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JOHN ESSIGMANN: Welcome
to the metabolism portion

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of Biological Chemistry 5.07.

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My name is John
Essigman and I teach

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this course with JoAnne Stubbe.

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I'm primarily a
chalkboard teacher,

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as you'll notice from my notes.

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In order to make things
as simple as possible,

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I use a lot of abbreviations,
and my abbreviations list

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will be appended elsewhere.

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Let's start by looking at
a metabolic chart, figure

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16-1 from the textbook.

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Obviously it looks very complex.

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Part of the challenge of
both teaching and learning

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biochemistry is
finding a way to look

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at this pig's breakfast
of biochemical reactions

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and find its
underlying structure.

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For the purpose of this course,
the underlying structure

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we're going to look for is
the biochemical pathways

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that let us function.

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For example, a pathway
could involve making ATP

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or it could be putting an amino
group onto an alpha-keto acid

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in order to make an amino acid.

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Although few people think
of biochemistry as simple,

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formatting the pig's
breakfast into pathways

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that have functional meaning
helps us simplify them and make

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them easier to remember.

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00:01:23,620 --> 00:01:26,980
The second simplifying point is
that all biochemical pathways

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are reversible.

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00:01:28,580 --> 00:01:31,420
The gray vertical bar in
the middle of this figure

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is the biochemical
pathway of glycolysis

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going from glucose to pyruvate.

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00:01:36,560 --> 00:01:38,170
There are 10 steps.

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00:01:38,170 --> 00:01:40,030
Some of these steps
have a negative delta

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00:01:40,030 --> 00:01:43,360
G. That is, they are favorable
in the direction drawn,

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and some of them
have a positive delta

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G. That is, those
steps are favorable

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00:01:47,890 --> 00:01:49,900
in the opposite direction.

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00:01:49,900 --> 00:01:51,940
But overall, when
you sum them up,

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00:01:51,940 --> 00:01:54,790
all of the free energies
of the glycolitic pathway,

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you get a negative
number, which means

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that the pathway of glycolysis
is overall thermodynamically

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irreversible, and progresses
from glucose to pyryvate.

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00:02:04,191 --> 00:02:06,190
It turns out that there's
another pathway called

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gluconeogenesis.

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That pathway involves taking
non carbohydrate precursors,

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such as pyruvate--

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that's just one
example molecule--

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and converting that
precursor to glucose.

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In other words,
gluconeogenesis, in effect,

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is the reverse of glycolysis.

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As I said, the pathway going
from glucose down to pyruvate

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is exergonic.

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So what about the pathway
from pyruvate up to glucose?

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In order to make the pathway
go from pyruvate to glucose,

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what nature did was invent
several biochemical steps that

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are highly exergonic.

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That is, what we'll
see is they're

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going to require ATP or some
other form of energy input

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in order to make the entire
pathway of gluconeogeneisis

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exergonic, as is
required of all pathways.

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So we can indeed convert
pyruvate to glucose,

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but it will require
energy input to make

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the pathway of gluconeogenesis
have a net negative delta

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G. That is, be favorable.

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The third thing that actually
makes biochemistry tractable

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is the fact that nature uses
only a very limited repertoire

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of chemical reactions.

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JoAnne showed us that
despite the complexity

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of this overall
metabolic chart, there

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are only about nine or 10
discrete chemical reactions

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that nature uses.

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So, at any given step, for
example, in glycolysis,

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you really only have
about nine or 10 options,

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and of that nine or 10,
only about one or two,

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perhaps three, would be
chemically reasonable.

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If you know your organic
chemistry and these nine or 10

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reaction types, you
should be able to navigate

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the biochemical chart
with comparative ease.

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The fourth point
I wanted to make

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is perhaps one of
the most important.

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It's that all biochemical
pathways are regulated.

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Chaos would result,
for example, if you

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made glucose and
at the same time

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took that molecule of
glucose and degraded it.

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That's an example of what
we call a futile cycle.

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Sometimes futile cycles can
be beneficial to a cell.

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For example, that could be
a way of generating heat,

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00:04:05,440 --> 00:04:07,990
but most of the time
we want to avoid them.

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Because we usually want
to avoid futile cycles,

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nature uses pathway
regulation to avoid them.

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To provide directionality to
pathways, what nature does

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is work thermodynamically
irreversible steps

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into the front and back
end of the pathway.

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Sometimes nature puts
in an irreversible step

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in the middle of a
pathway if that pathway

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has a branch point.

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That happens with
glycolysis, as we'll see.

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Sometimes regulation
is effected by putting

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covalent functionalities,
such as a phosphate,

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onto an amino acid on a protein.

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00:04:40,640 --> 00:04:43,010
That modification could
increase or decrease

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the biochemical activity
of that protein.

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Often a phosphorylated
protein is highly active,

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turning on a pathway, and
it is dephosphorylated

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00:04:51,650 --> 00:04:54,230
when the pathway needs
to be turned off.

