
there was biotin in the
active site of the enzyme.

00:56:11.620 --> 00:56:13.550
That released the phosphate.

00:56:13.550 --> 00:56:20.160
I had enzyme biotin
with a CO2 on it.

00:56:20.160 --> 00:56:24.710
And so if we take this
propionyl-CoA here,

00:56:24.710 --> 00:56:32.590
which is drawn in the keto
form, and we redraw it

00:56:32.590 --> 00:56:51.250
in enol form of
the propionyl-CoA,

00:56:51.250 --> 00:56:55.000
we carry out similar
reaction that we saw before.

00:56:55.000 --> 00:56:57.640
And now we end up
with this molecule.

00:57:10.710 --> 00:57:14.720
So, effectively, adding
the CO2 to this carbon

00:57:14.720 --> 00:57:16.400
to the second carbon in.

00:57:16.400 --> 00:57:21.858
And that's this molecule, which
is called methyl-malonyl-CoA.

00:57:27.750 --> 00:57:32.040
I'm going to redraw
methyl-malonyl-CoA just

00:57:32.040 --> 00:57:35.490
to show you how
cells deal with this.

00:58:08.610 --> 00:58:11.310
So this is methyl-malonyl-CoA.

00:58:11.310 --> 00:58:13.260
I just re-drew it in
a way that there's

00:58:13.260 --> 00:58:16.020
some colors on the
different molecules.

00:58:16.020 --> 00:58:17.850
What I'm going to
do is I'm basically

00:58:17.850 --> 00:58:21.810
going to take this
group and this group

00:58:21.810 --> 00:58:26.280
and swap their positions.

00:58:26.280 --> 00:58:52.710
And if I do that, I will
end up with this molecule,

00:58:52.710 --> 00:58:59.270
which hopefully you recognize
as succinyl-CoA from the TCA

00:58:59.270 --> 00:59:00.350
cycle.

00:59:00.350 --> 00:59:03.680
Now, the mechanism for
how that swap happens,

00:59:03.680 --> 00:59:05.790
I don't have time to go into.

00:59:05.790 --> 00:59:10.190
But this complex
intermolecular rearrangement

00:59:10.190 --> 00:59:11.930
requires a cofactor.

00:59:11.930 --> 00:59:15.800
That cofactor comes
from vitamin B12.

00:59:15.800 --> 00:59:18.123
And so here's a
picture of vitamin B12.

00:59:18.123 --> 00:59:19.790
You can see by looking
at it why I don't

00:59:19.790 --> 00:59:21.980
want to draw that out for you.

00:59:21.980 --> 00:59:24.890
It's a cobalt-containing
cofactor-- sometimes referred

00:59:24.890 --> 00:59:27.080
to as cobalamin.

00:59:27.080 --> 00:59:28.790
If you're interested,
you can look up

00:59:28.790 --> 00:59:34.490
the chemistry for how
vitamin B12 helps catalyze

00:59:34.490 --> 00:59:36.800
this intermolecular
rearrangement

00:59:36.800 --> 00:59:40.060
to go from methyl-malonyl-CoA
to succinyl-CoA.

00:59:40.060 --> 00:59:42.560
But the important take home is
that if you have an odd chain

00:59:42.560 --> 00:59:45.380
fatty acid, use a
biotin-containing enzyme

00:59:45.380 --> 00:59:50.150
to carboxylate propionyl-CoA
to methyl-malonyl-CoA, and then

00:59:50.150 --> 00:59:53.090
B12 to rearrange that
methyl-malonyl-CoA

00:59:53.090 --> 00:59:54.500
to succinyl-CoA.

00:59:54.500 --> 01:00:00.860
And now this can enter the TCA
cycle and be oxidized as well.

01:00:00.860 --> 01:00:03.380
So now you have
the details of how

01:00:03.380 --> 01:00:12.720
you can start with a fatty
acid and oxidize it to CO2.

01:00:12.720 --> 01:00:15.750
Now, I think it's
useful if we compare

01:00:15.750 --> 01:00:19.950
the output of what we can get
from glucose oxidation to CO2--

01:00:19.950 --> 01:00:22.320
carbohydrate oxidation to CO2--

01:00:22.320 --> 01:00:25.650
to what we can get if we
start with a fatty acid

01:00:25.650 --> 01:00:28.710
and oxidize it to
CO2 and sort of

01:00:28.710 --> 01:00:31.770
illustrate that there
are more calories in fat

01:00:31.770 --> 01:00:34.110
than there are in sugar.

