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JOHN ESSIGMANN: Welcome to the metabolism portion
of Biological Chemistry 5.07.
My name is John Essigman and I teach
this course with JoAnne Stubbe.
I'm primarily a chalkboard teacher,
as you'll notice from my notes.
In order to make things as simple as possible,
I use a lot of abbreviations, and my abbreviations list
will be appended elsewhere.
Let's start by looking at a metabolic chart, figure
16-1 from the textbook.
Obviously it looks very complex.
Part of the challenge of both teaching and learning
biochemistry is finding a way to look
at this pig's breakfast of biochemical reactions
and find its underlying structure.
For the purpose of this course, the underlying structure
we're going to look for is the biochemical pathways
that let us function.
For example, a pathway could involve making ATP
or it could be putting an amino group onto an alpha-keto acid
in order to make an amino acid.
Although few people think of biochemistry as simple,
formatting the pig's breakfast into pathways
that have functional meaning helps us simplify them and make
them easier to remember.
The second simplifying point is that all biochemical pathways
are reversible.
The gray vertical bar in the middle of this figure
is the biochemical pathway of glycolysis
going from glucose to pyruvate.
There are 10 steps.
Some of these steps have a negative delta
G. That is, they are favorable in the direction drawn,
and some of them have a positive delta
G. That is, those steps are favorable
in the opposite direction.
But overall, when you sum them up,
all of the free energies of the glycolitic pathway,
you get a negative number, which means
that the pathway of glycolysis is overall thermodynamically
irreversible, and progresses from glucose to pyryvate.
It turns out that there's another pathway called
gluconeogenesis.
That pathway involves taking non carbohydrate precursors,
such as pyruvate--
that's just one example molecule--
and converting that precursor to glucose.
In other words, gluconeogenesis, in effect,
is the reverse of glycolysis.
As I said, the pathway going from glucose down to pyruvate
is exergonic.
So what about the pathway from pyruvate up to glucose?
In order to make the pathway go from pyruvate to glucose,
what nature did was invent several biochemical steps that
are highly exergonic.
That is, what we'll see is they're
going to require ATP or some other form of energy input
in order to make the entire pathway of gluconeogeneisis
exergonic, as is required of all pathways.
So we can indeed convert pyruvate to glucose,
but it will require energy input to make
the pathway of gluconeogenesis have a net negative delta
G. That is, be favorable.
The third thing that actually makes biochemistry tractable
is the fact that nature uses only a very limited repertoire
of chemical reactions.
JoAnne showed us that despite the complexity
of this overall metabolic chart, there
are only about nine or 10 discrete chemical reactions
that nature uses.
So, at any given step, for example, in glycolysis,
you really only have about nine or 10 options,
and of that nine or 10, only about one or two,
perhaps three, would be chemically reasonable.
If you know your organic chemistry and these nine or 10
reaction types, you should be able to navigate
the biochemical chart with comparative ease.
The fourth point I wanted to make
is perhaps one of the most important.
It's that all biochemical pathways are regulated.
Chaos would result, for example, if you
made glucose and at the same time
took that molecule of glucose and degraded it.
That's an example of what we call a futile cycle.
Sometimes futile cycles can be beneficial to a cell.
For example, that could be a way of generating heat,
but most of the time we want to avoid them.
Because we usually want to avoid futile cycles,
nature uses pathway regulation to avoid them.
To provide directionality to pathways, what nature does
is work thermodynamically irreversible steps
into the front and back end of the pathway.
Sometimes nature puts in an irreversible step
in the middle of a pathway if that pathway
has a branch point.
That happens with glycolysis, as we'll see.
Sometimes regulation is effected by putting
covalent functionalities, such as a phosphate,
onto an amino acid on a protein.
That modification could increase or decrease
the biochemical activity of that protein.
Often a phosphorylated protein is highly active,
turning on a pathway, and it is dephosphorylated
when the pathway needs to be turned off.
A second way to regulate a step in the pathway
is by allosteric regulation of the enzymes of the pathway.
In that case, a small molecule will interact with the enzyme
in order to increase or decrease its activity.
JoAnne taught us about allostery when she taught us
how hemoglobin is regulated.
To reiterate, nature uses these regulatable C enzymes
at key places and overall metabolic pathways
to enable us to be able to achieve
the function of the pathway without wasting
energy or resources.
The last introductory point I want to make
is that all biochemical pathways tend
to be compartmentalized, at least in mammalian cells,
although it's increasingly becoming obvious that even
in bacteria there is some form of compartmentalization.
That is, clustering of enzymes for a particular pathway
in a particular area of the cell.
For example, in a mammalian cell,
the mitochondrian is the site of fatty acid beta-oxidation,
or break down.
The tricarboxylic acid cycle and enzymes
of the pyruvate dehydrogenase complex are also mitochondrial.
The cytoplasm is the site where we do fatty acid biosynthesis,
most of gluconeogenesis, glycolysis,
and the pentose phosphate pathway.
Compartmentalisation helps keep the metabolic chart
tidy and organized.