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00:04:54,230 --> 00:04:56,390
A second way to regulate
a step in the pathway

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is by allosteric regulation
of the enzymes of the pathway.

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00:05:00,020 --> 00:05:03,290
In that case, a small molecule
will interact with the enzyme

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00:05:03,290 --> 00:05:05,990
in order to increase or
decrease its activity.

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JoAnne taught us about
allostery when she taught us

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how hemoglobin is regulated.

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To reiterate, nature uses
these regulatable C enzymes

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at key places and overall
metabolic pathways

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to enable us to
be able to achieve

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the function of the
pathway without wasting

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energy or resources.

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00:05:24,550 --> 00:05:26,500
The last introductory
point I want to make

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is that all biochemical
pathways tend

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to be compartmentalized, at
least in mammalian cells,

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although it's increasingly
becoming obvious that even

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in bacteria there is some
form of compartmentalization.

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That is, clustering of enzymes
for a particular pathway

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in a particular
area of the cell.

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For example, in
a mammalian cell,

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the mitochondrian is the site
of fatty acid beta-oxidation,

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or break down.

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00:05:49,540 --> 00:05:52,390
The tricarboxylic
acid cycle and enzymes

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of the pyruvate dehydrogenase
complex are also mitochondrial.

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The cytoplasm is the site where
we do fatty acid biosynthesis,

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most of gluconeogenesis,
glycolysis,

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00:06:03,370 --> 00:06:05,470
and the pentose
phosphate pathway.

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Compartmentalisation helps
keep the metabolic chart

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00:06:08,860 --> 00:06:11,504
tidy and organized.

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With that in the way
of an introduction,

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let's turn to my lecture
notes, which I present

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in the format of storyboards.

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In the first
storyboard, panel A,

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I give the definition
of metabolism

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as the linked set of
biochemical reactions

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by which we obtain
and use free energy.

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That is, delta G, for life.

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We use that free energy
for a lot of things,

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but the use is really
divide into three areas.

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The first is to do
mechanical work,

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the second is to generate
concentration gradients,

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and the third is
for biosynthesis.

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In a few minutes, I'm
going to be giving you

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an example of all three.

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Panel B. Biochemists
divide metabolism

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into two subcategories.

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Catabolism and anabolism.

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Briefly, catabolism consists of
the energy yielding pathways,

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and anabolism is
basically biosynthesis.

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We use the free energy that
we generate through catabolism

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in order to assemble complex
molecules by way of anabolism.

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Let's look at panel
C. We're going

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to start 5.07 with a
discussion of catabolism.

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That is the energy
yielding pathways.

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By way of definitions,
a reduced molecule

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is one that is abundantly
supplied with electrons.

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Examples are carbohydrates,
fats, and proteins.

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These are typically our foods.

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The process of
catabolism involves

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finding a way to liberate the
electrons from those reduced

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substances and transfer those
electrons to mobile electron

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carriers, such as
NAD-plus to form NADH,

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or NADP-plus to form NADPH.

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The process by which electrons
are removed from a molecule

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is called oxidation, and
the oxidation products

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are, for example, carbon
dioxide that we breathe out,

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or in some organisms, lactate,
or other simple molecules

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that are excreted.

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00:07:58,230 --> 00:08:01,680
Simple, that is, compared to
the complex reduced molecules

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that we consume as food.

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NADH and FADH2, molecules
that JoAnne taught us,

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are what I'll refer to as
mobile electron carriers.

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They can usually move
around inside the cell,

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although sometimes they're
embedded within enzymes.

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That is usually the
case with FADH2.

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We consume an enormously large
number of reduced substances

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due to the complexities
of our diets,

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and catabolism involves
taking the electrons out

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of this enormously vast
array of substrates

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and transferring those electrons
to a small number of reduced

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electron carriers.

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00:08:35,850 --> 00:08:38,730
For example, NAD or flavins.

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In the process of respiration,
which we'll come to later,

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the electrons are further
transferred from the reduced

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electron carriers all the
way to molecular oxygen.

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The reduction of
molecular oxygen

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is a highly exothermic reaction.

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We're going to be able
to use the energy that's

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generated by oxygen reduction
in order to make ATP,

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and to do some other important
biochemical activities.

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Now I'm going to introduce
a physiological scenario

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00:09:03,990 --> 00:09:07,680
and use it in order to introduce
the pathway of glycolysis.

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In class at this
point, I usually

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ask a student to
stand up and sit down.

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00:09:13,010 --> 00:09:15,260
As you can imagine,
being called on in class

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creates more than a little
bit of anxiety in the student.

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00:09:18,890 --> 00:09:22,250
Let's look at panel D. The
signal to stand up and sit down

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is processed by the brain,
and an electrical signal then

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00:09:25,400 --> 00:09:28,280
goes by the nerves to the
muscles enabling the student

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to stand up.