01:00:34.110 --> 01:00:37.590
And so for this
comparison, we'll

01:00:37.590 --> 01:00:44.370
compare glucose, which, of
course, has six carbons in it

01:00:44.370 --> 01:00:49.410
to a 6:0 fatty acid--

01:00:49.410 --> 01:00:51.030
also six carbons.

01:00:51.030 --> 01:00:53.970
And what do we get if we
take this less reduced

01:00:53.970 --> 01:00:59.655
versus more reduced molecule
and fully oxidize it to CO2?

01:01:03.470 --> 01:01:07.730
Well, if we start with glucose--

01:01:07.730 --> 01:01:11.500
so if we take that glucose
and we run glycolysis--

01:01:11.500 --> 01:01:13.450
and so take that
glucose and turn it

01:01:13.450 --> 01:01:17.650
into two pyruvate
molecules, of course

01:01:17.650 --> 01:01:25.110
we get from that two
ATPs and two NADHs.

01:01:25.110 --> 01:01:30.670
And then if we take those two
pyruvate molecules and turn

01:01:30.670 --> 01:01:37.450
them into two acetyl-CoAs
plus two CO2s--

01:01:37.450 --> 01:01:40.330
that's the pyruvate
dehydrogenase reaction--

01:01:40.330 --> 01:01:43.870
we get two more NADHs.

01:01:43.870 --> 01:01:47.890
And then if we take
those two acetyl-CoAs

01:01:47.890 --> 01:01:52.150
and turn them into
four CO2s, that's

01:01:52.150 --> 01:01:54.490
the TSA cycle,
what do we get out?

01:01:54.490 --> 01:01:58.700
We get two GTP molecules.

01:01:58.700 --> 01:02:08.540
We get two FADH2 molecules from
the succinate dehydrogenase

01:02:08.540 --> 01:02:09.260
step.

01:02:09.260 --> 01:02:15.230
And we get 2 times 3
equals 6 more NADHs.

01:02:15.230 --> 01:02:22.550
And so our total yield is 4
ATP equivalents-- remember,

01:02:22.550 --> 01:02:25.490
the GTPs can be
interconverted with ATP--

01:02:25.490 --> 01:02:40.000
two FADH2s, and 6,
7, 8, 9, 10 NADHs.

01:02:40.000 --> 01:02:44.650
What if we start with
our 6:0 zero fatty acid?

01:02:44.650 --> 01:02:50.710
Well, to metabolize it, first
we have to take that fatty acid

01:02:50.710 --> 01:02:54.430
and we have to make
our fatty acyl-CoA.

01:02:54.430 --> 01:02:59.960
That's going to cost us two ATP.

01:02:59.960 --> 01:03:01.370
Why two ATP?

01:03:01.370 --> 01:03:04.940
Because remember when we
charge that fatty acetyl-CoA,

01:03:04.940 --> 01:03:09.530
which is now erased,
I think-- yes, it is--

01:03:09.530 --> 01:03:11.570
we converted an ATP to an AMP.

01:03:11.570 --> 01:03:14.330
And so that's two
ATP equivalents

01:03:14.330 --> 01:03:19.850
to charge that fatty
acid to a fatty acyl-CoA.

01:03:19.850 --> 01:03:23.070
Next, we take that
fatty acyl-CoA

01:03:23.070 --> 01:03:29.080
and we turn it into three
acetyl-CoA molecules

01:03:29.080 --> 01:03:32.620
via fatty acid oxidation cycle.

01:03:32.620 --> 01:03:39.250
That's two trips around to
generate the three acetyl-CoAs.

01:03:39.250 --> 01:03:44.440
So that will give us two
FADH2s and two NADHs.

01:03:47.610 --> 01:03:51.450
And then once we have
those three acetyl-CoA,

01:03:51.450 --> 01:03:56.390
we can turn them into six
CO2s in the TCA cycle.

01:03:56.390 --> 01:04:02.700
So that's three
GTPs, three FADH2s.

01:04:02.700 --> 01:04:12.120
And 3 times 3 is 9 NADHs for
a total yield of 3 minus 2

01:04:12.120 --> 01:04:30.010
is 1 ATP equivalent,
5 FADHs, and 11 NADHs.