With that in the way of an introduction,
let's turn to my lecture notes, which I present
in the format of storyboards.
In the first storyboard, panel A,
I give the definition of metabolism
as the linked set of biochemical reactions
by which we obtain and use free energy.
That is, delta G, for life.
We use that free energy for a lot of things,
but the use is really divide into three areas.
The first is to do mechanical work,
the second is to generate concentration gradients,
and the third is for biosynthesis.
In a few minutes, I'm going to be giving you
an example of all three.
Panel B. Biochemists divide metabolism
into two subcategories.
Catabolism and anabolism.
Briefly, catabolism consists of the energy yielding pathways,
and anabolism is basically biosynthesis.
We use the free energy that we generate through catabolism
in order to assemble complex molecules by way of anabolism.
Let's look at panel C. We're going
to start 5.07 with a discussion of catabolism.
That is the energy yielding pathways.
By way of definitions, a reduced molecule
is one that is abundantly supplied with electrons.
Examples are carbohydrates, fats, and proteins.
These are typically our foods.
The process of catabolism involves
finding a way to liberate the electrons from those reduced
substances and transfer those electrons to mobile electron
carriers, such as NAD-plus to form NADH,
or NADP-plus to form NADPH.
The process by which electrons are removed from a molecule
is called oxidation, and the oxidation products
are, for example, carbon dioxide that we breathe out,
or in some organisms, lactate, or other simple molecules
that are excreted.
Simple, that is, compared to the complex reduced molecules
that we consume as food.
NADH and FADH2, molecules that JoAnne taught us,
are what I'll refer to as mobile electron carriers.
They can usually move around inside the cell,
although sometimes they're embedded within enzymes.
That is usually the case with FADH2.
We consume an enormously large number of reduced substances
due to the complexities of our diets,
and catabolism involves taking the electrons out
of this enormously vast array of substrates
and transferring those electrons to a small number of reduced
electron carriers.
For example, NAD or flavins.
In the process of respiration, which we'll come to later,
the electrons are further transferred from the reduced
electron carriers all the way to molecular oxygen.
The reduction of molecular oxygen
is a highly exothermic reaction.
We're going to be able to use the energy that's
generated by oxygen reduction in order to make ATP,
and to do some other important biochemical activities.
Now I'm going to introduce a physiological scenario
and use it in order to introduce the pathway of glycolysis.
In class at this point, I usually
ask a student to stand up and sit down.
As you can imagine, being called on in class
creates more than a little bit of anxiety in the student.
Let's look at panel D. The signal to stand up and sit down
is processed by the brain, and an electrical signal then
goes by the nerves to the muscles enabling the student
to stand up.
The anxiety of being called on by the teacher in class results
in a nervous excitation of the adrenal gland,
specifically in the adrenal medulla, which releases
epinephrine.
Epinephrine is also known as adrenaline.
It goes to the muscles as well as other organs of the body,
as we'll see later in 5.07.
And the epinephrine will interact at cell membranes
by way of transmembrane receptors
in order to turn on pathways of catabolism,
in order to generate the ATP that's
needed to help the student deal with this stressful situation.
This is sometimes called the fight or flight response.
At this point in the class, if I really wanted to make my point
and have it transferred to every student,
I'd announce a pop quiz.
The announcement of a pop quiz would
cause kind of this cold feeling throughout your gut.
That's actually the feeling of adrenaline preparing your body
to deal with the stress situation, in that case,
of the quiz.
Let's look at panel E. As the scenario progresses,
let me introduce a few biochemical players.
Glycogen phosphorylase, glucose, glucose six phosphate,
and glucose one phosphate.
In panel F we see a muscle cell.
The epinephrine in the blood is only
going to reach a concentration of about 10
to the minus 10 molar.
That's a very, very low concentration.
The epinephrine is going to interact
at the beta and alpha adrenergic receptors in the muscle cell
membrane.
This interaction results in the activation
of a kinase, that is a molecule that
transfers a phosphate group.
And that kinase, which is called SPK, for synthase phosphorylase
kinase, phosphorylate serine 14 on glycogen phosphorylase.
Phosphorylation activates glycogen phosphorylase,
which will then begin to degrade glycogen--
the polymeric storage form of glucose in us, that is,
mammals--
to produce initially glucose one phosphate.
Glucose one phosphate will then go
through a number of transformations
and eventually be converted into other forms of glucose
and then other molecules that will generate energy.
In a nutshell, this stand up, sit down scenario results
in the generation of energy in a matter
of seconds which is one of the things
that we use metabolism for.
Another thing I said earlier was that you use metabolic energy
to generate concentration gradients.
And it turns out that generation of concentration gradients
is absolutely critical for muscle activity.
The sarcoplasmic reticulum in our muscle cells
must accumulate calcium and release it at precisely defined
moments in order to enable the muscle to be able to work.
That concentration grading of calcium has to be created,
and it's created with the energy that we get from metabolism.
Again, we'll see how calcium gradients help boot
up energy generation in the last lecture,
which deals with pathway regulation.