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00:09:29,810 --> 00:09:33,050
The anxiety of being called on
by the teacher in class results

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00:09:33,050 --> 00:09:35,930
in a nervous excitation
of the adrenal gland,

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specifically in the adrenal
medulla, which releases

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00:09:38,990 --> 00:09:40,400
epinephrine.

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00:09:40,400 --> 00:09:42,440
Epinephrine is also
known as adrenaline.

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00:09:42,440 --> 00:09:45,290
It goes to the muscles as well
as other organs of the body,

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00:09:45,290 --> 00:09:47,630
as we'll see later in 5.07.

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00:09:47,630 --> 00:09:50,630
And the epinephrine will
interact at cell membranes

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00:09:50,630 --> 00:09:52,670
by way of
transmembrane receptors

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00:09:52,670 --> 00:09:55,730
in order to turn on
pathways of catabolism,

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00:09:55,730 --> 00:09:58,070
in order to generate
the ATP that's

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needed to help the student deal
with this stressful situation.

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00:10:01,910 --> 00:10:05,840
This is sometimes called the
fight or flight response.

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00:10:05,840 --> 00:10:09,250
At this point in the class, if
I really wanted to make my point

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00:10:09,250 --> 00:10:11,690
and have it transferred
to every student,

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00:10:11,690 --> 00:10:14,540
I'd announce a pop quiz.

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00:10:14,540 --> 00:10:16,520
The announcement
of a pop quiz would

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00:10:16,520 --> 00:10:20,090
cause kind of this cold
feeling throughout your gut.

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00:10:20,090 --> 00:10:23,750
That's actually the feeling of
adrenaline preparing your body

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00:10:23,750 --> 00:10:26,120
to deal with the stress
situation, in that case,

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00:10:26,120 --> 00:10:27,600
of the quiz.

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00:10:27,600 --> 00:10:30,560
Let's look at panel E. As
the scenario progresses,

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00:10:30,560 --> 00:10:33,200
let me introduce a few
biochemical players.

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00:10:33,200 --> 00:10:37,040
Glycogen phosphorylase,
glucose, glucose six phosphate,

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00:10:37,040 --> 00:10:38,685
and glucose one phosphate.

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00:10:38,685 --> 00:10:42,110
In panel F we see a muscle cell.

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00:10:42,110 --> 00:10:44,480
The epinephrine in
the blood is only

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00:10:44,480 --> 00:10:46,910
going to reach a
concentration of about 10

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00:10:46,910 --> 00:10:48,650
to the minus 10 molar.

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00:10:48,650 --> 00:10:52,290
That's a very, very
low concentration.

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00:10:52,290 --> 00:10:54,560
The epinephrine is
going to interact

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00:10:54,560 --> 00:10:58,440
at the beta and alpha adrenergic
receptors in the muscle cell

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00:10:58,440 --> 00:10:59,590
membrane.

245
00:10:59,590 --> 00:11:01,560
This interaction results
in the activation

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00:11:01,560 --> 00:11:03,840
of a kinase, that
is a molecule that

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00:11:03,840 --> 00:11:06,060
transfers a phosphate group.

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00:11:06,060 --> 00:11:10,560
And that kinase, which is called
SPK, for synthase phosphorylase

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00:11:10,560 --> 00:11:15,430
kinase, phosphorylate serine
14 on glycogen phosphorylase.

250
00:11:15,430 --> 00:11:18,780
Phosphorylation activates
glycogen phosphorylase,

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which will then begin
to degrade glycogen--

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the polymeric storage form
of glucose in us, that is,

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mammals--

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to produce initially
glucose one phosphate.

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Glucose one phosphate
will then go

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00:11:29,730 --> 00:11:31,770
through a number
of transformations

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and eventually be converted
into other forms of glucose

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and then other molecules
that will generate energy.

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In a nutshell, this stand
up, sit down scenario results

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00:11:42,270 --> 00:11:44,070
in the generation of
energy in a matter

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00:11:44,070 --> 00:11:46,080
of seconds which is
one of the things

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00:11:46,080 --> 00:11:48,750
that we use metabolism for.

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Another thing I said earlier was
that you use metabolic energy

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to generate
concentration gradients.

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00:11:55,410 --> 00:11:58,320
And it turns out that generation
of concentration gradients

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is absolutely critical
for muscle activity.

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The sarcoplasmic reticulum
in our muscle cells

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00:12:04,110 --> 00:12:07,830
must accumulate calcium and
release it at precisely defined

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00:12:07,830 --> 00:12:11,640
moments in order to enable
the muscle to be able to work.

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00:12:11,640 --> 00:12:14,730
That concentration grading
of calcium has to be created,

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and it's created with the energy
that we get from metabolism.

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Again, we'll see how
calcium gradients help boot

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up energy generation
in the last lecture,

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which deals with
pathway regulation.