01:04:34.220 --> 01:04:38.430
Now, I went through
this exercise

01:04:38.430 --> 01:04:42.930
because it's not
immediately apparent

01:04:42.930 --> 01:04:46.020
that the yield of
fatty acid oxidation

01:04:46.020 --> 01:04:49.320
gives you more energy
from full oxidation

01:04:49.320 --> 01:04:53.670
than oxidizing the equivalent
carbohydrate, at least

01:04:53.670 --> 01:04:56.040
in terms of ATP.

01:04:56.040 --> 01:05:00.450
You get four ATPs directly
from full oxidation of glucose,

01:05:00.450 --> 01:05:04.410
whereas you only get one
ATP equivalent directly

01:05:04.410 --> 01:05:11.870
from the complete oxidation of
this 6-carbon fatty acyl-CoA.

01:05:11.870 --> 01:05:15.530
Now, I say this because most
of the energy, if you will,

01:05:15.530 --> 01:05:19.100
that's released from
oxidation of fat and sugar

01:05:19.100 --> 01:05:22.010
isn't actually
directly producing ATP.

01:05:22.010 --> 01:05:31.640
It's actually being used to
charge up this NADH, and NAD+,

01:05:31.640 --> 01:05:43.190
or FADH2/FAD ratios in the cell,
which we will see is also a lot

01:05:43.190 --> 01:05:45.830
of energy, because those
electrons can be transferred

01:05:45.830 --> 01:05:50.390
to oxygen and be used to do
other work down the road.

01:05:50.390 --> 01:05:55.670
Now, your book will tell
you that each of these NADHs

01:05:55.670 --> 01:06:00.560
or FADH2s are worth on the
order of one to three ATP.

01:06:00.560 --> 01:06:03.320
And I guess this kind
of fits intuitively what

01:06:03.320 --> 01:06:06.050
you might guess based on the
thermodynamics of the GAPDH

01:06:06.050 --> 01:06:06.630
reaction.

01:06:06.630 --> 01:06:08.450
So if you go back
to that, remember

01:06:08.450 --> 01:06:14.390
our oxidative phosphorylation
we described at GAPDH

01:06:14.390 --> 01:06:18.770
roughly generated an ATP.

01:06:18.770 --> 01:06:26.420
And so even if we say one ATP
equals an FADH2 or an NADH,

01:06:26.420 --> 01:06:30.380
which, of course, there's not
a direct relationship to that,

01:06:30.380 --> 01:06:32.360
you can still,
even with that, say

01:06:32.360 --> 01:06:35.930
that our fatty acid oxidation--
if we add up all these numbers,

01:06:35.930 --> 01:06:41.760
we would get 17, whereas if
we add up all these numbers,

01:06:41.760 --> 01:06:44.190
we get 16.

01:06:44.190 --> 01:06:47.900
So I guess that says
that there's more

01:06:47.900 --> 01:06:52.520
coming from fatty acid oxidation
than from complete glucose

01:06:52.520 --> 01:06:53.840
oxidation.

01:06:53.840 --> 01:06:56.630
But you probably also learned
in high school or somewhere else

01:06:56.630 --> 01:07:01.220
that NADH gives you
more ATP than FADH2.

01:07:01.220 --> 01:07:02.180
That's true.

01:07:02.180 --> 01:07:05.640
Our goal is to understand
why that's the case.

01:07:05.640 --> 01:07:10.190
And so those numbers
will only get better

01:07:10.190 --> 01:07:15.110
for fatty acid oxidation
in terms of ATP equivalents

01:07:15.110 --> 01:07:20.550
when we can describe how
to do those conversions.

01:07:20.550 --> 01:07:25.970
However, to really appreciate
how these electron carriers

01:07:25.970 --> 01:07:30.140
equal energy and equal
biological energy,

01:07:30.140 --> 01:07:32.900
we really need to
go back and revisit

01:07:32.900 --> 01:07:38.270
some concepts in bioenergetics
and thermodynamics

01:07:38.270 --> 01:07:42.350
to really understand what
biological energy is.

01:07:42.350 --> 01:07:45.530
And that will also
help us understand

01:07:45.530 --> 01:07:48.860
mitochondrial oxidative
phosphorylation, which

01:07:48.860 --> 01:07:52.520
is really the process that
allows us to interconvert

01:07:52.520 --> 01:07:57.470
these electron carriers
and their ability

01:07:57.470 --> 01:08:05.090
to transfer electrons to
oxygen as a way to generate

01:08:05.090 --> 01:08:06.990
favorably synthesized ATP.

01:08:17.950 --> 01:08:24.020
So hopefully, you will remember
from our previous lectures

01:08:24.020 --> 01:08:29.270
that for any reaction, any
pathway, any process to occur,

01:08:29.270 --> 01:08:31.729
it has to be thermodynamically
favorable-- that is,

01:08:31.729 --> 01:08:34.069
delta G has to be less than 0.

01:08:34.069 --> 01:08:37.790
And remember, ATP
to ADP was useful

01:08:37.790 --> 01:08:40.350
because that reaction
is very favorable.

01:08:40.350 --> 01:08:43.609
And so we could couple ATP to
ADP conversion to otherwise

01:08:43.609 --> 01:08:45.930
unfavorable reactions.

01:08:45.930 --> 01:08:50.370
And that is what allowed
us to have ATP be useful.

01:08:50.370 --> 01:08:55.319
And it was useful because delta
G equals delta G naught prime

01:08:55.319 --> 01:09:00.510
plus RT times a
log of the products

01:09:00.510 --> 01:09:05.529
of the reaction over the
reactants of the reaction.

01:09:05.529 --> 01:09:11.580
And so if ADP is a product
in ATP is a reactant,

01:09:11.580 --> 01:09:14.250
it was actually
that ATP/ADP ratio

01:09:14.250 --> 01:09:16.840
that was providing the
energy, if you will,

01:09:16.840 --> 01:09:19.530
to drive the reaction.

01:09:22.500 --> 01:09:27.689
This was also, if you
recall, why we described

01:09:27.689 --> 01:09:32.880
that oxidation of reduced
carbon because it was favorable,

01:09:32.880 --> 01:09:35.340
was able to be coupled
to reactions that

01:09:35.340 --> 01:09:39.870
keep this ATP/ADP ratio high, so
that that high ratio could then

01:09:39.870 --> 01:09:44.100
support otherwise
unfavorable reactions.

01:09:44.100 --> 01:09:46.170
But now, you
hopefully appreciate

01:09:46.170 --> 01:09:52.830
that in reality, most of the
energy from carbon oxidation

01:09:52.830 --> 01:09:55.320
is not directly captured as ATP.

01:09:55.320 --> 01:09:59.400
It's being used to charge
up these other ratios--

01:09:59.400 --> 01:10:03.180
NAD/NADH, FADH2/FAD.

01:10:03.180 --> 01:10:07.200
And the energetics of doing that
follow exactly the same rules

01:10:07.200 --> 01:10:11.310
as ATP or really
any other reaction.

01:10:11.310 --> 01:10:13.680
And effectively,
it's the transfer

01:10:13.680 --> 01:10:17.520
of electrons that is
favorable or not that

01:10:17.520 --> 01:10:24.360
really is going on
here, just like we

01:10:24.360 --> 01:10:28.650
discussed for ATP to ADP.

01:10:28.650 --> 01:10:32.340
And so we can couple other
reactions to those ratios

01:10:32.340 --> 01:10:37.380
as a way to make other
reactions possible.

01:10:37.380 --> 01:10:40.290
Now, ultimately it turns
out that these things,

01:10:40.290 --> 01:10:44.640
these redox ratios, are more
useful than ATP because these

01:10:44.640 --> 01:10:48.030
electron transfers-- favorable
electron transfers-- remember,

01:10:48.030 --> 01:10:51.780
biological energy is all about
oxidation and reduction--

01:10:51.780 --> 01:10:53.370
can be used to drive ATP.

01:10:53.370 --> 01:10:57.300
We'll see that when we described
how OXPHOS in the mitochondria

01:10:57.300 --> 01:10:58.860
really works.

01:10:58.860 --> 01:11:01.080
But it can be used for
other things as well.

01:11:01.080 --> 01:11:03.030
We'll see we can
use it to make heat.

01:11:03.030 --> 01:11:06.270
We can do it other work,
like move ions, et cetera.

01:11:06.270 --> 01:11:09.750
And so-- we can even
make glucose, right?

01:11:09.750 --> 01:11:10.770
gluconeogenesis.

01:11:10.770 --> 01:11:13.200
We needed a source of NADH.

01:11:13.200 --> 01:11:16.628
And so ultimately, all
biological energy, of course,

01:11:16.628 --> 01:11:17.670
has to come from the sun.

01:11:17.670 --> 01:11:22.020
And photosynthesis also is
about capturing solar energy

01:11:22.020 --> 01:11:26.190
as these oxidation
and reduction pairs.

01:11:26.190 --> 01:11:32.560
And so if we appreciate
this, what we realize

01:11:32.560 --> 01:11:34.855
is that it's really these
transfers of electrons.

01:11:34.855 --> 01:11:37.730
Remember, there's no free
electrons in biology.

01:11:37.730 --> 01:11:41.230
And so it's really coupling
oxidation and reduction

01:11:41.230 --> 01:11:43.540
reactions that
are favorable that

01:11:43.540 --> 01:11:48.840
ends up being how
bioenergetics largely works.

01:11:48.840 --> 01:11:51.010
Now, I like to be
explicit about this

01:11:51.010 --> 01:11:53.950
because sometimes
people get confused

01:11:53.950 --> 01:11:57.940
by oxidation and reduction
reactions and focus on charge.

01:11:57.940 --> 01:12:00.850
And I just want to point
out oxidation and reduction

01:12:00.850 --> 01:12:05.260
reactions are really
moving electrons.

01:12:05.260 --> 01:12:12.410
And this is
irrelevant of charge.

01:12:12.410 --> 01:12:14.990
So I add an electron to
an uncharged molecule,

01:12:14.990 --> 01:12:16.820
I get a negatively
charged molecule.

01:12:16.820 --> 01:12:18.710
Add it to a positively
charged molecule,

01:12:18.710 --> 01:12:20.150
get a neutral molecule.

01:12:20.150 --> 01:12:22.035
Add it to a more positively
charged molecule,

01:12:22.035 --> 01:12:23.660
now have a positively
charged molecule.

01:12:23.660 --> 01:12:25.220
It's adding these electrons.

01:12:25.220 --> 01:12:28.700
Each of these are
reduction reactions.

01:12:28.700 --> 01:12:32.700
In that direction, they
would be oxidation reactions.

01:12:32.700 --> 01:12:41.381
And so NAD+ plus 2
electrons going to NADH,

01:12:41.381 --> 01:12:48.620
FAD plus 2 electrons
going to FADH2--

01:12:48.620 --> 01:12:50.870
all reductions in
this direction, all

01:12:50.870 --> 01:12:55.020
oxidations in that direction.

01:12:55.020 --> 01:12:57.050
Now, because there's
not free electrons,

01:12:57.050 --> 01:12:59.960
these reactions have
to happen in pairs.

01:12:59.960 --> 01:13:02.270
And so if we consider
a pair, here's

01:13:02.270 --> 01:13:06.864
lactate interconversion
with pyruvate.

01:13:09.590 --> 01:13:15.110
So alcohol and lactate to
the ketone and pyruvate--

01:13:15.110 --> 01:13:17.060
this direction is an oxidation.

01:13:19.580 --> 01:13:23.690
That means the electrons
have to go somewhere--

01:13:23.690 --> 01:13:27.320
NAD+ to NADH.

01:13:27.320 --> 01:13:28.340
This is a reduction.

01:13:28.340 --> 01:13:32.240
If we go from pyruvate to
lactate, that's a reduction.

01:13:32.240 --> 01:13:37.370
We can reoxidize
NADH back to NAD+.

01:13:37.370 --> 01:13:40.350
Of course, you'll remember
from glycolysis fermentation,

01:13:40.350 --> 01:13:45.290
this inner conversion
is catalyzed by LDH.

01:13:45.290 --> 01:13:48.480
And effectively, if you're going
to use lactate for energy--

01:13:48.480 --> 01:13:51.700
so we oxidize the
lactate, generate NADH.

01:13:51.700 --> 01:13:53.960
If we're going to use
it for fermentation,

01:13:53.960 --> 01:14:00.930
we produce lactate, reoxidize
the NADH back to NAD+.

01:14:00.930 --> 01:14:05.070
How does LDH know which
direction to go in?

01:14:05.070 --> 01:14:07.650
How does any
reaction, any pathway

01:14:07.650 --> 01:14:09.900
know which direction to go in?

01:14:09.900 --> 01:14:11.090
Its delta G.

01:14:11.090 --> 01:14:14.400
Delta G-- well, it's delta
G naught prime plus RT times

01:14:14.400 --> 01:14:18.340
the log of, in this case, the
pyruvate lactate ratio times

01:14:18.340 --> 01:14:22.200
the NADH/NAD+ ratio.

01:14:22.200 --> 01:14:30.050
And so how oxidized or reduced
NAD+ to NADH is will determine

01:14:30.050 --> 01:14:35.990
how oxidized and reduced the
pyruvate lactate ratio is.

01:14:35.990 --> 01:14:39.170
In other words, this must
be true for absolutely

01:14:39.170 --> 01:14:41.840
any redox pair.

01:14:41.840 --> 01:14:45.380
And in general, remember
carbon oxidation is favorable.

01:14:45.380 --> 01:14:48.470
And that's because
oxidizing carbon

01:14:48.470 --> 01:14:51.290
to give those electrons
to something downstream,

01:14:51.290 --> 01:14:54.320
ultimately oxygen, is favorable.

01:14:54.320 --> 01:15:00.390
That's really what's driving
each of these pathways.

01:15:00.390 --> 01:15:03.240
Now, how favorable
any of this is,

01:15:03.240 --> 01:15:05.310
of course, can be quantified?

01:15:05.310 --> 01:15:07.780
And if we want to know
this for this redox pair

01:15:07.780 --> 01:15:10.410
or any redox pair,
of course, this

01:15:10.410 --> 01:15:13.470
is related to some
equilibrium constant.

01:15:13.470 --> 01:15:16.890
And we've already discussed
that we can have this term delta

01:15:16.890 --> 01:15:21.750
G naught prime that is relevant
to the equilibrium constant.

01:15:21.750 --> 01:15:24.330
But it's still, because delta
G determines what happens,

01:15:24.330 --> 01:15:26.310
it's still that
equilibrium constant

01:15:26.310 --> 01:15:29.760
plus the ratios of the reactants
and products that will really

01:15:29.760 --> 01:15:32.380
determine if the
reaction happens.

01:15:32.380 --> 01:15:36.510
However, it turns out it's
useful to think about--

01:15:36.510 --> 01:15:39.720
when electrons can go
to donated or accepted

01:15:39.720 --> 01:15:42.450
in lots of different
reactions, it's

01:15:42.450 --> 01:15:44.520
useful to come up
with a term that

01:15:44.520 --> 01:15:47.700
helps us know what
is the propensity

01:15:47.700 --> 01:15:51.090
of an individual pair
to accept or donate

01:15:51.090 --> 01:15:54.270
an electron in either direction.

01:15:54.270 --> 01:15:56.985
And we have a term for this.

01:15:56.985 --> 01:16:04.620
It's denoted E naught prime,
which is the standard reduction

01:16:04.620 --> 01:16:13.330
potential that
basically describes

01:16:13.330 --> 01:16:15.430
for a pair of molecules--

01:16:15.430 --> 01:16:18.610
NADH+, NADH, pyruvate,
and lactate--

01:16:18.610 --> 01:16:21.220
in an oxidation or
reduction reaction,

01:16:21.220 --> 01:16:24.790
how likely is it to
give up its electrons

01:16:24.790 --> 01:16:27.260
in one direction or the other.

01:16:27.260 --> 01:16:32.070
And so the units
of this is volts.

01:16:32.070 --> 01:16:34.860
And the standard
reduction potential

01:16:34.860 --> 01:16:37.690
can be calculated as follows.

01:16:37.690 --> 01:16:41.940
And of course, it's related
to the equilibrium constant

01:16:41.940 --> 01:16:44.950
of a reaction.

01:16:44.950 --> 01:16:48.060
And so the equilibrium
constant overreaction,

01:16:48.060 --> 01:16:51.150
delta G naught prime-- related
to the equilibrium constant--

01:16:51.150 --> 01:16:53.070
is this formula.

01:16:53.070 --> 01:16:55.530
N is the number of
electrons transferred,

01:16:55.530 --> 01:17:00.660
F is the Faraday constant,
and delta E naught prime

01:17:00.660 --> 01:17:03.450
is the change in
standard reduction

01:17:03.450 --> 01:17:10.230
potential from electron donation
from one pair to the next pair.

01:17:10.230 --> 01:17:14.190
So if we use our lactate
pyruvate example,

01:17:14.190 --> 01:17:25.610
we have lactate going to
pyruvate plus 2 electrons.

01:17:25.610 --> 01:17:28.040
So that's the electron donor.

01:17:28.040 --> 01:17:30.790
It's being oxidized.

01:17:30.790 --> 01:17:41.770
And then you have NAD+ plus
the electrons going to NADH.

01:17:41.770 --> 01:17:46.790
It's being reduced-- two
electrons, of course--

01:17:46.790 --> 01:17:48.790
it's being reduced.

01:17:48.790 --> 01:17:54.760
And so this has a standard
reduction potential.

01:17:54.760 --> 01:18:00.140
This half reaction has a
standard reduction potential.

01:18:00.140 --> 01:18:04.990
And so the difference between
these standard reduction

01:18:04.990 --> 01:18:06.130
potentials--

01:18:06.130 --> 01:18:10.080
that is, who receives
the electrons, delta E

01:18:10.080 --> 01:18:14.590
naught primed 2 minus
delta E naught prime 1

01:18:14.590 --> 01:18:19.870
gives us this change in standard
reduction potential, which

01:18:19.870 --> 01:18:23.320
I can plug into
this formula, which

01:18:23.320 --> 01:18:27.670
is related to the equilibrium
constant and tells me

01:18:27.670 --> 01:18:31.030
which direction of
electron transfer

01:18:31.030 --> 01:18:35.480
is going to be favored,
at least at equilibrium.

01:18:35.480 --> 01:18:42.400
And so if this number is
related to equilibrium,

01:18:42.400 --> 01:18:43.840
there's a negative here.

01:18:43.840 --> 01:18:49.600
And so if this term is
positive, delta G naught prime

01:18:49.600 --> 01:18:50.900
will be negative.

01:18:50.900 --> 01:18:52.690
And that means that
electron transfer

01:18:52.690 --> 01:18:54.880
will be favored at equilibrium.

01:18:54.880 --> 01:18:57.130
If this number is
negative, that means

01:18:57.130 --> 01:19:02.450
the reverse electron transfer
will be favored at equilibrium.

01:19:02.450 --> 01:19:08.510
And so it stands to reason
then that electron transfer

01:19:08.510 --> 01:19:21.910
from smaller standard reduction
potential to larger standard

01:19:21.910 --> 01:19:26.570
reduction potentials
will be favored.

01:19:26.570 --> 01:19:29.510
Hopefully that makes sense--

01:19:29.510 --> 01:19:30.820
so smaller to larger.

01:19:30.820 --> 01:19:35.340
Now, that could be
more negative to less

01:19:35.340 --> 01:19:40.500
negative, negative to positive,
positive to more positive.

01:19:40.500 --> 01:19:45.270
As long as that
delta is positive,

01:19:45.270 --> 01:19:49.170
electron transfer
will be favored.

01:19:49.170 --> 01:19:53.640
Now, of course, the
ratios still matter.

01:19:53.640 --> 01:19:55.980
But this standard
reduction potential

01:19:55.980 --> 01:19:58.860
is useful because
it can help us know

01:19:58.860 --> 01:20:04.590
which direction transfer wants
to occur between any redox

01:20:04.590 --> 01:20:07.790
pairs at equilibrium.

01:20:07.790 --> 01:20:12.380
And so recognizing
this, you must

01:20:12.380 --> 01:20:16.730
know that carbon oxidation
electron transfer in general

01:20:16.730 --> 01:20:23.870
is going to be favored
to NAD to make NADH.

01:20:23.870 --> 01:20:28.490
And in general, that
NADH electron transfer

01:20:28.490 --> 01:20:30.890
is going to be
favored to oxygen.

01:20:30.890 --> 01:20:34.460
And it's coupling those
favorable electron transfers

01:20:34.460 --> 01:20:37.730
that ultimately is
allowing the system

01:20:37.730 --> 01:20:44.180
to use oxidation and
reduction reactions to drive

01:20:44.180 --> 01:20:46.680
these various pathways.

01:20:46.680 --> 01:20:51.830
And that energy release
from these electron transfer

01:20:51.830 --> 01:20:56.180
reactions can be used to
make ATP and do other work,

01:20:56.180 --> 01:21:01.690
as we will talk about in great
detail in the next lecture.